Preparations and compositions containing polymer combination preparations

Abstract

The present disclosure provides techniques related to certain polymer combination preparations and their uses. In many embodiments, such polymer combination preparations are temperature-responsive. In some embodiments, such polymer combination preparations may be useful as immunomodulatory biomaterials, for example, to induce innate immunity or to resolve inflammation (e.g., immunosuppressive inflammation). In some embodiments, such polymer combination preparations may be useful for formulating compositions containing active agent(s).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Application No. 63 / 053,488, filed on 17 July 2020, and U.S. Provisional Application No. 63 / 108,861, filed on 2 November 2020 (the contents of each of these are incorporated herein by reference in their entirety). [Background technology]

[0002] Surgery is often the first-line treatment for solid tumors and is generally used in combination with systemic chemotherapy. However, the immunosuppression induced by surgery is linked to the development of postoperative infectious complications and tumor metastasis due to changes in various metabolic and endocrine responses, which ultimately lead to death in many patients (Hiller, J. Get al. Nature Reviews Clinical Oncology, 2018, 15, 205-218).

[0003] Systemic administration of drugs, nutrients, or other substances into the circulatory system affects the entire body. Systemic administration routes include enteral administration (e.g., oral administration resulting in drug absorption through the gastrointestinal tract) and parenteral administration (e.g., intravenous, intramuscular, and subcutaneous injection). Administration of immunotherapies typically relies on these systemic administration routes, which can lead to undesirable side effects. In some cases, certain promising therapeutic agents are extremely difficult to develop due to associated toxicity and limitations of current administration methods and systems. Hydrogels are a particularly attractive type of biomaterial and are used in a wide range of applications, including tissue engineering and regenerative medicine, diagnostic agents, cell immobilization, and / or drug delivery. However, existing hydrogels have several limitations that restrict the practical use of hydrogel-based drug delivery therapies. For example, bulk hydrogels have distinct dimensions, which can make them difficult to extrude through a needle, so typically, large quantities of hydrogels are formed in vitro and then implanted. While some hydrogels can be formed in situ in vivo, there may be potential risks and challenges associated with certain crosslinking agents, such as UV irradiation and / or crosslinking chemicals. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Hiller,JGet al.Nature Reviews Clinical Oncology,2018,15,205-218 [Overview of the Initiative]

[0005] The inventors of the present invention have previously described various systems (see, for example, PCT / US20 / 31169, filed on May 1, 2020, and published as WO2020 / 223698) or combinations of biomaterials and immunomodulatory payloads (see, for example, WO2018 / 045058 or WO2019 / 183216) that include immunomodulatory payload-independent immunomodulatory biomaterials, which may be particularly useful when administered to subjects who have undergone or are undergoing tumor resection. The characteristics of this system solve the causes of one or more problems associated with certain prior arts, including, for example, certain conventional methods of cancer treatment. For example, this system may reduce and / or avoid certain adverse events (e.g., rash, hepatitis, diarrhea, colitis, hypophysitis, thyroiditis, and adrenal insufficiency) that may be associated with systemic administration of immunotherapeutic drugs. In particular, this system can reduce or eliminate exposure of non-tumor-specific immune cells to systemically administered immunotherapeutic(s) drugs and / or exposure to high doses of such drugs(s) that are often required to achieve concentrations sufficient to elicit a desired response in the tumor. In particular, this system can provide local immunomodulation after tumor resection (e.g., local agonism of innate immunity), thereby improving efficacy by concentrating the immunomodulatory effect where it is needed. Additionally or alternatively, such a system providing local immunomodulation after resection (e.g., agonism of innate immunity) can, in particular, break local immune tolerance to cancer, enabling the development of systemic antitumor immunity, which in some embodiments may lead to the eradication of disseminated disease.

[0006] This disclosure provides insight into how certain biomaterial formulations may be particularly useful and / or provide certain beneficial effects, as described herein, for example.

[0007] In some embodiments, the disclosure identifies the source of a problem associated with a particular prior art, which includes, for example, a problem associated with a particular crosslinked biopolymer material. In particular, the disclosure understands that a particular crosslinking technique may produce toxic byproducts and / or adversely affect the stability and / or efficacy of a drug(s) (e.g., therapeutic agents) that may be combined with the biopolymer material before or during crosslinking.

[0008] Alternatively or additionally, this disclosure identifies the source of problems associated with technologies involving pre-forming biopolymer materials (e.g., by crosslinking) before introduction into a subject. For example, this disclosure understands that such pre-forming may produce materials with distinct sizes and / or structures, which may limit administration options. This disclosure provides technologies that include specific biomaterial preparations that enable administration by various routes and / or techniques, including methods such as injection and / or laparoscopic administration, which may be less invasive than transplantation. In some such embodiments, preparations having improved administration characteristics may be administered in a liquid state. In some embodiments, they may be administered in a pre-formed gel state characterized by flexible space-filling properties. In some such embodiments, the provided preparations consist of suitable materials in particulate form (e.g., such that the preparation includes a plurality of particles characterized by, for example, a size distribution and / or other parameters as described herein).

[0009] In particular, in some embodiments, the Disclosure provides temperature-responsive biomaterial preparations that can transition from an injectable state to another state having material properties that provide, for example, beneficial effects as described herein, without introducing, for example, cell-toxic crosslinking agents, such as UV irradiation and / or low molecular weight crosslinking agents. Accordingly, some such embodiments provide beneficial techniques for the in-situ formation of gelling materials, which have various advantages over alternative techniques and provide solutions to certain problems associated with such alternative techniques identified herein. For example, since various alternative techniques for in-situ gelation require processing (e.g., exposure to UV irradiation and / or low molecular weight crosslinking agents that may be toxic to or otherwise adversely affect drugs that may be present in or with the recipient and / or material), the Disclosure identifies a source of problems associated with numerous such techniques.

[0010] In some embodiments, the temperature-responsive biomaterial preparations provided (e.g., those described herein) may exhibit one or more immunomodulatory properties even in the absence of an immunomodulatory payload. For example, in some embodiments, the temperature-responsive biomaterial preparations provided may promote innate immunity when administered to a target site of a subject requiring administration (e.g., a subject undergoing tumor resection).

[0011] In some embodiments, the Disclosure recognizes, among other things, that certain conventional preparations used to form hydrogels, which are poloxamers or contain them, typically utilize poloxamers (e.g., poloxamer 407 (P407)) at a minimum concentration of 16–20% (w / w), or contain them at a minimum concentration of 16–20% (w / w). The Disclosure identifies the sources of problems associated with such conventional preparations, including that such preparations may have certain drawbacks with respect to administration to a subject, including high solution viscosity and / or tissue irritation due to high concentrations of poloxamers, which would make them unsuitable for injection. Furthermore, the Disclosure demonstrates that it is possible to develop useful preparations having significantly lower concentrations(s) of such poloxamers.

[0012] For example, in some embodiments, the disclosure provides insight that certain poloxamers (e.g., poloxamer 407 (P407)) that are typically used at a minimum concentration of 16–20% (w / w) to form hydrogels can be combined with one or more biocompatible polymers to form useful temperature-responsive biomaterials at concentrations of less than 16% (w / w), including, for example, less than 14% (w / w), less than 12% (w / w), less than 11% (w / w), less than 10.5% (w / w), less than 10% (w / w), less than 8% (w / w), less than 6% (w / w), or less. In some embodiments, such biocompatible polymers may be or include non-temperature-responsive polymers, for example, in some embodiments, this may be or include hyaluronic acid and / or chitosan or modified chitosan. In some embodiments, biomaterial preparations comprising a poloxamer at a concentration of 12.5% ​​(w / w) or less (e.g., 11% (w / w), 10.5% (w / w), 10% (w / w), 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), or less) and at least one additional non-poloxamer polymer may be immunomodulatory in the absence of an immunomodulatory payload. For example, in some embodiments, such biomaterial preparations may promote innate immunity when administered to a target site of a subject requiring administration (e.g., a subject undergoing tumor resection).

[0013] One embodiment provided herein relates to a preparation or composition comprising a polymer combination preparation comprising at least first and second polymer components, wherein the first polymer component is or comprises a poloxamer, the second polymer component is not a poloxamer, and the first polymer component is present in the polymer combination preparation at a concentration of 12.5% ​​(w / w) or less (for example, 11% (w / w), 10.5% (w / w), 10% (w / w), 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), or less). In some embodiments, the first polymer component is present in the polymer combination preparation at a concentration of 4%(w / w) to 11%(w / w), 4%(w / w) to 10.5%(w / w), or 4%(w / w) to 10%(w / w). In some embodiments, the first polymer component is present in the polymer combination preparation at a concentration of 5%(w / w) to 11%(w / w), 5%(w / w) to 10.5%(w / w), or 5%(w / w) to 10%(w / w). In some embodiments, the first polymer component is present in the polymer combination preparation at a concentration of 6%(w / w) to 11%(w / w), 6%(w / w) to 10.5%(w / w), or 6%(w / w) to 10%(w / w). In some embodiments, such polymer combination preparations are characterized by transitioning from a precursor state to a polymer network state in response to a gelation trigger. Such gelation triggers are one or more of the following: (a) a temperature above the critical gelation temperature (CGT) of the polymer combination preparation; (b) the critical gelation weight ratio of the first polymer component to the second polymer component; (c) the total polymer content; (d) the molecular weight of the first and / or second polymer components; or (e) a combination thereof.

[0014] In some embodiments, the crosslinks formed during the transition from the precursor state to the polymer network state do not include covalent crosslinks.

[0015] In many embodiments, such polymer combination preparations are temperature-responsive. In some such embodiments, such polymer combination preparations are characterized by transitioning from a precursor state to a polymer network state in response to a temperature above the CGT. For example, in some embodiments, the CGT of the provided polymer combination preparation is 18-39°C. In some embodiments, the CGT of the provided polymer combination preparation is room temperature. In some embodiments, the CGT of the provided polymer combination preparation is 20-25°C. In some embodiments, the CGT of the provided polymer combination preparation is 25-30°C. In some embodiments, the CGT of the polymer combination preparation is the body temperature of the subject.

[0016] While numerous different poloxamers may be used in the polymer combination preparations provided, in some embodiments, certain poloxamers, such as poloxamer 407 (P407), poloxamer 338 (P338), or poloxamer 188 (P188), are particularly useful in certain polymer combination preparations described herein. For example, in some embodiments, the poloxamer included as the first polymer component in the polymer combination preparations described herein is or includes P407. In some embodiments, the first polymer component (including, for example, P407) is present in the polymer combination preparations provided at concentrations of 4% (w / w) to 12.5% ​​(w / w), 4% (w / w) to 11% (w / w), 4% (w / w) to 10.5% (w / w), or 4% (w / w) to 10% (w / w). In some embodiments, the first polymer component (including, for example, P407) is present in the provided polymer combination preparation at concentrations of 5% (w / w) to 12.5% ​​(w / w), 5% (w / w) to 11% (w / w), 5% (w / w) to 10.5% (w / w), or 5% (w / w) to 10% (w / w). In some embodiments, the first polymer component (including, for example, P407) is present in the provided polymer combination preparation at concentrations of 6% (w / w) to 12.5% ​​(w / w), 6% (w / w) to 11% (w / w), 6% (w / w) to 10.5% (w / w), or 6% (w / w) to 10% (w / w).

[0017] In some embodiments, the polymer combination preparations described herein include polymers with a total content of at least 6% (w / w), at least 8% (w / w), at least 10% (w / w), at least 12%, or at least 15% (w / w). In some embodiments, the polymer combination preparations described herein include polymers with a total content of 6% (w / w) to 20% (w / w) or 6% (w / w) to 15% (w / w) or 7% (w / w) to 15% (w / w). In some embodiments, the polymer combination preparations described herein include polymers with a total content of 8% (w / w) to 20% (w / w) or 8% (w / w) to 15% (w / w) or 10% (w / w) to 15% (w / w).

[0018] In some embodiments, the polymer combination preparations described herein are characterized by a weight ratio of the first polymer component to the second polymer component of 1:1 to 14:1 or 1:1 to 10:1. In some embodiments, the polymer combination preparations described herein are characterized by a weight ratio of the first polymer component to the second polymer component of 1:1 to 1:3 or 1:1 to 1:2.

[0019] In some embodiments, the second polymer component in the provided polymer combination preparation is a carbohydrate polymer or includes it. Examples of carbohydrate polymers that may be useful in accordance with the present disclosure include, but are not limited to, hyaluronic acid, chitosan, alginate, and variants and combinations thereof. In some embodiments, the carbohydrate polymer in the provided polymer combination preparation may be present at a concentration of less than about 5% (w / w). In some embodiments, the carbohydrate polymer in the provided polymer combination preparation may be present at a concentration of 0.5% (w / w) to 10% (w / w) or 0.5% (w / w) to 5% (w / w) or 1% (w / w) to 10% (w / w) or 1% (w / w) to 5% (w / w) or 2% to 10% (w / w).

[0020] In some embodiments, the carbohydrate polymer useful in certain polymer combination preparations described herein is hyaluronic acid or includes it. In some embodiments, such hyaluronic acid can have an average molecular weight of 50 kDa to 2 MDa. In some embodiments, such hyaluronic acid can have an average molecular weight of 100 kDa to 500 kDa. In some embodiments, such hyaluronic acid can have an average molecular weight of 125 kDa to 375 kDa. In some embodiments, such hyaluronic acid can have an average molecular weight of 100 kDa to 400 kDa. In some embodiments, such hyaluronic acid can have an average molecular weight of 500 kDa to 1.5 MDa. In some embodiments, the molecular weight of hyaluronic acid is characterized by the weight-average molecular weight. In some embodiments, the molecular weight of hyaluronic acid is characterized by the viscosity-average molecular weight, which can be determined, in some embodiments, for example, by converting the intrinsic viscosity of hyaluronic acid to the average molecular weight using the Mark-Houwink equation. In some embodiments, the molecular weight of hyaluronic acid can be measured by size exclusion chromatography-multi-angle laser light scattering (SEC-MALLS).

[0021] In some embodiments, the number-average molecular weight (Mn), weight-average molecular weight (Mw), and / or dispersity (characterized by the polydispersity index) can be determined using SEC-MALLS.

[0022] In some embodiments, the carbohydrate polymer useful in certain polymer combination preparations described herein is chitosan or modified chitosan or includes it. In some embodiments, an exemplary modified chitosan is carboxymethyl chitosan or includes it.

[0023] In some embodiments, preparations or compositions comprising a polymer combination preparation in a precursor state, as used and / or described herein. In some embodiments, preparations or compositions comprising a polymer combination preparation in a polymer network state (for example, having one or more properties as described herein), as used and / or described herein.

[0024] In some embodiments, the polymer network state is or includes a viscous solution or colloid. In some embodiments, such a polymer network state may be characterized by a storage modulus of 100 Pa to 500 Pa. In some embodiments, the polymer network state is or includes a hydrogel. In some embodiments, such a polymer network state may be characterized by a storage modulus of 500 Pa to 10,000 Pa or 750 Pa to 7,500 Pa.

[0025] In some embodiments, the polymer network state of the provided polymer combination preparation is characterized by a storage modulus at least 40% lower than that of a hydrogel formed from an 18% (w / w) concentration P407 solution. In some embodiments, the polymer network state of the provided polymer combination preparation, whose precursor state has been stored for one month or longer at a temperature below the CGT (e.g., 2–8°C), is characterized by a storage modulus, for example, measured at 37°C, which is maintained at substantially the same level (e.g., within 20%, within 10%, within 5%, or less) as that of a polymer network formed from a newly prepared precursor state of such provided polymer combination preparation. As will be understood by those skilled in the art, the storage modulus of biomaterials can be affected by biodegradation, chemical degradation (e.g., oxidation), and / or phase separation of polymer components in the combination.

[0026] In some embodiments, the polymer combination preparations described and / or utilized herein have a pH of 5.0 to 8.5. In some embodiments, the polymer combination preparations described and / or utilized herein have a pH of 7 to 8 (e.g., pH 7.4). For example, in some embodiments, the precursor state of the polymer combination preparation is a solution of the polymer combination preparation in a solvent system having a pH of 5.0 to 8.5 (e.g., in some embodiments, pH 7 to 8). In some embodiments, such a solvent system is a buffer system. In some embodiments, such a buffer system may contain one or more salts (e.g., sodium phosphate and / or sodium bicarbonate). In some embodiments, such a solvent system is a buffer system with a higher buffering capacity than 10 mM phosphate buffer. In some embodiments, such a solvent system is a buffer system with a higher buffering capacity than 20 mM phosphate buffer.

[0027] In some embodiments, the preparations or compositions described herein may be useful for resulting in the sustained release of a payload incorporated therein. For example, in some embodiments, a polymer combination preparation providing a polymer network state is characterized in that, when tested in vitro at 37°C, such polymer combination preparation releases a payload (e.g., a lipophilic agent) incorporated therein at a rate equivalent to that of a hydrogel formed from an 18% (w / w) concentration P407 solution. In some embodiments, a polymer combination preparation providing a polymer network state is characterized in that, when tested in vitro at 37°C, 40% or less of the payload (e.g., a lipophilic agent) incorporated therein is released within 24 hours. In some embodiments, a polymer combination preparation providing a polymer network state is characterized in that, when tested in vitro at 37°C, more than 60% of the payload (e.g., a lipophilic agent) incorporated therein can be retained therein for at least 24 hours.

[0028] In some embodiments, a polymer combination preparation providing a polymer network state is characterized in that, when tested in vitro at 37°C, such a polymer combination preparation releases the payload incorporated therein (e.g., a hydrophilic agent) at a rate equivalent to or faster than that of a hydrogel formed from an 18% (w / w) concentration P407 solution. In some embodiments, a polymer combination preparation providing a polymer network state is characterized in that, when tested in vitro at 37°C, at least 40% of the payload incorporated therein (e.g., a hydrophilic agent) is released therein within 12 hours. In some embodiments, a polymer combination preparation providing a polymer network state is characterized in that, when tested in vitro at 37°C, the polymer combination preparation releases the payload incorporated therein (e.g., a hydrophilic agent) at a rate faster than that of a chemically crosslinked reference hydrogel (e.g., at least 20% within 48 hours). In some embodiments, such a chemically crosslinked reference hydrogel is a chemically crosslinked hyaluronic acid hydrogel, which is a hydrogel formed by mixing thiol-modified hyaluronic acid (Glycosil®) with a thiol-reactive PEGDA crosslinking agent (Extralink®) under conditions in which gelation occurs.

[0029] In some embodiments, the preparations or compositions described herein provide immunomodulatory polymer combination preparations comprising poloxamers (e.g., those described herein) and carbohydrate polymers (e.g., those described herein), substantially free of an immunomodulatory payload. In some embodiments, such immunomodulatory polymer combination preparations are characterized in that a group of test animals with spontaneous metastases having such polymer combination preparations in a polymer network state at the tumor resection site has a higher survival rate than a comparable group of test animals having poloxamer biomaterials at the tumor resection site, when evaluated two months after administration.

[0030] In some embodiments, the preparations or compositions described herein may include polymer combination preparations (e.g., those described herein) and one or more therapeutic agents for the treatment of, for example, a disease, disorder, or condition (e.g., cancer). In some embodiments, the one or more therapeutic agents that may be included in the preparations or compositions described herein are or include one or more chemotherapeutic agents. In some embodiments, the one or more therapeutic agents that may be included in the preparations or compositions described herein are or include one or more immunomodulatory agent payloads. Examples of immunomodulatory agent payloads that may be useful in accordance with this disclosure include, but are not limited to, activators of innate immune responses, activators of adaptive immune responses, modulators of macrophage effector function, modulators of inflammation, and combinations thereof.

[0031] In some embodiments, at least one therapeutic agent (e.g., at least one immunomodulatory agent payload) is incorporated into the polymer combination preparation described herein. In some embodiments, such polymer combination preparations are characterized in that a group of test animals with spontaneous metastasis having the polymer combination preparation in a polymer network state at the tumor resection site has a higher survival rate than a comparable group of test animals having the polymer combination preparation without an immunomodulatory agent payload at the tumor resection site, when evaluated 2 or 3 months after administration.

[0032] The preparations and / or compositions described herein may be useful for a variety of medical applications, including, but not limited to, immunomodulation and / or drug delivery. Accordingly, in some embodiments, the preparations and / or compositions described herein may be formulated into pharmaceutical compositions for administration to subjects in need of administration. Accordingly, in one embodiment, a method is provided herein that includes administering a preparation or composition described and / or utilized herein, or a pharmaceutical composition containing the same, to a subject in need of administration.

[0033] In some embodiments, preparations or compositions described and / or used herein, or pharmaceutical compositions containing them, may be useful for the treatment of cancer. In some such embodiments, the subjects to be administered are those who have cancer. In some embodiments, the subjects to be administered are those who have or are susceptible to recurrent or disseminated cancer. In some embodiments, the subjects to be administered are those undergoing tumor resection.

[0034] In some embodiments, the method includes administering a provided preparation or composition, or a pharmaceutical composition containing the same, to a target site subject to tumor resection. In some embodiments, such preparation or composition, or a pharmaceutical composition containing the same, is administered to the tumor resection site.

[0035] In some embodiments, administration may be carried out by implantation. For example, in some embodiments, a preparation or composition comprising a polymer combination preparation in a polymer network state (e.g., a hydrogel) may be administered by implantation.

[0036] In some embodiments, administration may be performed by injection. In some embodiments, injection may be performed by a robotic arm. For example, in some embodiments, a preparation comprising a polymer combination preparation in a precursor state (e.g., a liquid state or an injectable state) is administered by injection, where the precursor state transitions to a polymer network state (e.g., a more viscous solution or colloidal state or a hydrogel) upon administration.

[0037] In some embodiments, administration may be performed concurrently with or after laparoscopy. In some embodiments, administration may be performed concurrently with or after minimally invasive surgery (MIS), such as robot-assisted MIS for tumor resection, robotic surgery, and / or laparoscopic surgery.

[0038] These and other embodiments included in this disclosure are described in more detail below and in the claims. [Brief explanation of the drawing]

[0039] [Figure 1] A and B are heatmaps showing the gelling properties of exemplary temperature-responsive polymer combination preparations containing P407 at concentrations expressed as %(w / w) and hyaluronic acid (HA) with an average molecular weight of 1.5 MDa at concentrations expressed as %(w / w) in two different buffer systems. The temperature-responsive polymer combination preparations were exposed to a temperature of 37°C to observe any gel formation. A polymer combination preparation is determined to form a gel if such a polymer combination preparation becomes translucent or opaque and is not fluid when tilted or inverted. A corresponds to 10 mM phosphate-buffered saline (PBS) at pH 7.4. B corresponds to 0.1 M bicarbonate buffer at pH 8.0.

[0040] [Figure 2] A and B are heatmaps showing the gelation properties of exemplary temperature-responsive polymer combination preparations containing P407 at concentrations expressed as %(w / w) and hyaluronic acid (HA) with an average molecular weight of 730 kDa at concentrations expressed as %(w / w) in two different buffer systems. The polymer combination preparations were exposed to a temperature of 37°C to observe any gel formation. A polymer combination preparation is determined to form a gel if such a polymer combination preparation becomes translucent or opaque and is not fluid when tilted or inverted. A corresponds to 10 mM PBS at pH 7.4. B corresponds to 0.1 M bicarbonate buffer at pH 8.0.

[0041] [Figure 3]A heatmap is shown illustrating the gelling properties of exemplary temperature-responsive polymer combination preparations containing P407 at a concentration expressed as %(w / w) and modified chitosan (e.g., carboxymethyl chitosan; CMCH) at a concentration expressed as %(w / w) in 10 mM PBS at pH 7.4. The temperature-responsive polymer combination preparations were exposed to a temperature of 37°C to observe any gel formation. A polymer combination preparation is determined to form a gel if such a polymer combination preparation becomes translucent or opaque and is not fluid when tilted or inverted.

[0042] [Figure 4] Figures A and B show graphs illustrating the storage modulus of exemplary temperature-responsive polymer combination preparations compared to a control polymer composition after exposure to a temperature of 37°C. A: Linear scale. B: Logarithmic scale. Abbreviations: "18%P" = 18% (w / w) P407, "13.5%P+HA(10mM PBS)" = 13.5% (w / w) P407 + 0.65% (w / w) 1.5MDa HA in 10mM PBS at pH 7.4, "13.5%P+HA(0.1M bicarbonate)" = 13.5% (w / w) P407 + 0.65% (w / w) 1.5MDa HA in 0.1M bicarbonate buffer at pH 8, "10%P+1% HA(10mM PBS)" = 10% (w / w) P407 + 1% (w / w) 1.5 MDa HA, "13.5% P + CMCH" = 13.5% (w / w) P4O7 + 1.3% (w / w) CMCH in 10 mM PBS at pH 7.4, "12.5% ​​Extralink" = hyaluronic acid chemically crosslinked with 12.5% ​​Extralink thiol crosslinking agent, "1.5% Extralink" = hyaluronic acid chemically crosslinked with 1.5% Extralink thiol crosslinking agent, "0.5% Extralink" = hyaluronic acid chemically crosslinked with 0.5% Extralink thiol crosslinking agent.

[0043] [Figure 5]Figures A-D show graphs illustrating the homogeneity of exemplary temperature-responsive polymer combination preparations in a hydrogel state compared to a control polymer composition, based on weekly measurements at 37°C (above CGT) (assuming their precursor state is maintained at temperatures of 2-8°C for a period of one month). Gel homogeneity was determined by measuring the storage modulus of the hydrogel over a period of time. A: Control gel (18% w / w poloxamer 407). B: Temperature-responsive polymer combination preparation of 13.5% w / w poloxamer 407 and 0.65% w / w 1.5 MDa HA in 10 mM PBS at pH 7.4. C: Temperature-responsive polymer combination preparation of 10% w / w poloxamer 407 and 1% w / w 1.5 MDa HA in 10 mM PBS at pH 7.4. D: A temperature-responsive polymer combination preparation of 13.5% w / w poloxamer 407 and 0.65% w / w 1.5 MDa HA in 0.1 M bicarbonate buffer at pH 8.0.

[0044] [Figure 6] Figures A and B show graphs illustrating the cumulative release profiles of exemplary lipophilic agents in vitro over a period of time from exemplary temperature-responsive polymer combination preparations in a hydrogel state at a temperature of 37°C. A: Sudan Orange. B: Nile Red.

[0045] [Figure 7] Figures A and B show graphs illustrating the cumulative release profiles of exemplary hydrophilic agents in vitro over a period of time from exemplary temperature-responsive polymer combination preparations in a hydrogel state at a temperature of 37°C. Figure 7A: Methylene blue. Figure 7B: Rhodamine 6G.

[0046] [Figure 8]Figures A-E show graphs illustrating in vivo survival data in animals that underwent tumor resection and were administered either an exemplary temperature-responsive polymer combination preparation in hydrogel state alone or an exemplary temperature-responsive polymer combination preparation in hydrogel state incorporating a TLR7 / 8 agonist (e.g., regiquimod), compared to a chemically crosslinked control hyaluronic acid hydrogel alone or a chemically crosslinked control hyaluronic acid hydrogel incorporating a TLR7 / 8 agonist (e.g., regiquimod). The x-axis represents time after tumor inoculation. Tumor resection was performed 10 days after tumor inoculation, and the exemplary composition was administered post-tumor resection. A: Control 12.5% ​​(w / v) Extralink® hyaluronic acid hydrogel (HyStem®), with or without a TLR7 / 8 agonist (e.g., regiquimod). B: A combination of temperature-responsive polymer preparations containing or not containing a TLR7 / 8 agonist (e.g., regiquimod), consisting of 10% w / w poloxamer 407 and 1% w / w 1.5 MDa HA in 10 mM PBS at pH 7.4. C: A combination of temperature-responsive polymer preparations containing or not containing a TLR7 / 8 agonist (e.g., regiquimod), consisting of 13.5% w / w poloxamer 407 and 0.65% w / w 1.5 MDa HA in 10 mM PBS at pH 7.4. D: A combination of temperature-responsive polymer preparations containing or not containing a TLR7 / 8 agonist (e.g., regiquimod), consisting of 13.5% w / w poloxamer 407 and 0.65% w / w 1.5 MDa HA in 0.1 M bicarbonate buffer at pH 8.0. A temperature-responsive polymer combination preparation containing or without a TLR7 / 8 agonist (e.g., regiquimod) in 10 mM PBS at pH 7.4, comprising 13.5% w / w poloxamer 407 and 1.3% w / w CMCH.

[0047] [Figure 9]This shows survival data of animals administered a liquid preparation of an immunomodulatory polymer combination (e.g., a liquid preparation of a combination of carboxymethyl chitosan (CMCH) and poloxamer (e.g., P407) at different concentrations) compared to animals administered a liquid preparation of poloxamer (e.g., P407) alone. The x-axis represents time after tumor inoculation. Tumor resection was performed 10 days after tumor inoculation, and the exemplary composition was administered after tumor resection.

[0048] [Figure 10] Figures A-D show graphs illustrating in vivo survival data in animals that underwent tumor resection and were administered exemplary temperature-responsive polymer combination preparations (e.g., thermoresponsive liquid preparations containing combinations of hyaluronic acid (HA) and poloxamer (e.g., P407) at different concentrations of 730 kDa or 1.5 MDa) as single polymer combinations or as polymer combinations incorporating immunomodulatory payloads such as a TLR7 / 8 agonist (e.g., regiquimod, also known as R848). The x-axis represents time after tumor inoculation. Tumor resection was performed 10 days after tumor inoculation, and the exemplary compositions were administered post-tumor resection. A: Temperature-responsive polymer combination preparation containing or without a TLR7 / 8 agonist (e.g., regiquimod) in 12.5 mM PBS at pH 8, containing or without a TLR7 / 8 agonist (e.g., regiquimod). B: A temperature-responsive polymer combination preparation containing or not containing a TLR7 / 8 agonist (e.g., regiquimod) of 10% w / w poloxamer 407 and 2.25% w / w 730kDa HA in 25mM PBS at pH 8. C: A temperature-responsive polymer combination preparation containing or not containing a TLR7 / 8 agonist (e.g., regiquimod) of 12.5% ​​w / w poloxamer 407 and 1.625% 730kDa HA in 25mM PBS at pH 8. D: A temperature-responsive polymer combination preparation containing or not containing a TLR7 / 8 agonist (e.g., regiquimod) of 8% w / w poloxamer 407 and 2.25% w / w 730kDa HA in 25mM buffered saline at pH 8.

[0049] [Figure 11] The graph shows in vivo survival data in animals that underwent tumor resection and were administered exemplary temperature-responsive polymer combination preparations (e.g., a thermoresponsive liquid preparation containing a combination of 119 kDa hyaluronic acid (HA) and poloxamer (e.g., P407)) as a single polymer combination or as a polymer combination incorporating an immunomodulatory payload, such as a TLR7 / 8 agonist (e.g., regiquimod, also known as R848). The results for temperature-responsive polymer combination preparations containing or not containing a TLR7 / 8 agonist (e.g., regiquimod) in 25 mM buffered saline (pH 7.4) containing 10% w / w poloxamer 407 and 4% w / w 119 kDa HA are shown. The x-axis represents time after tumor inoculation. Tumor resection was performed 10 days after tumor inoculation, and the exemplary compositions were administered post-tumor resection.

[0050] [Figure 12] The graph shows in vivo survival data for a cohort of animals that underwent tumor resection and were administered exemplary temperature-responsive polymer combination preparations (e.g., a temperature-responsive liquid preparation containing a combination of 309 kDa hyaluronic acid (HA) and poloxamer (e.g., P407)) as a single polymer combination or as a polymer combination incorporating an immunomodulatory payload such as a TLR7 / 8 agonist (e.g., regiquimod, also known as R848), or a control animal cohort of poloxamer alone. The graph shows results for temperature-responsive polymer combination preparations of 10% w / w poloxamer 407 and 2% w / w 309 kDa HA in 25 mM buffered saline at pH 7.4, with or without a TLR7 / 8 agonist (e.g., regiquimod), and a control preparation of 15% poloxamer 407 biomaterial without the active agent. The x-axis represents time after tumor inoculation. Tumor resection was performed 10 days after tumor inoculation, and the exemplary composition was administered after tumor resection.

[0051] [Figure 13]This figure shows survival data of animals administered a liquid preparation of an exemplary immunomodulatory polymer combination (e.g., a liquid preparation of a combination of low molecular weight hyaluronic acid (HA) and poloxamer (e.g., P407)) compared to animals administered a liquid preparation of poloxamer (e.g., P407) alone. The x-axis represents time after tumor inoculation. Tumor resection was performed 10 days after tumor inoculation, and the exemplary composition was administered after tumor resection. [Modes for carrying out the invention]

[0052] A certain definition It should be noted that the concentrations of individual polymer components in the polymer combination preparations described herein are expressed in %(w / w) or weight %. When used herein, the %(w / w) concentration of a polymer component in a polymer combination preparation is determined based on (i) the total mass or total weight of all individual polymer components present in the polymer combination preparation and (ii) the mass or weight of the polymer component relative to the total mass or total weight of the solvent used in the polymer combination preparation.

[0053] Adaptive Immune Response Activators: The term “adaptive immune response activator” refers to a drug that activates (e.g., increases the activity of) the adaptive immune system (and / or one or more features of the adaptive immune system) of a target (e.g., a target to which it is administered and / or otherwise needs to be administered) compared to the absence of the drug. Such activation can restore or enhance antitumor function, for example, by neutralizing suppressive immune checkpoints and / or by activating costimulatory receptors, ultimately leading to helper and / or effector T cell responses to immunogenic antigens expressed by cancer cells and generating memory B cell and / or T cell populations. In certain embodiments, adaptive immune response activators are involved in the regulation of adaptive immune responses and / or leukocyte transport. Examples of adaptive immune response activators include, for example, those described in WO2018 / 045058, the entire contents of which are incorporated herein by reference for the purposes described herein.

[0054] Innate Immune Response Activator: The term “innate immune response activator” refers to a drug that activates (e.g., increases the activity of) the innate immune system (and / or one or more features of the innate immune system) of a target (e.g., a target to which it is administered and / or otherwise needs to be administered) compared to the absence of the drug. Such activation can stimulate (e.g., increase the expression level and / or activity of) one or more activators that help initiate an inflammatory response (e.g., an immunostimulatory inflammatory response) and / or induce an adaptive immune response, thereby resulting in, for example, the development of antigen-specific adaptive immunity. In some embodiments, activation of the innate immune system can result in the recruitment of relevant immune cells, including, but not limited to, neutrophils, basophils, eosinophils, natural killer cells, dendritic cells, monocytes, and macrophages, cytokine production, leukocyte proliferation and / or survival, and, for example, improved T cell priming by antigen presentation by antigen-presenting cells and / or increased expression levels and / or activity of costimulatory molecules. Examples of activators of the innate immune response include, for example, those described in WO2018 / 045058, the entire contents of which are incorporated herein by reference for the purposes described herein.

[0055] Administration: As used herein, the terms “administer,” “dosage,” or “administer” typically refer to the administration of a composition to a subject to achieve delivery of the composition, or a drug or payload contained therein, to a target site or site to be treated. Those skilled in the art will know, in appropriate circumstances, the various routes that may be used for the administration of different drugs to a subject, e.g., a human. For example, the terms “administer,” “dosage,” or “administer” may refer to implantation, absorption, ingestion, infusion, inhalation, parenteral administration, or otherwise introducing the composition described herein, but in the context of the administration of a composition comprising a polymer combination preparation provided (with or without a payload incorporated therein), administering may, in some embodiments, refer to implantation, or in some embodiments, to infusion.

[0056] Agonist: Those skilled in the art will understand that the term “agonist” may be used to refer to an active substance, state, or event whose presence, level, degree, type, or form correlates with an increase in the level and / or activity of another active substance (i.e., the stimulated active substance) and / or an increase or induction of one or more biological events. Generally, agonists can be or may include active substances of various chemical classifications, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, inorganic crystals, and / or any other substances exhibiting related activating activity. In some embodiments, agonists can be direct (in which case they directly affect the target). In some embodiments, agonists can be indirect (in which case they affect the target by means other than binding to the target, for example, by interacting with modifiers of the target such that the level or activity of the target is altered). Partial agonists compete with full agonists to interact with their targets and / or their regulators, thereby potentially acting as competitive antagonists in the presence of a full agonist, causing (i) a reduction in one or more effects of another drug and / or (ii) a reduction in one or more biological events compared to those observed with a full agonist alone.

[0057] Antagonist: Those skilled in the art will understand that the term “antagonist” can refer to an active substance, state, or event whose presence, level, degree, type, or form is associated with a reduction in the level and / or activity of another active substance (i.e., an antagonistic active substance) and / or a reduction or suppression of one or more biological events. Generally, antagonists can be active substances of various chemical classifications, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other substances exhibiting related inhibitory activity. In some embodiments, an antagonist may be a “direct antagonist” in that it binds directly to its target. In some embodiments, an antagonist may be an “indirect antagonist” in that it exerts its influence by means other than direct binding to its target, for example, by interacting with modifiers of the target in such a way that the level or activity of the target is altered.

[0058] Antibody: As used herein, the term “antibody” refers to a polypeptide containing a canonical immunoglobulin sequence element sufficient to confer specific binding to a particular target antigen. As is known in the art, naturally produced intact antibodies are approximately 150 kD tetrameric active substances composed of two identical heavy-chain polypeptides (each about 50 kD) and two identical light-chain polypeptides (each about 25 kD) that associate with each other to form a structure commonly referred to as a “Y-shaped” structure. Each heavy chain consists of at least four domains (each about 110 amino acids long): an amino-terminal variable (VH) domain (located at the tip of the Y structure), followed by three constant domains: CH1, CH2, and carboxy-terminal CH3 (located at the base of the trunk portion of the Y). A short region known as the “switch” links the heavy-chain variable region and the heavy-chain constant region. The “hinge” links the CH2 and CH3 domains to the remainder of the antibody. Two disulfide bonds in this hinge region link the two heavy-chain polypeptides together in an intact antibody. Each light chain consists of two domains separated from each other by another "switch": an amino-terminal variable (VL) domain followed by a carboxy-terminal constant (CL) domain. An intact antibody tetramer consists of two heavy-light dimers, each linked to the other by a single disulfide bond. Two other disulfide bonds link the heavy-chain hinge regions together so that the dimers are linked to each other and a tetramer is formed. Naturally produced antibodies typically have a glycosylated CH2 domain. Each domain in a natural antibody has a structure characterized by an "immunoglobulin fold" formed by two β-sheets (e.g., 3, 4, or 5-chain sheets) bundled together in a compressed antiparallel β-barrel. Each variable domain contains three hypervariable loops (CDR1, CDR2, and CDR3) known as "complementarity determination regions" and four somewhat immutable "framework" regions (FR1, FR2, FR3, and FR4).When a native antibody folds, the FR region forms a beta sheet that provides a structural framework for the domain, and the CDR loop regions of both the heavy and light chains assemble in three-dimensional space to produce a single hypervariable antigen-binding site located at the tip of the Y structure. The Fc region of a naturally occurring antibody binds to components of the complement system, including, for example, effector cells that mediate cytotoxicity, and also to receptors on effector cells. As is known in the art, the affinity and / or other binding properties of the Fc region to Fc receptors can be modulated by glycosylation or other modifications. In some embodiments, the antibody produced and / or utilized according to the present invention comprises a glycosylated Fc domain, which includes an Fc domain in which such glycosylation has been modified or manipulated. For the purposes of the present invention, in certain embodiments, any polypeptide or polypeptide complex containing sufficient immunoglobulin domain sequences found in natural antibodies may be referred to as an “antibody” and / or used as an antibody, regardless of whether such polypeptide is naturally occurring (e.g., produced by an organism that reacts to an antigen) or produced by recombinant engineering, chemical synthesis, or other artificial systems or methods. In some embodiments, the antibody is polyclonal. In some embodiments, the antibody is monoclonal. In some embodiments, the antibody has a constant region sequence characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, the antibody sequence element is humanized, primated, chimeric, etc., as is well known in the art. Furthermore, as used herein, the term “antibody” may, in appropriate embodiments (unless otherwise specified or otherwise evident from the context), refer to any construct or format known or developed in the art for utilizing the structural and functional characteristics of an antibody in an alternative offering.For example, in some embodiments, the antibodies used according to the present invention are, but are not limited to, intact IgA, IgG, IgE, and IgM antibodies; bispecific or polyspecific antibodies (e.g., Zybodies®); antibody fragments, e.g., Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single-chain Fv; polypeptide-Fc fusions; single-domain antibodies, alternative scaffolds, or antibody mimetic (e.g., antikalin, FN3 monobody, DARPin, Affibody, Affilin, Affimer, Affitin, Alphabody, Avimer, Fynomer, Im7, VLR, VNAR, Trimab, CrossMab, Trident); nanobodies, bi-nanobodies, F(ab')2, Fab', disdFv, single-domain antibodies, trifunctional antibodies, diabodies, and minibodies, in a format selected from the above. In some embodiments, a suitable format may or may include: Adnectin®; Affibody®; Affilin®; Anticalin®; Avimer®; BiTE®; Camel-like antibody; Centyrin®; Ankyrin repeat protein or DARPIN®; Biaffinity retargeting (DART) agent; Fynomer®; Shark single-domain antibody such as IgNAR; Immuno-mobilizing anti-cancer monoclonal T-cell receptor (ImmTAC); KALBITOR®; MicroProtein; Nanobody®, minibody; Masked antibody (e.g., Probody®); Small Modular ImmunoPharmaceutical ("SMIP®"); Single-chain or tandem diabody (TandAb®); TCR-like antibody; Trans-body®; TrimerX®; VHH. In some embodiments, antibodies may lack the covalent modifications (e.g., glycan linkages) that they have when naturally occurring.In some embodiments, the antibody may contain covalent modifications (e.g., the attachment of glycans, payloads [e.g., detectable portion, therapeutic portion, catalytic portion, etc.], or other pendant groups [e.g., polyethylene glycol, etc.]).

[0059] Bioadhesives: The term “bioadhesive” refers to a biocompatible agent that can adhere to a target surface, e.g., a tissue surface. In some embodiments, a bioadhesive can adhere to a target surface, e.g., a tissue surface, and can be retained on the target surface for a certain period of time. In some embodiments, a bioadhesive may be biodegradable. In some embodiments, a bioadhesive may be a natural agent, e.g., prepared or obtained by isolation or synthesis. In some embodiments, a bioadhesive may be a non-natural agent, e.g., designed and / or manufactured by human hands, e.g., by processing, synthesis and / or recombinant production depending on the agent, as understood by those skilled in the art. In some specific embodiments, a bioadhesive may be a polymeric substance, e.g., composed of or containing multiple monomers, e.g., sugars. Certain exemplary bioadhesives include various FDA-approved agents, e.g., cyanoacrylates (Dermabond, 2-octyl cyanoacrylate; Indermil, n-butyl-2-cyanoacrylate; Histoacryl and Histoacryl) Examples include Blue (n-butyl-2-cyanoacrylate), albumin and glutaraldehyde (BioGlue®, bovine serum albumin and 10% glutaraldehyde), fibrin glue (Tisseel®, pooled human plasma fibrinogen and thrombin; Evicel®, pooled human plasma fibrinogen and thrombin; Vitagel®, autologous plasma fibrinogen and thrombin; Cryoseal® system, autologous plasma fibrinogen and thrombin), gelatin and / or resorcinol crosslinked with formaldehyde and / or glutaraldehyde, polysaccharide-based adhesives (e.g., arginate, chitosan, collagen, dextran, and / or gelatin), PEG, acrylates, polyamines, or urethane variants (isocyanate-terminated prepolymers), and / or combinations thereof.For example, other examples of bioadhesives known in the art, such as those described in Mehdizadeh and Yang, “Design Strategies and Applications of Tissue Bioadhesives,” Macromol Biosci 13:271-288 (2013), may be used for the methods described herein. In some embodiments, the bioadhesive may be a biodegradable bioadhesive. Examples of such biodegradable bioadhesives include, but are not limited to, fibrin glue, gelatin-resorcinol-formaldehyde / glutaraldehyde glue, poly(ethylene glycol) (PEG)-based hydrogel glue, polysaccharide glue, polypeptide glue, polymer glue, biomimetic bioadhesives, and those described in Bhagat and Becker, “Degradable Adhesives for Surgery and Tissue Engineering,” Biomacromolecules 18:3009-3039 (2017).

[0060] Biocompatibility: As used herein, the term “biocompatibility” refers to a substance that, for example, does not cause significant harm to living tissue when placed in contact with such tissue in vivo. The biocompatibility of a substance may be evaluated by its ability to pass biocompatibility tests described in International Organization for Standardization (ISO) standard number 10993 and / or United States Pharmacopeia (USP) 23 and / or U.S. Food and Drug Administration (FDA) Blue Book Memorandum #G95-1 entitled “Use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part-1: Evaluation and Testing.” Typically, these tests measure the toxicity, infectivity, pyrogenicity, irritancy, reactivity, hemolytic activity, carcinogenicity, and / or immunogenicity of a substance. In certain embodiments, a substance is “biocompatible” if it is not toxic to cells in itself in the in vivo environment of its intended use. In certain embodiments, a substance is "biocompatible" if its in vitro addition to cells results in no more than 20% cell death, and / or its in vivo administration does not induce significantly severe inflammation or other such adverse effects that are clinically undesirable for the purposes described herein. As will be understood by those skilled in the art, such significantly severe inflammation is distinguishable from transient mild inflammation typically associated with surgery or the introduction of a foreign body into the body. Furthermore, those skilled in the art who read this disclosure will understand that in some embodiments, the polymer combination preparations and / or their individual polymer components described herein are biocompatible if the degree of immunomodulation (e.g., innate immune agonism) over a predetermined period of time is clinically beneficial and / or desirable, for example, to produce antitumor immunity.

[0061] Biodegradability: As used herein, the term “biodegradable” means a substance that, when introduced into a cell, is broken down (e.g., by cellular mechanisms, e.g., by enzymatic degradation, by hydrolysis, and / or a combination thereof) into components that the cell can reuse or remove without significant toxic effects on the cell. In certain embodiments, the components produced by the degradation of a biodegradable substance are biocompatible and therefore do not induce significantly serious inflammation and / or other adverse effects in vivo that are clinically undesirable for the purposes described herein. In some embodiments, biodegradable polymer substances are broken down into their constituent monomers. In some embodiments, biodegradable polymer substances may be degraded by organisms, e.g., by enzymatic activity or cellular mechanisms, possibly by exposure to lysozyme (e.g., having a relatively low pH), or by simple hydrolysis. In some embodiments, the degradation of a biodegradable substance (e.g., including a biodegradable polymer substance) involves hydrolysis of ester bonds. Alternatively or additionally, in some embodiments, the decomposition of biodegradable materials (e.g., including biodegradable polymer materials) involves the cleavage of urethane bonds. Exemplary biodegradable polymers include, but are not limited to, polymers of hydroxy acids such as lactic acid and glycolic acid, including poly(hydroxyl acid), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic acid-glycolic acid copolymer) (PLGA), and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(caprolactone), poly(hydroxyalkanoate), poly(lactide-caprolactone copolymer), mixtures thereof, and copolymers thereof. For example, many naturally occurring polymers, including proteins such as albumin, collagen, gelatin, and prolamins (e.g., zein), as well as polysaccharides such as arginates, cellulose variants, and polyhydroxyalkanoates such as polyhydroxybutyric acid, mixtures thereof, and copolymers, are also biodegradable.Those skilled in the art will be able to understand or determine when such polymer is biocompatible and / or when it is a biodegradable variant thereof (for example, related to the parent polymer by substantially identical structure, differing only in the substitution or addition of certain chemical groups, as is known in the art).

[0062] Biological Products: The terms “biological products,” “biological drugs,” and “biological products” refer to a wide range of products, such as vaccines, blood and blood components, allergens, somatic cells, gene therapies, tissues, nucleic acids, and proteins. Biological products may include sugars, proteins, or nucleic acids, or complex combinations thereof, or they may be living organisms such as cells and tissues. Biological products may be isolated from various natural sources (e.g., humans, animals, microorganisms) and / or produced by biotechnological methods and / or other techniques.

[0063] Biological specimen: The term “biological specimen” refers to a primary specimen obtained from a biological source, and / or, in some embodiments, a specimen obtained therefrom (e.g., by processing). Those skilled in the art will understand that biological specimens may include, for example, tissue specimens (e.g., tissue sections and tissue needle biopsies); cell specimens (e.g., cytological smears (e.g., Pap smears or blood smears) or specimens of cells obtained by microdissection); specimens of whole organisms (e.g., specimens of yeast or bacteria); or cell fractions, cell fragments, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or by other means), or that biological specimens may be selected from among these. Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, breast milk, vaginal fluid, saliva, swabs (e.g., oral swabs), or any substance containing biomolecules derived from a primary biological sample.

[0064] Biomaterials: The term "biomaterial" refers to a biocompatible substance characterized by being able to be administered to a subject for medical purposes (e.g., treatment, diagnosis) without inducing an unacceptable reaction (by sound medical judgment). Biomaterials may be obtained from nature, derived from nature, or synthesized. In some embodiments, a biomaterial may be or include a polymeric biomaterial. For example, in some embodiments, a polymeric biomaterial may include at least one or more (e.g., at least two or more) polymer components. In some embodiments, a biomaterial may be in the form of a polymer network. In some embodiments, a biomaterial may be in an injectable form, such as a viscous solution. For example, a biomaterial may include precursor components of the biomaterial that are formed in situ in vivo (e.g., when administered to a subject). In some embodiments, a biomaterial may be a liquid. In some embodiments, a biomaterial is a viscous solution. In some embodiments, a biomaterial is a colloid. In some embodiments, a biomaterial may be a solid. In some embodiments, a biomaterial may be a crystal (e.g., an inorganic crystal). In some embodiments, the biomaterial is not nucleic acid. In some embodiments, the biomaterial is not polypeptide.

[0065] Cancer: The term "cancer" refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). Particularly relevant in the context of some embodiments of this disclosure are cancers treated by cytotoxic and / or debridement therapies (e.g., surgical resection and / or specific chemotherapy therapies, e.g., cytotoxic therapy). In some embodiments, the cancers treated according to this disclosure are surgically resected (i.e., at least one tumor has been surgically resected). In some embodiments, the cancers treated according to this disclosure are those for which resection is the standard treatment. In some embodiments, the cancers treated according to this disclosure are metastatic. In certain embodiments, exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, intralymphatic sarcoma, angiosarcoma); appendiceal cancer; benign monoclonal immunoglobulinosis; biliary tract cancer (e.g., cholangiocarcinoma); cholangiocarcinoma; bladder cancer; bone cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial cancer; carcinoid tumor; cardiac tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colon Rectal adenocarcinoma; connective tissue carcinoma; epithelial carcinoma; intraductal carcinoma in situ; ependymoma; endometrial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial carcinoma (e.g., uterine carcinoma, uterine sarcoma); esophageal carcinoma (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; ocular carcinoma (e.g., intraocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder carcinoma; gastric carcinoma (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell carcinoma; head and neck carcinoma (e.g., head and neck squamous cell carcinoma), oral carcinoma (e.g., oral squamous cell carcinoma), pharyngeal carcinoma (e.g., laryngeal carcinoma, pharyngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma);Hematopoietic cancers (e.g., leukemia, e.g., acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomas, e.g., Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse large cell lymphoma) Lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström macroglobulinemia), pilocytic cell leukemia (HCL), immunoblastic large lymphoma Lymphoma, progenitor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; as well as T-cell NHL, e.g., progenitor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Césarley syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); one or more combinations of leukemia / lymphoma as described above; multiple myeloma; heavy chain disease ( For example, alpha-chain disease, gamma-chain disease, and μ-chain disease; hemangioblastoma; histiocytosis; hypopharyngeal carcinoma; inflammatory myofibroblastic neoplasm; immune cell amyloidosis; kidney cancer (for example, nephroblastoma (also known as Wilms' tumor), renal cell carcinoma); liver cancer (for example, hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (for example, bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (for example, systemic mastocytosis); melanoma; midline carcinoma; multiple endocrine neoplasia syndrome; muscle cancer; myelodysplastic syndrome (MDS); mesothelioma;Myeloproliferative disorders (MPDs) (e.g., polycythemia eugenics (PV), essential thrombocythemia (ET), myeloid metaplasia of unknown cause (AMM) (also known as myelofibrosis (MF)), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES)); nasopharyngeal carcinoma; neuroblastoma; neurofibroma (e.g., neurofibromatosis type 1 or type 2 (NF), schwannoma); Neuroendocrine carcinomas (e.g., gastrointestinal neuroendocrine tumors (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone cancer); ovarian cancers (e.g., cystadenocarcinoma, embryonous ovarian carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancers (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumors); parathyroid cancers; papillary adenocarcinomas; penile cancers (e.g., Paget's disease of the penis and scrotum); pharyngeal cancers; pineal gland tumors; ptosis Endometrial cancer; pleuropneumonoma; primitive neuroectodermal neoplasm (PNT); plasma cell neoplasm; paraneoplastic syndrome; neoplasm in situ; prostate cancer (e.g., adenocarcinoma of the prostate); rectal cancer; rhabdomyosarcoma; retinoblastoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (e.g., appendiceal cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH)); This may include one or more of the following: liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma; sebaceous carcinoma; gastric cancer; small intestinal cancer; sweat gland carcinoma; synoviomas; testicular cancer (e.g., seminomas, embryonal testicular carcinoma); thymic carcinoma; thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; uterine cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0066] Carbohydrate Polymers: The term "carbohydrate polymer" refers to, for example, one or more carbohydrates having a carbohydrate backbone, or a polymer containing such carbohydrates. For example, in some embodiments, a carbohydrate polymer refers to a polymer containing polysaccharides or oligosaccharides, or multiple monosaccharide units linked by covalent bonds. The monosaccharide units may all be identical, or, in some cases, two or more types of monosaccharide units may be present within the carbohydrate polymer. In certain embodiments, the carbohydrate polymer is naturally occurring. In certain embodiments, the carbohydrate polymer is synthetic (i.e., not naturally occurring). In some embodiments, the carbohydrate polymer may be chemically modified. In some embodiments, the carbohydrate polymer is a linear polymer. In some embodiments, the carbohydrate polymer is a branched polymer.

[0067] Chemotherapy drugs: The term "chemotherapy drugs" refers to therapeutic agents known to be useful in the chemotherapy of cancer. For example, in some embodiments, chemotherapy drugs may inhibit the proliferation of rapidly growing cancer cells and / or kill cancer cells. Examples of such chemotherapy drugs, but not limited to, include alkylating agents, antimetabolites, topoisomerase inhibitors, and / or mitotic inhibitors.

[0068] Combination Therapy: As used herein, the term “combination therapy” refers to a situation in which a subject is simultaneously exposed to two or more treatment programs (e.g., two or more therapeutic agents). In some embodiments, two or more treatment programs may be administered simultaneously. In some embodiments, such treatment programs may be administered sequentially (e.g., all “dose” of the first treatment program are administered before any dose of the second treatment program). In some embodiments, such agents are administered in partially overlapping dosing programs. In some embodiments, “administration” of combination therapy may include the administration of one or more agents or treatments in combination with a subject receiving other agents or treatments. For clarity, combination therapy does not require that individual agents be administered together (or even simultaneously) in a single composition; however, in some embodiments, two or more agents or their active parts may be administered together as a mixed composition, or even as a combination of compounds (e.g., as part of a single chemical complex or covalent bond).

[0069] Colloid: As used herein, the term “colloid” refers to a homogeneous solution or suspension of particles (e.g., polymer particles) dispersed in a dispersion medium (e.g., an aqueous buffer system). In some embodiments, the colloid is an emulsion. In some embodiments, the colloid is a sol. In some embodiments, the colloid is a gel.

[0070] Comparable: As used herein, the term “comparable” means two or more sets of drugs, entities, situations, conditions, etc., which do not necessarily have to be identical to each other, but are similar enough to allow comparison between them, such that a person skilled in the art would understand that a reasonable conclusion can be drawn based on observed differences or similarities. In some embodiments, a comparable set of conditions, situations, individuals, or groups features several substantially identical features and one or a few varying features. A person skilled in the art will understand the degree of identity required for two or more such sets of drugs, entities, situations, conditions, etc., to be considered comparable in any given context. For example, a person skilled in the art will understand that sets of situations, individuals, or groups are comparable if they feature a sufficient number and variety of substantially identical features to ensure a reasonable conclusion that differences in results or observed phenomena under or using different sets of situations, individuals, or groups are caused by or indicate the existence of various differences in those features. Those skilled in the art will also understand that when the term “comparable” is used in the context of comparing two or more values, such values ​​are equivalent to one another such that a difference in the values ​​does not result in a substantial difference in treatment outcomes, such as the induction of antitumor immunity and / or the incidence of tumor regrowth and / or metastasis. For example, in some embodiments, equivalent release rates refer to values ​​of such release rates within 15% over 48 hours. In some embodiments, equivalent release rates refer to values ​​of such release rates within 20% over 48 hours. In some embodiments, equivalent release rates refer to values ​​of such release rates within 15% over 24 hours.

[0071] Condition, disease, or disorder: The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0072] Corresponding: As used herein, the term “corresponding” refers to a relationship between two or more entities. For example, the term “corresponding” may be used to indicate the position / identity of a structural element in a compound or composition compared to another compound or composition (e.g., to a suitable reference compound or reference composition). For example, in some embodiments, a monomeric residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) may be identified as “corresponding” to a residue in a suitable reference polymer. For example, those skilled in the art will understand that, for brevity, residues in a polypeptide are often designated based on the relevant reference polypeptide using a standard numbering system, and therefore the amino acid “corresponding” to the residue at position 190 does not necessarily have to be, for example, the 190th amino acid in a particular amino acid chain, but rather corresponds to the residue found at position 190 in the reference polypeptide. Those skilled in the art will readily understand how to identify “corresponding” amino acids. For example, a person skilled in the art will know of various sequence alignment methods, including, for example, software programs such as BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH / GLSEARCH, Genoogle, HMMER, HHpred / HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPE, which may be used to identify “corresponding” residues in polypeptides and / or nucleic acids in accordance with this disclosure. A person skilled in the art will also understand that, in some cases, the term “corresponding” may be used to describe an event or entity that shares a relevant similarity with another event or entity (e.g., a suitable reference event or entity).To give just one example, a gene or protein in one organism may be described as "corresponding" to a gene or protein in another organism in some embodiments to indicate that it plays a similar role or performs a similar function, and / or that it exhibits a certain degree of sequence identity or homology, or that it shares certain characteristic sequence elements.

[0073] Critical Gelation Temperature: As used herein, the term “CGT” is abbreviated as “CGT” and refers to a threshold temperature at which a precursor state of a polymer combination preparation (e.g., as described herein) transitions to a polymer network state (e.g., a hydrogel state) as described herein. In some embodiments, the critical gelation temperature may correspond to a sol-gel transition temperature. In some embodiments, the critical gelation temperature may correspond to a lower critical solution temperature. For a general description of thermoresponsive gels, see Taylor et al., “Thermoresponsive Gels” Gels (2017) 3:4 (this content is incorporated herein by reference for the purposes described herein). As described herein, certain embodiments of the polymer combination preparations described herein are shown to form a polymer network state when exposed to a temperature of about 35–40°C. Those skilled in the art who read this disclosure will understand that such polymer combination preparations do not necessarily have a CGT of about 35–40°C, but rather may have a CGT of less than 35–40°C. For example, in some embodiments, the provided polymer combination preparations may have a CGT of about 20–28°C.

[0074] Critical Gelation Weight Ratio: As used herein, the term “critical gelation weight ratio” refers to a threshold weight ratio of at least two polymer components in a provided polymer combination preparation such that a precursor state (e.g., as described herein) of such polymer combination preparation transitions to a polymer network state (e.g., a hydrogel state) as described herein. In some embodiments, such a precursor-polymer network state transition occurs when both the critical gelation temperature and the critical gelation weight ratio of the provided polymer combination preparation are achieved.

[0075] Crosslinking: As used herein, the term “crosslinking” refers to the interaction and / or bonding between one entity and another to form a network. For example, in some embodiments, crosslinking present in a polymer network may be or include intramolecular crosslinking, intermolecular crosslinking, or both. In some embodiments, crosslinking may include the interaction and / or bonding between one polymer chain(s) and another polymer chain(s) to form a polymer network. In some embodiments, crosslinking may be achieved using one or more physical crosslinking techniques, which may include, for example, one or more environmental triggers and / or physiological interactions. Examples of environmental triggers include, but are not limited to, pH, temperature, and / or ionic strength. Non-exclusive examples of physiological interactions include hydrophobic interactions, charge interactions, hydrogen bonding interactions, stereocomplex formation, and / or supramolecular chemistry. In some embodiments, crosslinking may be achieved using one or more covalent crosslinking techniques based on chemical reactions (e.g., the bond between two entities is or includes a covalent bond), for example, in some embodiments, this may include reactions that form Schiff bases of aldehydes and amines, reactions that form hydrazines of aldehydes and hydrazides, and / or Michael reactions that form a secondary amine or sulfide of acrylic acid and either a primary amine or a thiol. Examples of such covalent crosslinking techniques include, but are not limited to, low molecular weight crosslinking and polymer-polymer crosslinking. Various methods for physical and covalent crosslinking of polymer chains are known in the art, for example, as described in Hoare and Kohane, “Hydrogels in drug delivery: Progress and challenges” Polymer (2008) 49:1993-2007 (the entire contents of which are incorporated herein by reference for the purposes described herein).

[0076] Crosslinking agent: As used interchangeably herein, the term “crosslinking agent” or “crosslinking agent” refers to an agent that links one entity (e.g., one polymer chain) to another entity (e.g., another polymer chain). In some embodiments, the bond between the two entities (i.e., “crosslinking”) is or includes a covalent bond. In some embodiments, the bond between the two entities is or includes an ionic bond or ionic interaction. In some embodiments, the crosslinking agent is a chemical crosslinking agent, which, for example, in some embodiments may be or include a low molecular weight (e.g., a dialdehyde or genipine) for inducing covalent bond formation between an aldehyde group and an amino group. In some embodiments, the crosslinking agent includes a photosensitive functional group. In some embodiments, the crosslinking agent includes a pH-sensitive functional group. In some embodiments, the crosslinking agent includes a heat-sensitive functional group.

[0077] Disease: As used herein, the term “disease” usually refers to a disorder or condition that impairs the normal function of a tissue or system in an object (e.g., a human object) and is usually characterized by distinctive signs and / or symptoms. Examples of diseases suitable for the technologies provided herein include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer’s disease, and hormone-related disorders. In some embodiments, cancer is a disease suitable for the technologies provided herein.

[0078] Effective dose: An "effective dose" is an amount sufficient to induce a desired biological response, for example, to treat a condition that a subject may be suffering from. As will be understood by those skilled in the art, the effective dose of a composition or the agent contained in such a composition may vary depending on factors such as the desired biological endpoint, the physical, chemical, and / or biological characteristics of the agent in the composition (e.g., pharmacokinetics and / or degradation), the condition being treated, and the age and health status of the subject. In some embodiments, the dose may be effective for a therapeutic treatment. Alternatively or additionally, in some embodiments, the dose may be effective for a preventive treatment. For example, in the treatment of cancer, the effective dose may prevent tumor regrowth, reduce tumor burden, or halt tumor growth or spread. Those skilled in the art will understand that the effective dose does not need to be contained in a single dosage form. Rather, the administration of an effective dose may require multiple doses over time (e.g., according to a dosage plan). For example, in some embodiments, the effective dose may be an amount administered in a dosage plan established to achieve a specific result with statistical significance when administered to an appropriate population.

[0079] Hydrate: As used herein, the term “hydrate” has the meaning understood in the art and refers to a compound (which may be in the form of a salt of the compound) and an aggregate of one or more water molecules. Typically, the number of water molecules contained in a hydrate of a compound is a constant ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may be represented, for example, by the general formula R × x H₂O, where R is the compound and x is a number greater than 0. A given compound may form two or more types of hydrates, including, for example, a monohydrate (where x is 1), a lower-order hydrate (where x is a number greater than 0 and less than 1 (e.g., a hemihydrate (R × 0.5 H₂O))), and a polyhydrate (where x is a number greater than 1 (e.g., a dihydrate (R × 2 H₂O) and a hexahydrate (R × 6 H₂O))).

[0080] Hydrogel: The term "hydrogel" has the meaning understood in the art and refers to a substance formed from a network of hydrophilic polymer chains, sometimes found as a colloidal gel with an aqueous phase as the dispersion medium. In some embodiments, a hydrogel is a natural or synthetic polymer network that is highly absorbent (e.g., capable of absorbing and / or retaining more than 90% water). In some embodiments, a hydrogel has a degree of flexibility comparable to that of a natural tissue, for example, due to their prominent water content.

[0081] Immunotherapy: The term "immunotherapy" refers to therapeutic drugs that promote the treatment of disease by inducing, enhancing, or suppressing the immune response. Immunotherapy designed to induce or amplify the immune response is classified as activating immunotherapy, while immunotherapy that reduces or suppresses the immune response is classified as suppressive immunotherapy. Immunotherapy is usually a biological drug, but not always. Numerous immunotherapies are used to treat cancer. These include, but are not limited to, monoclonal antibodies, adoptive cell transfer, cytokines, chemokines, vaccines, nucleic acids, small molecule inhibitors, and small molecule agonists. For example, useful immunotherapies may include, but are not limited to, type I interferon inducers, interferon, interferon gene stimulating factor (STING) agonists, TLR7 / 8 agonists, IL-15 superagonists, COX inhibitors (e.g., COX-1 inhibitors and / or COX-2 inhibitors), anti-PD-1 antibodies, anti-CD137 antibodies, and anti-CTLA-4 antibodies. In some embodiments, certain polymer combination preparations provided herein are immunomodulatory in the absence of immunotherapy (e.g., sufficiently to induce antitumor immunity) and therefore do not involve the administration of such immunotherapy as described herein.

[0082] Immunomodulatory Payload: As used herein, the term “immunomodulatory payload” means a separate immunomodulatory agent (e.g., a small molecule, a polypeptide (e.g., containing cytokines), a nucleic acid, etc.) that can be held by or dispersed in a polymer combination preparation (e.g., one provided and / or utilized herein), wherein the immunomodulatory agent provides a therapeutic effect by modulating or altering (e.g., inducing, enhancing, or suppressing) one or more aspects of the immune response in a subject. Examples of immunomodulatory payloads include, but are not limited to, activators of adaptive immune responses, activators of innate immune responses, inhibitors of pro-inflammatory pathways, immunomodulatory cytokines, or immunomodulatory therapeutic agents, as described in WO2018 / 045058 and WO2019 / 183216, and any combination thereof. The contents of the above-mentioned patent applications are incorporated herein by reference for the purposes described herein. In some embodiments, the immunomodulatory payload is or includes an innate immunomodulatory payload (e.g., an immunomodulatory payload that induces or stimulates innate immunity and / or one or more features of innate immunity). In some embodiments, the innate immunomodulatory payload is or includes an activator of the innate immune response. In some embodiments, the immunomodulatory payload is an adaptive immunomodulatory payload, e.g., an activator of the adaptive immune response. In some embodiments, the immunomodulatory payload is an inhibitor of a pro-inflammatory pathway, e.g., an inhibitor of a pro-inflammatory immune response mediated by the p38 mitogen-activated protein kinase (MAPK) pathway. In some embodiments, the immunomodulatory payload is or includes an immunomodulatory cytokine. In some embodiments, the immunomodulatory payload is or includes an immunomodulatory therapeutic agent. As will be understood by those skilled in the art, the immunomodulatory payload does not include components (e.g., precursor components) of polymer combination preparations (e.g., those described and / or utilized herein) and / or by-products generated by, for example, chemical reactions, enzymatic reactions, and / or biological reactions such as degradation.

[0083] Transplantation: The terms “transplantable,” “transplant,” “transplanting,” and “graft” refer to the placement of a composition of interest at a specific location on the subject, for example, within a tumor resection site or in a sentinel lymph node, typically by conventional surgical methods.

[0084] Increase, induce, or decrease: As used herein, these terms or grammatically equivalent comparative terms indicate values ​​relative to comparable reference measurements. For example, in some embodiments, an evaluation value obtained by a provided polymer combination preparation (e.g., in a precursor state or polymer network state) may be an "increase" compared to an evaluation value obtained by a comparable reference biomaterial preparation (e.g., a biomaterial of 18% (w / w) poloxamer 407 or a chemically crosslinked hydrogel, e.g., a chemically crosslinked hyaluronic acid hydrogel). Alternatively or additionally, in some embodiments, an evaluation value achieved in a subject may be an "increase" compared to an evaluation value obtained in the same subject under different conditions (e.g., before or after an event; or in the presence or absence of an event such as administration of a composition or preparation described and / or utilized herein), or in a different comparable subject (e.g., a comparable subject different from the subject of interest in prior exposure to the conditions, e.g., in a comparable subject not administered with a composition or preparation described and / or utilized herein). In some embodiments, the comparative term refers to a statistically significant difference (e.g., one with a sufficiently high incidence and / or magnitude to achieve a statistically significant relationship). A person skilled in the art will know, or be able to easily determine, the degree and / or incidence of the difference necessary or sufficient to achieve such a statistically significant difference in a given context.

[0085] Inhibition: The term “inhibition” or “to inhibit” is not limited to complete inhibition. Therefore, in some embodiments, partial inhibition or relative reduction falls within the scope of the term “inhibition.” For example, in the context of regulating the level of a target (e.g., expression and / or activity), the term, in some embodiments, refers to a reduction of the level of the target (e.g., expression and / or activity) to a level that is reproducibly and / or statistically significantly lower than, for example, an initial level that may be the baseline level of the target or another appropriate reference level. In some embodiments, this term refers to a reduction of the target level (e.g., expression and / or activity) to a level that is, for example, less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001%. In the context of the risk and / or incidence of tumor recurrence and / or metastasis, this term refers, in some embodiments, to a reduction in the risk or incidence of tumor recurrence and / or metastasis to a level that is reproducibly and / or statistically significantly lower than, for example, the initial level that may be the baseline level of the risk or incidence of tumor recurrence and / or metastasis in the absence of administration of the composition described herein, or before administration, or other appropriate reference levels. In some embodiments, this term refers to a reduction in the risk or incidence of tumor recurrence and / or metastasis to a level that may be less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% in the absence of or before administration of the compositions described herein.

[0086] Inhibitor: As used herein, the term “inhibitor” refers to a drug whose presence or level is associated with a reduction in the level or activity of a target being modulated. In some embodiments, the inhibitor may act directly (for example, by binding to the target and thus directly affecting that target). In some embodiments, the inhibitor may act indirectly (for example, by interacting with and / or altering modifiers of the target so that the level and / or activity of the target is reduced). In some embodiments, the inhibitor’s presence or level correlates with a level or activity of a target that is reduced compared to a particular reference level or activity (for example, one observed under appropriate reference conditions, e.g., in the presence of a known inhibitor or in the absence of an inhibitor disclosed herein).

[0087] Inhibitors of Pro-inflammatory Pathways: As used herein, the term “inhibitor of pro-inflammatory pathways” refers, in some embodiments, to agents that inhibit or reduce inflammation associated with immunosuppression. In some embodiments, such inhibitors of pro-inflammatory pathways refer to agents that prevent the recruitment of immunosuppressive cells or prevent acute inflammation. Such acute inflammation and / or recruitment of immunosuppressive cells may occur after local trauma, including that caused by surgery. In some embodiments, inhibitors of pro-inflammatory pathways may inhibit immune responses that induce inflammation, for example, including the production of inflammatory cytokines (including, but not limited to, TGF-β and IL-10), increased activity and / or proliferation of M2-like macrophages, and the recruitment of related immune cells, including, but not limited to, myeloid cells, neutrophils, and mast cells. Examples of inhibitors of pro-inflammatory pathways include, for example, those described in International Patent Application No. WO2019 / 183216 (the contents of which are incorporated herein in their entirety by reference for the purposes described herein).

[0088] Isomers: Compounds that have the same molecular formula but differ in the nature or order of their atomic bonding or the arrangement of their atoms in space are also called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers."

[0089] Lymph node: As is well known in the art, the term “lymph node” refers to a component of the lymphatic system, a small structure found throughout the body through which lymph fluid flows. Lymph nodes are known to filter certain substances from the lymph fluid. Lymph nodes may contain, for example, immune cells that can be involved in a systemic immune response. In some embodiments, a lymph node may be or include a sentinel lymph node (i.e., the lymph node from which cancer cells are most likely to spread from the primary tumor).

[0090] Marker: As used herein, a marker refers to an entity or part whose presence or level is characteristic of a particular condition or event. In some embodiments, the presence or level of a particular marker may be characteristic of the presence or stage of a disease, disorder, or condition. For example, in some embodiments, the term refers to a gene expression product that is characteristic of a particular tumor, tumor subclass, tumor stage, etc. Alternatively or additionally, in some embodiments, the presence or level of a particular marker correlates, for example, with the activity (or level of activity) of a particular signaling pathway that may be characteristic of a particular class of tumor. The statistical significance of the presence or absence of a marker may vary depending on the particular marker. In some embodiments, the detection of a marker is highly specific in that it reflects a high probability that the tumor belongs to a particular subclass. Such specificity may be achieved at the expense of sensitivity (i.e., a negative result may occur even if the tumor is expected to express that marker). Conversely, a marker with high sensitivity may have lower specificity than one with lower sensitivity. Those skilled in the art will understand that in many embodiments, a useful marker does not need to be identified with 100% accuracy.

[0091] Metastasis: The terms “metastasis,” “metastatic,” or “to metastasize” refer to the spread or migration of cancer cells from a primary tumor or initial tumor to another organ or tissue, and are typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the histological type of the primary tumor or original tumor, which is not of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has spread to the bone is called metastatic prostate cancer and contains cancerous prostate cancer cells that proliferate in bone tissue.

[0092] Microparticles: As used herein, the term “microparticles” refers to particles having a maximum dimension (e.g., diameter) of 1 micrometer to 1,000 micrometers (μm). In some embodiments, microparticles may feature a maximum dimension (e.g., diameter) of 1 μm to 500 μm. In some embodiments, microparticles may feature a maximum dimension (e.g., diameter) of 1 μm to 100 μm. In many embodiments, a population of microparticles features an average size (e.g., maximum dimension) of less than about 1,000 μm, less than about 500 μm, less than about 100 μm, less than about 50 μm, less than about 40 μm, less than about 30 μm, less than about 20 μm, or less than about 10 μm and often greater than about 1 μm. In many embodiments, microparticles may be substantially spherical (e.g., their maximum dimension may be their diameter).

[0093] Monosaccharide: As used herein, the term “monosaccharide” is given its common meaning as used in the art and refers to a simple form of sugar consisting of a single sugar unit that cannot be further broken down into smaller sugar units or parts. Common examples of monosaccharides include, for example, glucose (dextrose), fructose, galactose, mannose, and ribose. Monosaccharides can be classified according to the number of carbon atoms in the carbohydrate. For example, trioses having 3 carbon atoms, e.g., glyceraldehyde and / or dihydroxyacetone; tetroses having 4 carbon atoms, e.g., erythrose, threose, and / or erythrulose; pentoses having 5 carbon atoms, e.g., arabinose, lyxose, ribose, xylose, ribulose, and / or xylulose; hexoses having 6 carbon atoms, e.g., allose, altrose, galactose, glucose, growth, idose, mannose, talose, fructose, psicose, sorbose, and / or tagatose; heptoses having 7 carbon atoms, e.g., mannoheptulose and / or sedoheptulose; octose having 8 carbon atoms, e.g., 2-keto-3-deoxy-mannno-octonate; nonoses having 9 carbon atoms, e.g., sialose; and decorose having 10 carbon atoms. The above monosaccharides include D-monosaccharides and L-monosaccharides. Alternatively, a monosaccharide may be a monosaccharide variant in which the sugar unit contains one or more substituents other than a hydroxyl group (e.g., deoxy, H substituent, heteroatom substituent (e.g., S, Cl, F, etc.)). Such variants may be, but are not limited to, ethers, esters, amides, acids, phosphates, and amines. Examples of amine variants (i.e., amino sugars) include glucosamine, galactosamine, fructosamine, and / or mannosamine. Examples of amide variants include N-acetylated amine variants of sugars (e.g., N-acetylglucosamine and / or N-acetylgalactosamine).

[0094] Modulator: As used herein, the term “modulator” may be or include an entity whose presence or level in a system in which the activity of interest is observed correlates with a change in the level and / or properties of that activity compared to the level and / or properties observed under other comparable conditions in the absence of the modulator. In some embodiments, the modulator is an activator or agonist in which the activity of interest increases in its presence compared to the activity observed under other comparable conditions in the absence of the modulator. In some embodiments, the modulator is an antagonist or inhibitor in which the activity of interest decreases in its presence compared to other comparable conditions in the absence of the modulator. In some embodiments, the modulator directly interacts with the target entity of interest whose activity is of interest. In some embodiments, the modulator indirectly interacts with the target entity of interest whose activity is of interest (e.g., interacting with the target entity and / or interacting with one or more entities associated with the target entity). In some embodiments, the modulator affects the level of the target entity of interest. Alternatively or additionally, in some embodiments, the modulator affects the activity of the target entity of interest without affecting the level of the target entity. In some embodiments, the modulator affects both the level and activity of the target entity of interest, and as a result, the observed difference in activity is not fully explained by or commensurate with the observed difference in level.

[0095] Macrophage Effector Function Modulators: The term "macrophage effector function modulator" refers to a substance that activates macrophage effector function or reduces immunosuppressive macrophages or macrophage-derived suppressor cells. Such enhancement can mobilize macrophages and bone marrow components to destroy their substrates, including tumors and tumor vascular systems. Macrophages may be induced to secrete antitumor cytokines and / or perform phagocytosis, which includes antibody-dependent cell phagocytosis.

[0096] Neutrophil Function Modulators: The terms “neutrophil modulator” and “neutrophil function modulator,” as used interchangeably herein, refer to modulators of one or more biological functions and / or phenotypes of neutrophils. For example, in some embodiments, a neutrophil function modulator may inhibit neutrophil recruitment, survival, and / or proliferation. Additionally or alternatively, in some embodiments, a neutrophil function modulator may modulate neutrophil-related effector functions, including, but not limited to, the regulation of the production and / or secretion of one or more immunomodulatory molecules (e.g., immunomodulatory cytokines and / or chemokines), and / or alter the ability of neutrophils to alter the extracellular matrix. In some embodiments, a neutrophil function modulator (e.g., those described herein) may act only on neutrophils or target only neutrophils. In some embodiments, a neutrophil function modulator (e.g., as described herein) may act on neutrophils and at least one additional immune cell, such as myeloid-derived suppressor cells (MDSCs), macrophages, and / or other subsets of monocytes.Those skilled in the art will understand that at least one subset of neutrophils may exhibit similar immunoactivity to one or more specific subsets of MDSCs and thus may be considered polymorphonuclear MDSCs and / or granulocyte-type MDSCs (see, for example, Mehmeti-Ajradini et al., “Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer,” Life Science Alliance, September 21, 2020, and Brandau et al., “A subset of mature neutrophils contains the strongest PMN-MDSC activity in blood and tissue of patients with head and neck cancer,” The Journal of Immunology, May 1, 2020 (the contents of each of these are incorporated herein by reference for the purposes described herein)).

[0097] Nanoparticles: As used herein, the term “nanoparticles” refers to particles having a longest dimension (e.g., diameter) of less than 1,000 nanometers (nm). In some embodiments, nanoparticles may feature a longest dimension (e.g., diameter) of less than 300 nm. In some embodiments, nanoparticles may feature a longest dimension (e.g., diameter) of less than 100 nm. In many embodiments, nanoparticles may feature a longest dimension of about 1 nm to about 100 nm, about 1 μm to about 500 nm, or about 1 nm to 1,000 nm. In many embodiments, a population of nanoparticles may feature an average size (e.g., longest dimension) of less than about 1,000 nm, less than about 500 nm, less than about 100 nm, less than about 50 nm, less than about 40 nm, less than about 30 nm, less than about 20 nm, or less than about 10 nm and often greater than about 1 nm. In many embodiments, nanoparticles may be substantially spherical, and as a result, their longest dimension may be their diameter. In some embodiments, the nanoparticles have a diameter of less than 100 nm, as defined by the National Institutes of Health.

[0098] Neoplasms and Tumors: The terms “neoplasm” and “tumor” are used interchangeably herein and refer to abnormal masses of tissue whose growth exceeds and does not coordinate with the growth of normal tissue. Neoplasms or tumors may be “benign” or “malignant” depending on the following characteristics: degree of cellular differentiation (including morphology and function), growth rate, local invasion, and metastasis. “Benign neoplasms” are generally well-differentiated, have characteristically slower growth than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms do not have the ability to invade, invade, or metastasize to distal sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromes, adenomas, acrochordon, senile hemangiomas, seborrheic keratosis, lentigo, and sebaceous gland hyperplasia. In some cases, certain "benign" tumors can later develop into malignant neoplasms, which may result from further genetic changes in a subpopulation of tumor cells; these tumors are referred to as "pre-malignant neoplasms." An example of a pre-malignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and characterized by rapid growth accompanied by progressive invasion, invasion, and destruction of surrounding tissue. Furthermore, malignant neoplasms generally have the ability to metastasize to distal sites.

[0099] Payload: Generally, as used herein, the term “payload” refers to a drug that may be incorporated into the polymer combination preparations described herein. In some embodiments, the payload may refer to a compound, molecule, or entity of any chemical classification, including, for example, small molecules, peptides, polypeptides, nucleic acids, sugars (e.g., polysaccharides), lipids, metals, or combinations or complexes thereof. In some embodiments, the payload may be or include biological modifiers, detectable drugs (e.g., dyes, fluorophores, radiolabels, etc.), detection reagents, nutrients, therapeutic agents, minerals, growth factors, cytokines, antibodies, hormones, extracellular matrix proteins (e.g., collagen, vitronectin, fibrin, etc.), extracellular matrix sugars, chemoattractants, polynucleotides (e.g., DNA, RNA, antisense molecules, plasmids, etc.), microorganisms (e.g., viruses), etc., or combinations thereof. In some embodiments, the payload is or includes a therapeutic agent. Examples of therapeutic agents include, but are not limited to, analgesics, antibiotics, antibodies, anticoagulants, antiemetics, cells, coagulants, cytokines, growth factors, hormones, immunomodulators, polynucleotides (e.g., DNA, RNA, antisense molecules, plasmids, etc.), and combinations thereof. In some embodiments, the payload may be or include cells or organisms, or fractions, extracts, or components thereof. In some embodiments, the payload may be or include natural products in that they are found and / or obtained in nature. Alternatively or additionally, in some embodiments, this term may be used to refer to one or more entities that are artificial in that they are designed, manipulated and / or produced by human hands and / or not found in nature. In some embodiments, the payload may be or include a drug in an isolated or pure form. In some embodiments, such a drug may be in a crude form.

[0100] pharmaceutically acceptable salts: The term “pharmaceutically acceptable salt” refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with, for example, human and / or animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (their contents are incorporated herein by reference for the purposes described herein). Examples of pharmaceutically acceptable salts that may be used according to certain embodiments of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed by inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or by organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfons, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptons, glycerophosphates, glucons, hemisulfates, heptanoates, hexanoates, hydroiodides, and 2-hydroxyethanesulfonic acid. Examples of salts include lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, and valersates. Salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium, and N+ (C1-4 alkyl)4 - Examples include salts. Typical alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, and magnesium salts. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0101] Poloxamer: As used herein, the term “poloxamer” refers to a polymer preparation of one or more poloxamers, or a polymer preparation containing one or more poloxamers. In some embodiments, the poloxamers in the polymer preparation may not be conjugated or modified, for example, this is typically a triblock copolymer containing a hydrophobic chain of polyoxypropylene (polypropylene glycol, PPG) sandwiched between two hydrophilic chains of polyoxyethylene (polyethylene glycol, PEG). In some embodiments, the polymer preparation of one or more poloxamers or a polymer preparation containing one or more poloxamers may not be filtered (for example, such a polymer preparation may contain impurities and / or polymer molecules with relatively low molecular weight compared to an equivalent filtered polymer preparation). Examples of poloxamers, though not limited to them, include poloxamer 124 (P124, also known as Pluronic L44 NF), poloxamer 188 (P188, also known as Pluronic F68 NF), poloxamer 237 (P237, also known as Pluronic F87 NF), poloxamer 338 (P338, also known as Pluronic F108 NF), poloxamer 407 (P407, also known as Pluronic F127 NF), and combinations thereof.

[0102] Polymer: The term "polymer" is given its common meaning as used in the art, namely, a molecular structure comprising one or more repeating units (monomers) linked by covalent bonds. The repeating units may all be identical, or there may be two or more types of repeating units present in the polymer (e.g., copolymer). In certain embodiments, the polymer is naturally occurring. In certain embodiments, the polymer is synthetic (i.e., not naturally occurring). In some embodiments, the polymer is a linear polymer. In some embodiments, the polymer is a branched polymer. In some embodiments, the polymer for use according to this disclosure is not a polypeptide. In some embodiments, the polymer for use according to this disclosure is not a nucleic acid.

[0103] Polymer combination preparations: As used herein, the term “polymer combination preparation” refers to a polymer biomaterial comprising at least two distinct polymer components. For example, in many embodiments, the polymer combination preparations described herein are polymer biomaterials comprising a first polymer component and a second first polymer component, wherein the first polymer component is or comprises at least one poloxamer, and the second polymer component is or comprises a polymer that is not a poloxamer. In some embodiments, the polymer combination preparations described herein are, for example, precursor polymer biomaterials that may be useful for administration to a subject. In some embodiments, the polymer combination preparations described herein are polymer biomaterials in a polymer network state.

[0104] Polymeric Biomaterials: “Polymeric biomaterials” are materials that are biocompatible and comprise at least one polymer or at least one polymer portion, as described herein. In many embodiments, polymeric biomaterials comprise at least one polymer. In some embodiments, the polymer may be a copolymer or comprise a copolymer. In some embodiments, polymeric biomaterials comprise preparations of at least two distinct polymer components (e.g., preparations comprising a poloxamer and a second polymer component that is not a poloxamer) or comprise a copolymer. Those skilled in the art will know that a particular polymer may exist and / or be available in various forms (e.g., length, molecular weight, charge, topography, interfacial chemistry, degree and / or type of modification, e.g., alkylation, acylation, quaternization, hydroxyalkylation, carboxyalkylation, thiolation, phosphorylation, glycosylation, etc.). In some embodiments, preparations of such polymers may comprise such or more forms at a specified level and / or distribution. Those skilled in the art will understand that, in some embodiments, one or more immunomodulatory properties of a polymer biomaterial may be tuned by biomaterial properties of the polymer biomaterial, including, for example, the interfacial chemistry of the polymer biomaterial (tuned by, for example, the hydrophobic and / or hydrophilic parts, chemical parts, and / or charge properties of the polymer biomaterial) and / or the topography of the polymer biomaterial (tuned by, for example, the size, shape, and / or surface texture), as described, for example, Mariani et al. “Biomaterials: Foreign Bodies or Tuners for the Immune Response?” International Journal of Molecular Sciences, 2019, 20, 636.

[0105] Polymer Networks: The term “polymer network” is used herein to describe an assembly of polymer chains that interact with one another. In some embodiments, polymer networks form three-dimensional structural materials. In some embodiments, polymer networks may be formed by linking polymer chains using crosslinking agents (e.g., as described herein) (“crosslinked polymer network”). In some embodiments, polymer networks are transitioned from a precursor state when the precursor state is exposed to a temperature above its critical gelation temperature, wherein the polymer network state has a viscosity substantially greater than that of the precursor state (e.g., at least 50%), and the polymer network state includes crosslinks that were not present in the precursor state. In some embodiments, polymer networks may be formed by non-covalent or non-ionic intermolecular bonds of polymer chains, for example, by hydrogen bonds. In some embodiments, polymer networks may be formed by a combination of chemical crosslinking of polymer chains and non-covalent or non-ionic intermolecular bonds of polymer chains.

[0106] Prodrug: The term "prodrug" refers to a form of an active compound that contains one or more cleavable groups that are removed by solvolysis or under physiological conditions so that the active compound is released. Exemplary prodrug forms include, but are not limited to, choline ester derivatives and N-alkylmorpholine esters. In some embodiments, the prodrug may be an acid derivative, such as an ester prepared by reaction with a suitable hydrophilic alcohol, an amide, acid anhydride, or mixed anhydride prepared by reaction with a substituted or unsubstituted amine of a hydrophilic compound, as is known in the art. Simple aliphatic or aromatic esters, amides, and anhydrides derived from the acidic group associated with the compound of interest are specific examples of prodrug forms. In some cases, it may be desirable to prepare double ester prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters of the compound of interest, C1-C8 alkyl esters, C2-C8 alkenyl esters, C2-C8 alkynyl esters, aryl esters, C7-C12 substituted aryl esters, and C7-C12 arylalkyl esters.

[0107] Inflammatory cytokines: As used herein, the term “inflammatory cytokines” refers to proteins or glycoprotein molecules secreted by cells that induce an inflammatory response (e.g., cells of the immune system). As will be understood by those skilled in the art, inflammation can be immunostimulant or immunosuppressive, depending on the biological context.

[0108] Pro-inflammatory immune response: As used herein, the term “pro-inflammatory immune response” refers to an immune response that induces inflammation, including, for example, the production of inflammatory cytokines (including, but not limited to, CXCL10, IFN-α, IFN-β, IL-1β, IL-6, IL-18, and / or TNF-α), increased Th1 cell activity and / or proliferation, recruitment of myeloid cells, and the like. In some embodiments, the pro-inflammatory immune response may be or may include either or both acute inflammation and chronic inflammation.

[0109] Proliferative disorders: “Proliferative disorders” refer to diseases caused by abnormal growth or expansion due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative disorders may be associated with 1) pathological proliferation of normally quiescent cells, 2) pathological migration of cells from their normal locations (e.g., metastasis of neogenes), 3) pathological expression of proteases such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase), or 4) pathological angiogenesis, such as in proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis or angiogenesis-related diseases, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0110] Prophylactically Effective Dose: A “prophylactically effective dose” is an amount sufficient to prevent a condition (for example, significantly delaying the onset or recurrence of one or more symptoms or characteristics of the condition, so that, for example, it / they are not detected at the time they would be expected without such dose). The prophylactically effective dose of a composition means the amount of the therapeutic agent, alone or in combination with other agents, that provides a preventive effect in the prevention of a condition. The term “prophylactically effective dose” may include an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent. Those skilled in the art will understand that a prophylactically effective dose does not need to be contained in a single dosage form. Rather, an effective dose may require multiple doses over time (e.g., according to a dosage schedule).

[0111] Risk: As understood from the context, the “risk” of a disease, disorder, and / or condition refers to the likelihood that a particular individual will develop that disease, disorder, and / or condition. In some embodiments, the risk is expressed as a percentage. In some embodiments, the risk is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, up to 100%. In some embodiments, the risk is expressed as a risk relative to a reference sample or group of reference samples. In some embodiments, the reference sample or group of reference samples has a known risk of the disease, disorder, condition, and / or event. In some embodiments, the reference sample or group of reference samples is derived from an individual comparable to a particular individual. In some embodiments, the relative risk is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or higher. In some embodiments, risk may reflect one or more genetic traits that may (or may not) predispose an individual to developing a particular disease, disorder, and / or condition. In some embodiments, risk may reflect one or more epigenetic events or epigenetic traits and / or one or more lifestyle or environmental events or environmental traits.

[0112] Salt: As used herein, the term “salt” means all salts, including pharmaceutically acceptable salts.

[0113] Sample: As used herein, the term “sample” typically refers to an aliquot of a substance obtained from or derived from a source of interest, as described herein. In some embodiments, the source of interest is a biological or environmental source. In some embodiments, the source of interest may be or may include cells or organisms, such as microorganisms, plants, or animals (e.g., humans). In some embodiments, the source of interest may be or may include biological tissues or biological fluids. In some embodiments, biological tissue or bodily fluid may be or include amniotic fluid, aqueous humor, ascites, bile, bone marrow, blood, breast milk, cerebrospinal fluid, earwax, chyle, porridge, ejaculated semen, endolymph, exudate, feces, gastric acid, gastric juice, lymph, mucus, pericardial fluid, perilymph, peritoneal fluid, pleural fluid, pus, mucosal secretions, saliva, sebum, semen, serum, smegma, sputum, synovial fluid, sweat, tears, urine, vaginal secretions, vitreous fluid, vomit, and / or combinations or components thereof. In some embodiments, bodily fluid may be or include intracellular fluid, extracellular fluid, intravascular fluid (plasma), interstitial fluid, lymph, and / or cell permeable fluid. In some embodiments, bodily fluid may be or include plant exudate. In some embodiments, biological tissue or biological specimens may be obtained, for example, by aspiration, biopsy (e.g., fine-needle biopsy or tissue biopsy), swab (e.g., oral swab, nasal swab, skin swab, or vaginal swab), scraping, surgery, washing or washing (e.g., bronchoalveolar lavage or washing solution, tubal lavage or washing solution, nasal lavage or washing solution, eye lavage or washing solution, oral lavage or washing solution, uterine lavage or washing solution, vaginal lavage or washing solution, or other washing or washing solution). In some embodiments, the biological specimen is or contains cells obtained from an individual. In some embodiments, the specimen is a “primary specimen” obtained directly from a source of interest by any suitable means. In some embodiments, as is evident from the context, the term “specimen” refers to a preparation obtained by processing a primary specimen (e.g., by removing one or more components of the primary specimen and / or by adding one or more agents). For example, filtration using a semipermeable membrane.Such “processed sample” may include, for example, nucleic acids or proteins extracted from the sample, or obtained by subjecting the primary sample to one or more techniques such as nucleic acid amplification or reverse transcription, isolation and / or purification of a particular component.

[0114] Low molecular weight: The term “low molecular weight” or “low molecular weight therapeutic” refers to molecules with a relatively low molecular weight, whether naturally occurring or artificially produced (e.g., by chemical synthesis). Typically, low molecular weights are organic compounds (i.e., they contain carbon). Low molecular weights may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, and heterocyclics). In certain embodiments, the molecular weight of a low molecular weight is about 1,000 g / mol or less, about 900 g / mol or less, about 800 g / mol or less, about 700 g / mol or less, about 600 g / mol or less, about 500 g / mol or less, about 400 g / mol or less, about 300 g / mol or less, about 200 g / mol or less, or about 100 g / mol or less. In certain embodiments, the molecular weight of the low molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol and less than or equal to about 500 g / mol) are also possible. In certain embodiments, the low molecule is a therapeutic agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration, as listed in the Code of Federal Regulations (CFR)). The low molecule may form complexes with one or more metal atoms and / or metal ions. In this example, the low molecule is also referred to as an “organometallic low molecule”. Preferred low molecules are biologically active in that they produce biological effects in animals, preferably mammals, and more preferably humans. Examples of small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, but not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate government or regulatory body.For example, drugs approved for human use are listed by the FDA pursuant to 21C.FR §§330.5, 331-361, and 440-460, which are incorporated herein by reference, and drugs for veterinary use are listed by the FDA pursuant to 21C.FR §§500-589 (the contents of each of these are incorporated herein by reference for the purposes described herein). Such listed drugs are generally considered acceptable for use as described herein.

[0115] Solvates: As used herein, the term “solvate” has the meaning understood in the art and refers to a compound (which may be, for example, a salt of the compound) and aggregates of one or more solvent atoms or molecules. In some embodiments, the solvate is a liquid. In some embodiments, the solvate is in solid form (for example, crystalline form). In some embodiments, solvates in solid form are suitable for isolation. In some embodiments, the association between the solvent atom(s) in the solvate and the compound is a non-covalent association. In some embodiments, such association is or includes hydrogen bonding, van der Waals interaction, or a combination thereof. In some embodiments, the solvent, whose atoms(s) are included in the solvate, may be or include one or more of water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. Preferred solvates may be pharmaceutically acceptable solvates. In some specific embodiments, the solvate is a hydrate, an ethanol adduct, or a methanol adduct. In some embodiments, the solvate may be a stoichiometric solvate or a non-stoichiometric solvate.

[0116] Target: The “targets” to whom administration is intended include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., crab-eating macaques, rhesus macaques); domestic animals, e.g., cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds (e.g., chickens, ducks, geese, and / or turkeys)). In certain embodiments, the animal is a mammal (e.g., at any developmental stage). In some embodiments, the animal (e.g., a non-human animal) may be a transgenic animal or a genetically modified animal. In some embodiments, the target is a subject undergoing tumor resection, e.g., a subject who has recently undergone tumor resection. In some embodiments, the subjects of tumor resection are those who underwent tumor resection less than 72 hours prior to administration of the composition described herein (e.g., less than 48 hours, less than 24 hours, less than 12 hours, less than 6 hours, or shorter). In some embodiments, the subjects of tumor resection are those who underwent tumor resection less than 48 hours prior to administration of the composition described herein. In some embodiments, the subjects of tumor resection are those who underwent tumor resection less than 24 hours prior to administration of the composition described herein. In some embodiments, the subjects of tumor resection are those who underwent tumor resection less than 12 hours prior to administration of the composition described herein.

[0117] Substantial: As used herein, the term “substantial” refers to a qualitative state that exhibits a characteristic or feature of the subject of interest to a complete or near-complete degree. Those skilled in the art will understand that the agent of interest will not, if any, achieve or avoid absolute results, for example, that the agent of interest will not actually have an effect on an immune response, for example, inflammation. Accordingly, the term “substantial” is used herein to express the possibility of a lack of absoluteness inherent in many biological and chemical effects.

[0118] Sustained: As used interchangeably herein, the terms “extended” or “sustained” typically refer to prolonging an effect and / or process over a desired period of time. For example, in the context of sustained immunomodulation (e.g., in the presence of compositions or preparations described and / or utilized herein), such immunomodulatory effects may be observed for a longer period in the context of compositions containing biomaterial preparations, and otherwise, as described herein, after administration of a particular immunomodulatory payload compared to those observed with administration of the same payload in the absence of such biomaterial preparations. In the context of sustained release of one or more agents of interest from compositions and / or preparations described herein over a period of time (e.g., one or more aspects of an immune response, e.g., modulating innate immune agonism, e.g., payloads incorporated into polymer combination preparations described herein and / or degradation or dissolution products and / or soluble components of polymer combination preparations described herein), such release may occur on a timescale ranging from about 30 minutes to several weeks. In some embodiments, the degree of sustained or prolonged release can be characterized in vitro or in vivo. For example, in some embodiments, the release kinetics can be tested in vitro by placing the preparations and / or compositions described herein in an aqueous buffer (e.g., PBS at pH 7.4). In some embodiments, when the preparations and / or compositions described herein are placed in an aqueous buffer (e.g., PBS at pH 7.4), one or more agents of interest (e.g., less than 100% (including less than 90%, less than 80%, less than 70%, less than 50%, or less) are released from the biomaterial within 3 hours.In some embodiments, the release kinetics can be tested in vivo by, for example, implanting the composition into a target site (e.g., mammary gland fat pad) of an animal subject (e.g., a mouse subject). In some embodiments, when the composition is implanted into a target site (e.g., a mammary gland fat pad) of an animal subject (e.g., a mouse subject), 70% or less (including, for example, 60% or less, 50% or less, less than 40%, less than 30%, or less) of one or more agents of interest (e.g., one or more aspects of the immune response, e.g., modulating innate immune agonism, etc., the payload incorporated into the polymer combination preparation described herein and / or the degradation or lysis products and / or soluble components of the polymer combination preparation described herein) are released in vivo 8 hours after implantation.

[0119] Targeted Therapy: When used in relation to anticancer drugs, the term "targeted therapy" refers to drugs that inhibit the growth and spread of cancer by interfering with specific molecules ("molecular targets") involved in the growth, progression, and / or spread of cancer. Targeted therapy is sometimes referred to as "targeted cancer therapy," "molecular targeted drugs," "molecular targeted therapy," or "precision medicine." Targeted therapy differs from conventional chemotherapy in that targeted drugs act on specific molecular targets that are typically associated with cancer and / or a particular tumor or tumor type, stage, etc., while many chemotherapeutic drugs act on all rapidly dividing cells (for example, whether the cells are cancerous or not). Targeted therapy drugs are strategically selected or designed to interact with their targets, while many standard chemotherapeutic drugs are identified because they kill cells.

[0120] Tautomers: The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from the formal transfer of at least one hydrogen atom and a change in at least one bond valence (e.g., single bond to double bond, triple bond to double bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that yields a tautomer pair) can be catalyzed by an acid or a base. Exemplary tautomerizations include tautomerization from keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different) enamine.

[0121] Subject of study: As used herein, the term “subject of study” refers to a subject to which the techniques provided herein are applied for experimental studies to evaluate the efficacy of the compositions and / or preparations described herein in, for example, the degradation of biomaterials and / or antitumor immunity. In some embodiments, the subject of study may be a human subject or a population of human subjects. For example, in some embodiments, a human subject of study may be a normal, healthy subject. In some embodiments, a human subject of study may be a subject of tumor resection. In some embodiments, the subject of study may be a non-human mammal or a population of non-human mammals. Non-limiting examples of such non-human mammals include mice, rats, dogs, pigs, rabbits, etc., which may be normal, healthy subjects in some embodiments, while in some embodiments they may be subjects of tumor resection. In some embodiments, a non-human mammal may be a transgenic animal or a genetically modified animal.

[0122] Therapeutic Agent: The term “therapeutic agent” refers to a drug having one or more properties that produce a desired and generally beneficial physiological effect. For example, a therapeutic agent may treat, improve, and / or prevent a disease. A person skilled in the art reading this disclosure will understand that, as used herein, the term “therapeutic agent” does not require a particular level or type of therapeutic activity that a regulatory body may need to consider a drug to be “therapeutic” for regulatory purposes. As will be understood by a person skilled in the art reading this disclosure, in some embodiments, certain polymer combination preparations described herein (in the absence of an immunomodulatory payload) may have one or more properties that contribute to and / or achieve a desired physiological effect and may therefore be considered a “therapeutic agent” (whether or not such biomaterial is considered pharmaceutically active by any particular regulatory body), which is the same as the term “therapeutic agent” as used herein. In some embodiments, therapeutic agents that may be used in preparations, compositions, and / or methods described herein (e.g., requiring a polymer combination preparation described herein) do not include an immunomodulatory payload (e.g., described herein). In some embodiments, the therapeutic agents that can be used in the preparations, compositions, and / or methods described herein (for example, requiring the polymer combination preparations described herein) may be or include immunomodulatory payloads. In some embodiments, the therapeutic agents that can be used in the preparations, compositions, and / or methods described herein (for example, requiring the polymer combination preparations described herein) may be or include non-immunomodulatory payloads, such as biological agents, small molecules, nucleic acids, polypeptides, or combinations thereof. In some embodiments, the therapeutic agents that can be used in the preparations, compositions, and / or methods described herein (for example, requiring the polymer combination preparations described herein) may, in some embodiments, be cytotoxic agents, or include chemotherapeutic agents.

[0123] Therapeutic Dose: A “therapeutic dose” is a quantity sufficient to provide a therapeutic effect in the treatment of a condition, which may include, for example, a reduction in frequency and / or severity and / or a delay in the onset of one or more characteristics or symptoms associated with the condition. A therapeutic dose means the quantity(s) of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic effect in the treatment of a condition. The term “therapeutic dose” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of the condition, or enhances the therapeutic effect of another therapeutic agent. Those skilled in the art will understand that a therapeutic dose does not necessarily have to be contained in a single dosage form. Rather, an effective dose may require multiple doses, sometimes over time (e.g., according to a dosage regimen, particularly one established to provide the appropriate effect with the desired degree of statistical reliability when applied to an appropriate population).

[0124] Temperature Responsiveness: As used herein, in the context of temperature-responsive polymers or biomaterials (e.g., polymer biomaterials), the term “temperature responsiveness” means a polymer or biomaterial (e.g., polymer biomaterial) that exhibits an instantaneous or intermittent change at a critical temperature (e.g., critical gelation temperature) in one or more of its properties. For example, in some embodiments, one or more of such properties is or includes the solubility of the polymer or biomaterial in a particular solvent. As merely an example, in some embodiments, the temperature-responsive polymer or biomaterial (e.g., polymer biomaterial) is a homogeneous polymer solution or colloid that is stable below a critical temperature (e.g., critical gelation temperature) and is characterized by instantaneously forming a polymer network (e.g., hydrogel) when the critical temperature (e.g., critical gelation temperature) is reached or exceeded. In some embodiments, the temperature-responsive polymer or biomaterial (e.g., polymer biomaterial) may be temperature-reversible, where, for example, in some embodiments, the polymer solution may instantaneously form a polymer network at or above its critical gelation temperature, and such obtained polymer network may instantaneously revert to a homogeneous polymer solution when the temperature drops below the critical gelation temperature.

[0125] Treatment: The terms “treatment,” “to treat,” and “to treat” mean “a condition” as described herein (e.g., a disease, disorder, or state, including one or more signs or symptoms thereof), such as reducing, alleviating, delaying the onset of, or inhibiting the progression of cancer or a tumor. In some embodiments, treatment may be administered after one or more signs or symptoms have developed or been observed. Treatment may be continued after the symptoms have subsided, for example, to delay or prevent recurrence and / or spread.

[0126] Tumor: The terms “tumor” and “neoplasm” are used interchangeably herein and refer to an abnormal mass of tissue whose growth exceeds and does not coordinate with the growth of normal tissue. Neoplasms or tumors may be “benign” or “malignant” depending on the following characteristics: degree of cellular differentiation (including morphology and function), growth rate, local invasion, and metastasis. “Benign neoplasms” are generally well-differentiated, have characteristically slower growth than malignant neoplasms, and remain localized at the site of origin. In addition, benign neoplasms do not have the ability to invade, invade, or metastasize to distal sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromes, adenomas, acrochordon, senile hemangiomas, seborrheic keratosis, lentigo, and sebaceous gland hyperplasia. In some cases, certain "benign" tumors can later develop into malignant neoplasms, which may result from further genetic changes in a subpopulation of tumor cells; these tumors are referred to as "pre-malignant neoplasms." An example of a pre-malignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and characterized by rapid growth accompanied by progressive invasion, invasion, and destruction of surrounding tissue. Furthermore, malignant neoplasms generally have the ability to metastasize to distal sites.

[0127] Tumor Removal: As used herein, the term “tumor removal” encompasses the partial or complete removal of a tumor that may result from cancer treatment, such as surgical resection. In some embodiments, tumor removal refers to the physical removal of part or all of a tumor by surgery (i.e., “tumor resection”). In some embodiments, tumor removal may result from surgical tumor resection and adjuvant therapy (e.g., chemotherapy, immunotherapy, and / or radiotherapy). In some embodiments, adjuvant therapy may be administered after surgical tumor resection, for example, at least 24 hours after surgical tumor resection.

[0128] Subjects undergoing tumor resection: As used herein, the term “subjects undergoing tumor resection” refers to subjects who have undergone or recently undergone tumor resection. In some embodiments, subjects undergoing tumor resection are subjects from which at least 70% (including at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or more (including 100%)) of the total tumor weight has been removed by surgical resection. In some cases, even if macroscopic examination indicates that all of the total tumor weight has been clearly removed, those skilled in the art will understand that there may be some residual cancer cells microscopically present at the visible resection margins. In some embodiments, subjects undergoing tumor resection may be determined to have negative resection margins (i.e., no cancer cells are microscopically observed at the resection margins, for example, based on histological evaluation of the tissue surrounding the tumor resection site). In some embodiments, subjects undergoing tumor resection may be determined to have positive resection margins (i.e., cancer cells are microscopically observed at the resection margins, for example, based on histological evaluation of the tissue surrounding the tumor resection site). In some embodiments, the subject of tumor resection may have micrometastatic lesions and / or dormant disseminated cancer cells that may be promoted to progress / proliferate by a physiological response to the surgery. In some embodiments, the subject of tumor resection is administered a composition (e.g., administered during surgery) immediately after the tumor resection is performed. In some embodiments, the subject of tumor resection is administered a composition (e.g., administered within 24 hours or less after surgery (e.g., within 18 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 30 minutes, or less).

[0129] Tumor site: In some embodiments, the term “tumor site” may be the site where at least a portion of the tumor is present or was present before the resection. In some embodiments, the tumor site may still have the entirety of the present tumor. On the other hand, in some embodiments, the tumor site may have had part or all of the tumor removed, for example, by tumor resection.

[0130] Variant: As used herein, the term “variant” refers to a substance that exhibits significant structural identity with a reference substance but is structurally different from the reference substance in the presence or level of one or more chemical moieties. In many embodiments, a variant is also functionally different from its reference substance. Generally, whether a particular substance is considered a “variant” of a reference substance depends on the degree of structural identity with the reference substance. As will be understood by those skilled in the art, any biological or chemical reference substance has certain characteristic structural elements. By definition, a variant is a different chemical substance that shares one or more such characteristic structural elements. To give only a few examples, small molecules may have a characteristic core structural element (e.g., a macroring core) and / or one or more characteristic pendant portions, so that variants of small molecules share the core structural element and characteristic pendant portions but differ in the types of bonds present in the other pendant portions and / or within the core (e.g., single-paired-double, E-paired-Z); polypeptides may have a characteristic sequence element consisting of multiple amino acids that have designated positions in a linear or three-dimensional space and / or contribute to a specific biological function; nucleic acids may have a characteristic sequence element consisting of multiple nucleotide residues that have designated positions in a linear or three-dimensional space. For example, a variant biomaterial (e.g., a variant polymer or a polymer biomaterial containing a variant polymer) may differ from a reference biomaterial (e.g., a reference polymer or a reference polymer biomaterial) as a result of one or more structural modifications (e.g., addition, removal, and / or modification of chemical moieties, and / or grafting), provided that the variant biomaterial (e.g., a variant polymer or a polymer biomaterial containing such a variant polymer) may retain desired properties (multiple properties) and / or functions (multiple properties) (e.g., immunomodulation and / or temperature responsiveness) of the reference biomaterial.For example, variants of immunomodulatory biomaterials may differ from immunomodulatory reference biomaterials (e.g., reference polymers or reference polymer biomaterials) as a result of one or more structural modifications (e.g., addition, removal, and / or modification of chemical moieties, and / or grafting), provided that the variant biomaterials (e.g., variant polymers or polymer biomaterials containing such variant polymers) may act on the immune system (e.g., by stimulating innate immunity) when used, for example, in the methods described herein. In some embodiments, an immunomodulatory variant biomaterial (e.g., a variant polymer or a polymer biomaterial containing a variant polymer) is characterized in that, when evaluated 24 hours after administration of such immunomodulatory variant biomaterial (e.g., a variant polymer or a polymer biomaterial containing a variant polymer) to a target site of a subject, the amount of one or more inflammatory cytokines (e.g., but not limited to CXCL10, IFN-α, IFN-β, IL-1β, IL-6, IL-18, and / or TNF-α) observed at the target site of the subject and / or in systemic circulation is at least 60% or more (e.g., at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or up to 100%) of the amount observed when a reference biomaterial (e.g., a reference polymer or a reference polymer biomaterial) is administered to the target site.In some embodiments, an immunomodulatory variant biomaterial (e.g., a variant polymer or a polymer biomaterial containing a variant polymer) is characterized in that, when evaluated 24 hours after administration of such variant biomaterial (e.g., a variant polymer or a polymer biomaterial containing a variant polymer) to a target site of a subject, the amount of one or more inflammatory cytokines (e.g., but not limited to CXCL10, IFN-α, IFN-β, IL-1β, IL-6, IL-18, and / or TNF-α) observed at the target site of the subject and / or in systemic circulation is at least 1.1 times or more (e.g., at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, or more) the amount observed when a reference biomaterial (e.g., a reference polymer biomaterial) is administered to the target site. In some embodiments, the variant biomaterial (e.g., a variant polymer biomaterial) exhibits at least one physical property that differs from that of the reference biomaterial (e.g., a reference polymer biomaterial). For example, in some embodiments, the variant biomaterial (e.g., the variant polymer biomaterial) may exhibit increased water solubility compared to the water solubility (e.g., at physiological pH) of the reference biomaterial (e.g., the reference polymer biomaterial). In some embodiments, the variant has 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 structural modification compared to the reference. In some embodiments, the variant has a small number (e.g., fewer than 5, 4, 3, 2, or 1) structural modifications (e.g., alkylation, acylation, quaternization, hydroxyalkylation, carboxyalkylation, thiolation, phosphorylation, glycosylation, etc.). In some embodiments, the variant has no more than 5, 4, 3, 2, or 1 chemical moiety additions or deletions compared to the reference, and in some embodiments, no additions or deletions. In some embodiments, the variant is a substance that can be produced from the reference by chemical manipulation. In some embodiments, the variant is a substance that may be produced by performing a synthesis process that is substantially similar to (e.g., sharing multiple steps) that produces the reference.

[0131] Detailed description of a specific embodiment This disclosure provides, in particular, a technology that includes certain biomaterial preparations that may be especially useful and / or may provide certain beneficial effects as described herein.

[0132] In particular, this disclosure understands that certain crosslinking techniques may generate toxic byproducts and / or adversely affect the stability and / or efficacy of a drug(s) (e.g., therapeutic agents) that may be combined with the biopolymer material before or during crosslinking. In some embodiments, this disclosure provides techniques to address such problems associated with certain prior art, particularly those involving certain crosslinked biopolymer materials.

[0133] Alternatively or additionally, the Disclosure recognizes that techniques involving pre-forming biopolymer materials (e.g., by chemical crosslinking) before introduction into a subject may result in materials having distinct sizes and / or structures, limiting administration options. The Disclosure provides techniques that include specific biomaterial preparations enabling administration by various routes and / or techniques, including methods such as injection and / or laparoscopic administration, which may be less invasive than transplantation. In some such embodiments, preparations having improved administration characteristics may be administered in liquid form. In some embodiments, they may be administered in a pre-formed gel state characterized by flexible space-filling properties. In some such embodiments, the provided preparations consist of suitable materials in particulate form (e.g., such that the preparation comprises a plurality of particles characterized, for example, by a size distribution and / or other parameters as described herein).

[0134] In particular, in some embodiments, the Disclosure provides temperature-responsive biomaterial preparations that can transition from an injectable state to a polymer network state having material properties that provide the beneficial effects described herein, for example, without introducing cell-toxic crosslinking agents, such as UV irradiation and / or chemical crosslinking agents (e.g., low molecular weight crosslinking agents). Accordingly, some such embodiments provide a beneficial technique for the in-situ formation of gelling materials, which has various advantages over alternative techniques and provides solutions to certain problems associated with such alternative techniques identified herein. For example, since various alternative techniques for in-situ gelation require treatments (e.g., exposure to UV irradiation and / or chemical crosslinking agents, such as low molecular weight crosslinking agents) that may be present in or with the recipient and / or material, or that may otherwise have adverse effects, the Disclosure identifies a source of problems associated with numerous such techniques.

[0135] In some embodiments, the Disclosure recognizes, among other things, that certain conventional preparations used to form hydrogels, which are or contain poloxamer, are typically utilized to contain or be present in a minimum concentration of poloxamer (e.g., poloxamer 407 (P407)) of 16–20% (w / w). The Disclosure identifies the sources of problems associated with such conventional preparations, including that such preparations may have certain drawbacks with respect to administration to a subject, including high solution viscosity and / or tissue irritation due to high concentrations of poloxamer, which makes them less ideal for injection. Furthermore, the Disclosure demonstrates that it is possible to develop useful preparations having significantly lower concentrations(s) of such poloxamer.

[0136] For example, in some embodiments, the disclosure provides insight that certain poloxamers (e.g., poloxamer 407 (P407)) commonly used at a minimum concentration of 16–20% (w / w) to form hydrogels can be combined with one or more biocompatible polymers to form useful temperature-responsive biomaterials at concentrations of less than 16% (w / w), including, for example, less than 14% (w / w), less than 12% (w / w), less than 11% (w / w), less than 10.5% (w / w), less than 10% (w / w), less than 9% (w / w), less than 8% (w / w), less than 7% (w / w), or less than 6% (w / w), less than 5% (w / w). In some embodiments, such biocompatible polymers may be or include non-temperature-responsive polymers, for example, in some embodiments, this may be or include hyaluronic acid and / or chitosan or modified chitosan.

[0137] Alternatively or additionally, in some embodiments, the Disclosure provides the insight that more flexible hydrogels may provide a higher therapeutic effect than high-concentration P407 hydrogels (e.g., 16-20% (w / w) concentration) and / or chemically crosslinked hydrogels. For example, in some embodiments, the Disclosure shows that certain polymer combination preparations described herein having a lower storage modulus with an incorporated immunomodulatory payload may provide a higher survival effect in tumor-resected animals compared to, for example, the survival effect observed in tumor-resected animals administered a chemically crosslinked hyaluronic acid hydrogel with the same immunomodulatory payload.

[0138] In some embodiments, the temperature-responsive biomaterial preparations provided (e.g., those described herein) may exhibit one or more immunomodulatory properties even in the absence of an immunomodulatory payload. In some embodiments, a biomaterial preparation comprising a poloxamer at a concentration of 12.5% ​​(w / w) or less (e.g., 11% (w / w), 10.5% (w / w), 10% (w / w), 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), or less) and at least one additional non-poloxamer polymer may itself be immunomodulatory in the absence of an immunomodulatory payload. For example, in some embodiments, such biomaterial preparations comprising poloxamer and at least one carbohydrate polymer (e.g., hyaluronic acid or chitosan) at concentrations of 12.5% ​​(w / w) or less (e.g., 11% (w / w), 10.5% (w / w), 10% (w / w), 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), or less) may promote innate immunity when administered to a target site of a subject requiring administration (e.g., a subject undergoing tumor resection).

[0139] I. Compositions or preparations containing the provided polymer combination preparations In some embodiments, the present disclosure provides compositions and / or preparations comprising polymer combination preparations (e.g., those described herein) that enable in-situ gelation of a target site in vivo in the absence of crosslinking treatments (e.g., UV irradiation and / or introduction of chemical crosslinking agents) that are temperature-responsive and therefore may be toxic to or otherwise adversely affect a payload that may be contained in or contained with a recipient and / or biomaterial.

[0140] In some embodiments, the Disclosure provides compositions and / or compositions comprising certain polymer combination preparations that are useful for providing sustained release of payloads incorporated into polymer combination preparations. For example, in some embodiments, certain compositions and / or preparations described herein may be particularly useful when such compositions incorporating one or more immunomodulatory payloads (e.g., those described herein and / or those described in WO2018 / 045058, the contents of which are incorporated herein by reference for the purposes described herein) are administered to subjects who have undergone or are undergoing tumor resection. Just as an example, in some embodiments, the compositions or preparations of the Disclosure may comprise at least one innate immunomodulatory payload. In some embodiments, the compositions or preparations of the Disclosure may comprise at least one innate immunomodulatory payload and at least one adaptive immunomodulatory payload. In some embodiments, the compositions or preparations of the Disclosure may comprise at least one innate immunomodulatory payload, at least one adaptive immunomodulatory payload, and at least one immunomodulatory cytokine. In some embodiments, the compositions or preparations of the present disclosure may comprise at least one pro-inflammatory immune response inhibitor.

[0141] In some embodiments, the Disclosure provides compositions and / or compositions comprising certain polymer combination preparations that are sufficient to produce an immunomodulatory response (e.g., a sufficient innate immune agonism) on their own to achieve a beneficial effect without the need for a separate immunomodulatory payload. In some embodiments, the polymer combination preparations described and / or utilized herein are not only substantially free of immunomodulatory payloads (e.g., innate immunomodulatory payloads), but such compositions or preparations of the Disclosure do not necessarily require the inclusion of at least one (e.g., at least two, at least three) other types of immunomodulatory payloads, including adaptive immunomodulatory payloads, immunomodulatory cytokines, immunomodulatory chemotherapeutic agents, immunomodulatory therapeutic agents, and / or combinations thereof. Just as an example, in some embodiments, the compositions or preparations of the Disclosure are substantially free of innate immunomodulatory payloads and adaptive immunomodulatory payloads. In some embodiments, the compositions or preparations of the Disclosure are substantially free of innate immunomodulatory payloads, adaptive immunomodulatory payloads, and immunomodulatory cytokines. In some embodiments, the compositions or preparations of the Disclosure are substantially free of pro-inflammatory response inhibitors. In some embodiments, the compositions or preparations of the present disclosure include polymer combination preparations provided in the absence of an immunomodulatory payload.

[0142] In some embodiments, the polymer combination preparation may include a biomaterial preparation and, in many embodiments, a payload agent which is an immune system modulator (e.g., an immunomodulatory payload) as described herein. Alternatively, in some embodiments, the immunomodulatory composition used, comprising the polymer combination preparation, may substantially not contain a known immunomodulatory payload.

[0143] In some embodiments, the polymer combination preparations described herein are characterized by forming a polymer network. It should be noted that, without being bound by any particular theory, in some embodiments, such a network may function as a scaffold or depot for a payload (e.g., an immunomodulatory payload) within the polymer combination preparation.

[0144] In some embodiments, polymer combination preparations comprising a biomaterial preparation and a payload drug (e.g., an immunomodulatory payload in some embodiments) may function as sustained-release formulations in that the payload is released from the composition more slowly (i.e., over a longer period of time) than is observed in other comparable compositions lacking the polymer combination preparation (e.g., lacking one or all of its polymer components).

[0145] In some embodiments, the polymer combination preparation used as described herein comprises one or more polymers (e.g., those described herein). In certain embodiments, the polymer combination preparation may comprise one or more positively charged polymers. In some embodiments, the polymer combination preparation used as described herein may comprise one or more negatively charged polymers. In some embodiments, the polymer combination preparation used as described herein may comprise one or more neutral polymers.

[0146] Provided polymer combination preparations In some embodiments, the Disclosure provides, among other things, a polymer combination preparation comprising at least first and second polymer components, wherein the first polymer component is or comprises a poloxamer (e.g., as described herein), and the second polymer component is not a poloxamer, and the first polymer component is present in the polymer combination preparation at a concentration of 12.5% ​​(w / w) or less. In some embodiments, such a polymer combination preparation is characterized by transitioning from a precursor state to a polymer network state in response to a gelation trigger, the gelation trigger being or comprising one or more of the following: (a) a temperature above the critical gelation temperature (CGT) of the polymer combination preparation, (b) the critical gelation weight ratio of the first polymer component to the second polymer component, (c) the total polymer content, (d) the molecular weight of the first and / or second polymer components, or (e) a combination thereof. The polymer network state of the provided polymer combination preparation has a viscosity substantially exceeding that of the precursor state and includes crosslinks not present in the precursor state. In some embodiments, the precursor state of the polymer combination preparation provided is a liquid state. In some embodiments, the precursor state of the polymer combination preparation provided is an injectable state. In some embodiments, the polymer network state of the polymer combination preparation provided is a more viscous liquid state. In some embodiments, the polymer network state of the polymer combination preparation provided is a hydrogel.

[0147] In some embodiments, the polymer combination preparations provided are temperature-responsive, such that their gelation (e.g., transition from a liquid state to a gelled state) may occur upon exposure to a specific temperature. In many such embodiments, exposure to body temperature (e.g., by application to a site) is sufficient to induce such gelation. In some embodiments, heat may be further applied. As merely one example, in some embodiments, the temperature-responsive polymer combination preparations described herein are characterized by transitioning from a precursor state (e.g., a liquid state or an injectable state) to a polymer network state (e.g., a more viscous state or a hydrogel) having a viscosity and / or storage modulus substantially exceeding that of the precursor state, where the trigger for gelation is or includes a temperature above the critical gelation temperature (CGT) of the polymer combination preparation. In some embodiments, the CGT of the provided polymer combination preparation is at least 10°C or higher (e.g., including at least 10°C, at least 11°C, at least 12°C, at least 13°C, at least 14°C, at least 15°C, at least 16°C, at least 17°C, at least 18°C, at least 19°C, at least 20°C, at least 21°C, at least 22°C, at least 23°C, at least 24°C, at least 25°C, at least 26°C, at least 27°C, at least 28°C, at least 29°C, at least 30°C, at least 31°C, at least 32°C, 33°C, at least 34°C, at least 35°C, at least 36°C, at least 37°C, at least 38°C, at least 39°C, at least 40°C or higher). In some embodiments, the CGT of the provided polymer combination preparation is about 10°C to about 15°C. In some embodiments, the CGT of the provided polymer combination preparation is about 12°C to about 17°C. In some embodiments, the CGT of the provided polymer combination preparation is about 14°C to about 19°C. In some embodiments, the CGT of the provided polymer combination preparation is about 16°C to about 21°C.In some embodiments, the CGT of the provided polymer combination preparation is about 18°C ​​to about 23°C. In some embodiments, the CGT of the provided polymer combination preparation is about 20°C to about 25°C. In some embodiments, the CGT of the provided polymer combination preparation is about 22°C to about 27°C. In some embodiments, the CGT of the provided polymer combination preparation is about 24°C to about 29°C. In some embodiments, the CGT of the provided polymer combination preparation is about 26°C to about 31°C. In some embodiments, the CGT of the provided polymer combination preparation is about 28°C to about 33°C. In some embodiments, the CGT of the provided polymer combination preparation is about 30°C to about 35°C. In some embodiments, the CGT of the provided polymer combination preparation is about 32°C to about 37°C. In some embodiments, the CGT of the provided polymer combination preparation is about 34°C to about 39°C. In some embodiments, the CGT of the provided polymer combination preparation is about 35°C to about 39°C. In some embodiments, the CGT of the provided polymer combination preparation is at or near the physiological temperature of the subject to whom such polymer combination preparation is administered (e.g., a human subject).

[0148] In some embodiments, the polymer combination preparations provided are temperature reversible. For example, in some embodiments, the polymer combination preparations provided are characterized in that, when exposed to a temperature above the critical gelation temperature (CGT) of the polymer combination preparation, they transition from a precursor state (e.g., a liquid state or an injectable state) to a polymer network state (e.g., a more viscous state or a hydrogel) having a viscosity and / or storage modulus substantially higher than that of the precursor state, and the polymer combination preparation can return from the polymer network state to a state (e.g., a liquid state or the original state of the polymer combination preparation) having a viscosity and / or storage modulus substantially lower than that of the polymer network state.

[0149] In some embodiments, the polymer combination preparations described herein do not contain chemical crosslinking agents. Those skilled in the art will understand that in some embodiments, chemical crosslinking agents are characterized by facilitating the formation of crosslinks by covalent bonds between polymer chains. In some embodiments, the chemical crosslinking agent may be derived from natural sources or may be synthesized, or may include low molecular weight crosslinking agents. Non-limiting examples of low molecular weight crosslinking agents include genipine, dialdehydes, glutaraldehydes, glyoxal, diisocyanates, glutaric acid, succinic acid, adipic acid, acrylic acid, and diacrylates. In some embodiments, the chemical crosslinking agent may involve the use of thiols (e.g., EXTRACEL®, HYSTEM®), methacrylates, hexadecylamides (e.g., HYMOVIS®), and / or tyramines (e.g., CORGEL®). In some embodiments, the chemical crosslinking agent may involve the use of formaldehyde (e.g., HYLAN-A®), divinyl sulfone (DVS) (e.g., HYLAN-B®), 1,4-butanediol diglycidyl ether (BDDE) (e.g., RESTYLANE®), glutaraldehyde, and / or genipine (see, for example, Khunmanee et al. “Crosslinking method of hyaluronic-based hydrogel for biomedical applications” J Tissue Eng.8:1-16(2017)). Thus, in some embodiments, the crosslinks formed during the transition from the precursor state to the polymer network state include covalent crosslinking.

[0150] In some embodiments, the first polymer component (e.g., poloxamer as described herein) and the second polymer component (e.g., as described herein) are present in the polymer combination preparation in critical gelation weight ratios of 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, 10:1, 10.5:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, or 20:1. In some embodiments, a first polymer component (e.g., poloxamer as described herein) and a second polymer component (e.g., as described herein) are present in the polymer combination preparation at a critical gelation weight ratio of 1:1 to 20:1, or 1:1 to 18:1, or 1:1 to 14:1, or 1.5:1 to 14:1, or 2:1 to 13:1, or 1:1 to 10:1, or 2:1 to 20:1, or 2:1 to 18:1, or 2:1 to 10:1. In some embodiments, a first polymer component (e.g., poloxamer as described herein) and a second polymer component (e.g., as described herein) are present in the polymer combination preparation at a critical gelation weight ratio of 1:1 to 10:1. In some embodiments, a first polymer component (e.g., poloxamer as described herein) and a second polymer component (e.g., as described herein) are present in the polymer combination preparation at a critical gelation weight ratio of 2:1 to 10:1. In some embodiments, a first polymer component (e.g., a poloxamer as described herein) and a second polymer component (e.g., as described herein) are present in the polymer combination preparation at a critical gelation weight ratio such that the second polymer component may be present in an amount greater than the weight of the first polymer component. For example, in some embodiments, the first polymer component (e.g., a poloxamer as described herein) and the second polymer component (e.g., as described herein) are present in the polymer combination preparation at critical gelation weight ratios such as 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, and 1:2.In some such embodiments, the concentration of poloxamer may be less than or equal to 7% (w / w), for example, 6% (w / w), 5% (w / w), 4% (w / w), or less.

[0151] In some embodiments, a polymer combination preparation provided herein, comprising at least first and second polymer components (e.g., those described herein), may comprise at least one additional polymer component (e.g., at least one, at least two, at least three, at least four, at least five, at least six, or more additional polymer components), the at least one additional polymer component may, in some embodiments, be or comprise a biocompatible and / or biodegradable polymer component (e.g., those described herein).

[0152] In some embodiments, the provided polymer combination preparation contains a polymer with a total content of at least 5% (w / w) or more (for example, at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), at least 10% (w / w), at least 11% (w / w), at least 12% (w / w), at least 13% (w / w), at least 14% (w / w), at least 15% (w / w), at least 16% (w / w), at least 17% (w / w), at least 18% (w / w), at least 19% (w / w), at least 20% (w / w), or more). In some embodiments, the polymer combination preparations provided contain polymers with a total content of 5% (w / w) to 20% (w / w), 6% (w / w) to 18% (w / w), 8% (w / w) to 15% (w / w), or 9% (w / w) to 12% (w / w). In some embodiments, the polymer combination preparations described herein contain polymers with a total content of 6% (w / w) to 20% (w / w), 8% (w / w) to 20% (w / w), or 10% (w / w) to 15% (w / w).

[0153] In some embodiments, a first polymer component that is or contains a poloxamer is present in the provided polymer combination preparation at a concentration of 12.5% ​​(w / w) or less (for example, including 12% (w / w) or less, 11.5% (w / w) or less, 11% (w / w) or less, 10.5% (w / w) or less, 10% (w / w) or less, 9.5% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less), 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, or 4% (w / w) or less). In some embodiments, a first polymer component that is or contains a poloxamer is present in the provided polymer combination preparation at concentrations of 5%(w / w) to 12.5%(w / w), 8%(w / w) to 12.5%(w / w), 5%(w / w) to 11%(w / w), 5%(w / w) to 10%(w / w), 6%(w / w) to 10%(w / w), or 8%(w / w) to 10%(w / w). In some embodiments, a first polymer component that is or contains a poloxamer is present in the provided polymer combination preparation at concentrations of 4%(w / w) to 12.5%(w / w), 4%(w / w) to 11%(w / w), 4%(w / w) to 10.5%(w / w), or 4%(w / w) to 10%(w / w). In some embodiments, a first polymer component that is or contains a poloxamer is present in the provided polymer combination preparation at concentrations of 5% (w / w) to 12.5% ​​(w / w), 5% (w / w) to 11% (w / w), 5% (w / w) to 10.5% (w / w), or 5% (w / w) to 10% (w / w). In some embodiments, a first polymer component that is or contains a poloxamer is present in the provided polymer combination preparation at concentrations of 6% (w / w) to 12.5% ​​(w / w), 6% (w / w) to 11% (w / w), 6% (w / w) to 10.5% (w / w), or 6% (w / w) to 10% (w / w).

[0154] In some embodiments, the second polymer component may be present in the provided polymer combination preparation at a concentration of 15% (w / w) or less. In some embodiments, the second polymer component may be present in the provided polymer combination preparation at a concentration of 10% (w / w) or less (for example, concentrations of 10% (w / w), 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.5% (w / w), or less). In some embodiments, the second polymer component is at least 0.1% (w / w) (e.g., at least 0.2% (w / w), at least 0.3% (w / w), at least 0.4% (w / w), at least 0.5% (w / w), at least 0.6% (w / w), at least 0.7% (w / w), at least 0.8% (w / w), at least 0.9% (w / w), at least 1% (w / w), at least 1.5% (w / w), at least 2% ( The second polymer component may be present in the provided polymer combination preparation at concentrations of 0.1%(w / w) to 10%(w / w), 0.1%(w / w) to 8%(w / w), 0.1%(w / w) to 5%(w / w), or 1%(w / w) to 5%(w / w), or more. In some embodiments, the second polymer component in the provided polymer combination preparation may be present at concentrations of 0.1%(w / w) to 10%(w / w), or 0.1%(w / w) to 8%(w / w), or 0.1%(w / w) to 5%(w / w), or 1%(w / w) to 5%(w / w). In some embodiments, the second polymer component in the provided polymer combination preparation may be present at concentrations of 0.5% (w / w) to 10% (w / w), 0.5% (w / w) to 5% (w / w), 1% (w / w) to 10% (w / w), 1% (w / w) to 5% (w / w), or 2% to 10% (w / w).

[0155] A. A first polymer component comprising one or more exemplary poloxamers and their variants. In some embodiments, the polymer combination preparations provided include poloxamers or variants thereof. Poloxamers are typically block copolymers comprising a hydrophobic chain of polyoxypropylene (e.g., polypropylene glycol (PPG) and / or poly(propylene oxide) (PPO)) sandwiched between two hydrophilic chains of polyoxyethylene (e.g., polyethylene glycol (PEG) and / or poly(ethylene oxide) (PEO)). Poloxamers are known by the trade names Synperonic, Pluronic, and / or Kolliphor. Generally, poloxamers are nonionic surfactants that, in some embodiments, may have good solubilizing ability, low toxicity, and / or high compatibility with cells, body fluids, and a wide range of chemicals.

[0156] In some embodiments, the poloxamers used in accordance with this disclosure may be poloxamers known in the art. For example, as will be understood by those skilled in the art, poloxamers are generally named using the letter P (derived from poloxamer), followed by three digits, where the first two digits multiplied by 100 indicate the approximate molecular mass of the polyoxypropylene chain, and the last digit multiplied by 10 indicates the polyoxyethylene content. Simply as an example, P407 refers to a poloxamer having a polyoxypropylene molecular mass of 4,000 g / mol and a polyoxyethylene content of 70%. Those skilled in the art will also understand that in the trade names Pluronic and Synperonic, the coding of such poloxamers begins with a letter indicating the physical form at room temperature (e.g., L=liquid, P=paste, F=flake (solid)), followed by two or three digits, where the first digit multiplied by 300 in the digit symbol (the second digit in the three-digit symbol) indicates the approximate molecular weight of the polyoxypropylene chain, and the last digit multiplied by 10 indicates the polyoxyethylene content. Just as an example, L61 refers to a liquid preparation of poloxamer having a polyoxypropylene molecular mass of 1,800 g / mol and a polyoxyethylene content of 10%. Furthermore, as will be apparent to those skilled in the art, poloxamer 181 (P181) corresponds to Pluronic L61 and Synperonic PE / L61.

[0157] In some embodiments, the poloxamers that may be included in the polymer combination preparations described herein may be poloxamer 124 (e.g., Pluronic L44 NF), poloxamer 188 (e.g., Pluronic F68 NF), poloxamer 181 (e.g., Pluronic L61), poloxamer 182 (e.g., Pluronic L62), poloxamer 184 (e.g., Pluronic L64), poloxamer 237 (e.g., Pluronic F87 NF), poloxamer 338 (e.g., Pluronic F108 NF), poloxamer 331 (e.g., Pluronic L101), poloxamer 407 (e.g., Pluronic F127 NF), or combinations thereof, or may include such combinations. In some embodiments, the provided polymer combination preparations may contain at least two or more different poloxamers. Additional poloxamers listed in Table 1 of Russo and Villa “Poloxamer Hydrogels for Biomedical Applications” Pharmaceutics (2019) 11(12):671 (the contents of which are incorporated herein by reference for the purposes described herein) may also be useful in the polymer combination preparations described herein.

[0158] In some embodiments, the poloxamer that may be included in the polymer combination preparations described herein may be or may include poloxamer 407 (P407). In some embodiments, P407 is a poloxamer that is a triblock copolymer having a hydrophobic PPO block sandwiched between two hydrophilic PEO blocks. The approximate length of the two PEO blocks is typically 101 repeat units, while the approximate length of the PPO block is 56 repeat units. In some embodiments, P407 has an average molecular weight of about 12,600 Da, of which about 70% corresponds to PEO. In some embodiments, P407 may self-assemble immediately, depending on the concentration and ambient temperature, to form micelles. Although not bound by any particular theory, the combination of hydration of the PEO block and dehydration of the hydrophobic PPO block may result in the formation of spherical micelles, and the subsequent filling of the micelle structure results in a 3D cubic lattice that constitutes the main structure of the poloxamer hydrogel. Furthermore, they are biodegradable, non-toxic, and stable, making them suitable for applications involving the control of therapeutic drug release. As will be understood by those skilled in the art, the concentration of P407 in hydrogel formulations primarily composed of a poloxamer / water mixture is typically in the range of 16–20% w / v, with approximately 18% w / v being the most commonly used value. See, for example, Pereia et al. “Formulation and Characterization of Poloxamer 407®: Thermoreversible Gel Containing Polymeric Microparticles and Hyaluronic Acid” Quim. Nova, Vol. 36, No. 8, 1121–1125 (2013) (the contents of which are incorporated herein by reference in their entirety).

[0159] Various crosslinking techniques, such as chemical crosslinking and enzyme-mediated crosslinking, were used at P407 concentrations below the typical range of 16–20% w / v, either to crosslink P407 alone or in combination with other polymers. For example, Ryu et al. “Catechol-functionalized chitosan / pluronic hydrogels for tissue adhesives and hemostatic materials” Biomacromolecules (2011) 12(7):2653-2659, Lee et al. “Thermo-sensitive, injectable, and tissue adhesive sol-gel transition hyaluronic acid / pluronic composite hydrogels prepared from bio-inspired catechol-thiol reaction” Soft Matter (2010) 6:977-983, and Chung et al. “Thermo-sensitive biodegradable hydrogels based on stereocomplexed pluronic multi-block copolymers for controlled protein delivery” J Control Release (2008) 127:22-30, and Lee et al. “Enzyme-mediated cross-linking of pluronic copolymer micelles for injectable and in situ forming hydrogels” Acta Biomater (2011) See 7:1468-76 (the contents of each of these are incorporated by reference). However, in some embodiments, such crosslinking methods require the use of chemical crosslinking agents or enzymes and / or modified P407, which may be undesirable for in vivo administration.In some embodiments, the disclosure provides insight that certain polymer combination preparations (e.g., those described herein) may be particularly useful for forming temperature-responsive hydrogels in the absence of chemical or enzyme-mediated crosslinking when the concentration of P407 in the polymer combination preparation is 12.5% ​​(w / w) or less (e.g., including 12% (w / w) or less, 11.5% (w / w) or less, 11% (w / w) or less, 10.5% (w / w) or less, 10% (w / w) or less, 9.5% (w / w) or less, 9% (w / w) or less, and 8% (w / w) or less). In some embodiments, the concentration of P407 is present in the provided polymer combination at concentrations of 5%(w / w) to 12.5%(w / w), or 5%(w / w) to 11%(w / w), or 8%(w / w) to 12.5%(w / w), or 5%(w / w) to 10%(w / w), or 8%(w / w) to 10%(w / w), or 6%(w / w) to 10%(w / w). In some embodiments, the concentration of P407 is present in the provided polymer combination at concentrations of 4%(w / w) to 12.5%(w / w), or 4%(w / w) to 11%(w / w), or 4%(w / w) to 10.5%(w / w), or 4%(w / w) to 10%(w / w). In some embodiments, the concentration of P407 is present in the provided polymer combination at concentrations of 5%(w / w) to 12.5%(w / w), 5%(w / w) to 11%(w / w), 5%(w / w) to 10.5%(w / w), or 5%(w / w) to 10%(w / w). In some embodiments, the concentration of P407 is present in the provided polymer combination at concentrations of 6%(w / w) to 12.5%(w / w), 6%(w / w) to 11%(w / w), 6%(w / w) to 10.5%(w / w), or 6%(w / w) to 10%(w / w).

[0160] In some embodiments, the P407 that may be included in the polymer combination preparations described herein may be or may include the poloxamer 407 listed in the official compendium. In some embodiments, the poloxamer 407 included in the provided polymer combination preparation has not undergone any additional purification steps. In some embodiments, the poloxamer 407 included in the provided polymer combination preparation is unmodified (e.g., in some embodiments, ungenetically modified). In some embodiments, the P407 that may be useful in the polymer combination preparations described herein has a sol-gel transition temperature (T) of at least 18°C ​​or higher in PBS (e.g., including 18.5°C, 19°C, 19.5°C, 20°C, 20.5°C, 21°C, 21.5°C, 22°C, 22.5°C, 23°C, or 23.5°C). sol-gel ) may have. In some embodiments, P407 which may be useful in the polymer combination preparations described herein may have an average molecular weight of 12 kDa or less, for example, 11.5 kDa or less, 11 kDa or less, 10.5 kDa or less, or less. As will be understood by those skilled in the art, the T of P407 in PBS sol-gel and / or the average molecular weight may vary by purification. For example, in some embodiments, if low molecular weight copolymer molecules and / or impurities are removed from the officially listed P407, the T of P407 in PBS sol-gel and / or the average molecular weight may increase. Alternatively, if high molecular weight copolymer molecules and / or impurities are removed from P407 listed in the official compendium, the T of P407 in PBS may increase. sol-gel And / or the average molecular weight may decrease. See, for example, Fakhari et al. “Thermogelling properties of purified poloxamer 407” Heliyon (2017) 3(8):e00390 (the contents of which are incorporated herein by reference in their entirety).

[0161] In some embodiments, the P407 contained in the polymer combination preparations described herein may be unconjugated or unmodified P407 (e.g., P407 not covalently conjugated to a polymer or amino acid portion). Examples of conjugated P407 include, but are not limited to, carbohydrate polymers of P407, e.g., grafted onto chitosan or thiolated P407. See, for example, Park et al. “Thermosensitive chitosan-Pluronic hydrogel as an injectable cell delivery carrier for cartilage regeneration” Acta Biomaterialia (2009) 5(6):1956-1965, and Ryu et al. “Catechol-functionalized chitosan / pluronic hydrogels for tissue adhesives and hemostatic materials” Biomacromolecules (2011) 12(7):2653-2659 (the contents of each of these are incorporated herein by reference in their entirety).

[0162] In some embodiments, the poloxamer that may be included in the polymer combination preparations described herein may be or may include poloxamer 338.

[0163] In some embodiments, the poloxamer that may be included in the polymer combination preparations described herein may be or may include poloxamer 331.

[0164] In some embodiments, the poloxamer that may be included in the polymer combination preparations described herein may be or may include poloxamer 237.

[0165] In some embodiments, the poloxamer that may be included in the polymer combination preparations described herein may be or may include poloxamer 188.

[0166] In some embodiments, the poloxamer that may be included in the polymer combination preparations described herein may be or may include poloxamer 184.

[0167] In some embodiments, the poloxamer that may be included in the polymer combination preparations described herein may be or may include poloxamer 182.

[0168] In some embodiments, the poloxamer that may be included in the polymer combination preparations described herein may be or may include poloxamer 181.

[0169] In some embodiments, the poloxamer that may be included in the polymer combination preparations described herein may be or may include poloxamer 124.

[0170] In some embodiments, the poloxamer that may be contained in the polymer combination preparations described herein may have polyoxyethylene in an amount of at least 30% by weight (e.g., including at least 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, or more). In some embodiments, the poloxamer may have polyoxyethylene in an amount of 50-90% by weight. In some embodiments, the poloxamer has polyoxyethylene in an amount of 60-90%. In some embodiments, the poloxamer has polyoxyethylene in an amount of 70-90%. In some embodiments, the poloxamer has polyoxyethylene in an amount of about 70%. In some embodiments, the poloxamer has polyoxyethylene in an amount of about 80%.

[0171] In some embodiments, the poloxamer that may be included in the polymer combination preparations described herein is present in an amount of at least 1,500 g / mol (for example, at least 2,000 g / mol, at least 2,500 g / mol, at least 3,000 g / mol, at least 4,000 g / mol, at least 5,000 g / mol, at least 6,000 g / mol, at least 7,000 g / mol, at least 8,000 g / mol, at least 9,000 g / mol, It may have an average molecular weight of at least 10,000 g / mol, at least 11,000 g / mol, at least 12,000 g / mol, at least 13,000 g / mol, at least 14,000 g / mol, at least 15,000 g / mol, at least 16,000 g / mol, at least 17,000 g / mol, at least 18,000 g / mol, at least 19,000 g / mol, at least 20,000 g / mol, or more. In some embodiments, poloxamers may have an average molecular weight of about 1,500 to 20,000 g / mol. In some embodiments, poloxamers may have an average molecular weight of about 4,000 to 12,000 g / mol. In some embodiments, poloxamers may have an average molecular weight of approximately 5,000 to 15,000 g / mol, 9,000 to 15,000 g / mol, 10,000 to 15,000 g / mol, approximately 11,000 to 14,000 g / mol, approximately 11,500 to 13,000 g / mol, approximately 12,000 to 13,000 g / mol, approximately 6,000 to 10,000 g / mol, approximately 7,000 to 9,000 g / mol, or approximately 7,500 to 8,500 g / mol. In some embodiments, poloxamers may have an average molecular weight of 9,500 to 15,000 g / mol. In some embodiments, poloxamers may have an average molecular weight of 6,000 to 10,000 g / mol. In some embodiments, the poloxamer may have an average molecular weight of 12,000 to 18,000 g / mol. In some embodiments, the poloxamer may have an average molecular weight of 1,500 to 3,000 g / mol. In some embodiments, the poloxamer may have an average molecular weight of 6,000 to 9,000 g / mol.Those skilled in the art will understand that the average molecular weight described herein may be a number-average molecular weight, a viscosity-average molecular weight, or a weight-average molecular weight. In some embodiments, the polymers described herein (e.g., poloxamer and other polymers described herein) are characterized by their weight-average molecular weight. In some embodiments, the polymers described herein (e.g., hyaluronic acid described herein) are characterized by their viscosity-average molecular weight, which in some embodiments may be determined by converting intrinsic viscosity measurements to average molecular weights using, for example, the Marc-Hauinck formula.

[0172] In some embodiments, the poloxamers that may be included in the polymer combination preparations described herein may have polyoxypropylene having an average molecular weight of 1,000 to 5,000 g / mol or 1,500 to 4,500 g / mol.

[0173] In some embodiments, the poloxamers that may be included in the polymer combination preparations described herein may be poloxamer variants. Examples of poloxamer variants include, but are not limited to, poloxamine (e.g., an amphiphilic block copolymer formed by four arms of a poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) block bonded to a central ethylenediamine moiety), acrylate-modified poloxamers, thiol-modified poloxamers, and combinations thereof. See, for example, Niu et al., J. Controlled Release, 2009, 137:49-56, and Alvarex-Lorenzo et al. “Poloxamine-based nanomaterials for drug delivery” Frontiers in Bioscience (2010) (the contents of each of these are incorporated herein by reference at least for disclosure relating to modified poloxamers).

[0174] B. A second polymer component containing one or more exemplary polymers other than poloxamers.In some embodiments, the polymer combination preparations described herein may contain at least two polymer components (e.g., at least three, at least four, at least five, or more polymer components). In some embodiments, the second polymer component of a provided polymer combination preparation containing poloxamer as the first polymer component at a concentration of 12.5% ​​(w / w) or less may be or contain at least one biocompatible and / or biodegradable polymer component (e.g., at least two, at least three, at least four, or more).Examples of such biocompatible and / or biodegradable polymer components include, but are not limited to, immunomodulatory polymers, carbohydrate polymers (e.g., carbohydrates, e.g., polymers that are or contain a carbohydrate backbone (e.g., chitosan, arginate, hyaluronic acid, and / or their variants)), polyacrylic acid, silica gel, polyethyleneimine (PEI), polyphosphazene, and / or their variants, cellulose, chitin, chondroitin sulfate, collagen, dextran, gelatin, ethylene vinyl acetate (EVA), fibrin, lactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polyethylene glycol (PEG), PEG diacrylate (PEGDA), disulfide-containing PEGDA (PEGSSDA), PEG dimethacrylate (PEGDMA), polydioxanone (PDO), polyhydroxybutyrate (PHB), poly(2-hydroxyethyl methacrylate) (pHEMA), and polycarboxybetaine (PC). B) Polysulfobetaine (PSB), polycaprolactone (PCL), poly(β-aminoester) (PBAE), poly(esteramide), poly(propylene glycol) (PPG), poly(aspartic acid), poly(glutamic acid), poly(propylene fumarate) (PPF), poly(sebacic anhydride) (PSA), poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyltyrosine alkyl ester carbonate) (PDTE), poly[bis(trifluoroethoxy)phosphazene], polio Examples include ximethylene, single-walled carbon nanotubes, polyanhydrides, poly(N-vinyl-2-pyrrolidone) (PVP), poly(vinyl alcohol) (PVA), poly(acrylic acid) (PAA), poly(methacrylic acid) (PMA), polyacetals, poly(α-esters), poly(orthoesters), polyphosphoesters, polyurethanes, polycarbonates, polyamides, polyhydroxyalkanoates, polyglycerols, polyglucuronic acid, starch, their variants, and / or combinations thereof.

[0175] In some embodiments, the second polymer component of the provided polymer combination preparation is or includes a nonionic polymer component. Examples of such nonionic polymer components include, but are not limited to, polyvinyl alcohol (PVA), polyethylene oxide (PEO), and combinations thereof. In some embodiments, the second polymer component of the provided polymer combination preparation is a cationic polymer component, such as, but are not limited to, chitosan, amino group-containing polymers, collagen, gelatin, and combinations thereof, or includes such a component. In some embodiments, the second polymer component of the provided polymer combination preparation is or includes an anionic polymer component, and examples of anionic polymer components include, but are not limited to, arginate, gellan gum, pectin, xanthan gum, carboxymethylcellulose (CMC), polyacrylic acid, polyaspartic acid, and combinations thereof.

[0176] In some embodiments, the second polymer component of the provided polymer combination preparation is or includes an immunomodulatory polymer, e.g., a polymer that modulates one or more aspects of the immune response (e.g., a polymer that induces innate immune agonism). In some embodiments, the immunomodulatory polymer may be or include an innate immune polymer agonist, as described in International Patent Application PCT / US20 / 31169, filed on 1 May 2020 (published as WO2020 / 223698A1). In some embodiments, the immunomodulatory polymer may be or include a carbohydrate polymer (e.g., a carbohydrate, e.g., a carbohydrate backbone, or a polymer containing such a backbone (e.g., chitosan, arginate, hyaluronic acid, and / or variants thereof)).

[0177] In some embodiments, the provided polymer combination preparation comprises at least one poloxamer and a second polymer component at a concentration of 12.5% or less (e.g., 11% (w / w), 10.5% (w / w), 10% (w / w), 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), or less), wherein the second polymer component can be or include a carbohydrate polymer (e.g., a carbohydrate, e.g., a polymer having or containing a carbohydrate backbone (e.g., including, but not limited to, hyaluronic acid, chitosan, and / or variants thereof)).

[0178] (i) Exemplary hyaluronic acid and its variants In some embodiments, the carbohydrate polymer contained in the provided polymer combination preparation comprising a poloxamer is or includes hyaluronic acid or a variant thereof. Hyaluronic acid (HA), also known as hyaluronan or hyaluronate, is an unsulfated member of a class of polymers known as glycosaminoglycans (GAGs) that are widely distributed in body tissues. HA is found as a component of the extracellular matrix of tissues that form the pericellular coat on the cell surface. In some embodiments, HA is a polysaccharide having the molecular formula (C 14 H 21 NO 11 ) n (which may exist as salts in some embodiments, e.g., sodium salt, potassium salt, and / or calcium salt), where n can vary depending on the source, isolation technique, and / or measurement method.

[0179] In some embodiments, HAs that may be useful according to this disclosure may be isolated from or derived from a number of natural sources. For example, in some embodiments, HA may be isolated from or derived from, for example, human umbilical cord, chicken comb, and / or vertebrate connective tissue matrix. In some embodiments, HA may be isolated from or derived from the capsular components of bacteria such as Streptococcus. See, for example, Kendall et al, (1937), Biochem. Biophys. Acta, 279, 401-405. In some embodiments, HA and / or variants may be produced by microbial fermentation. In some embodiments, HA and / or variants may be recombinant HA or variants produced using, for example, Gram-positive and / or Gram-negative bacteria (including, but not limited to, Bacillus, Lactococcus lactis, Agrobacterium, and / or Escherichia coli) as hosts.

[0180] As stated in international patent application PCT / US20 / 31169 (published as WO2020 / 223698A1), filed on May 1, 2020, the biological activity of HA varies depending on its molecular weight. For example, high molecular weight HA may have anti-inflammatory or immunosuppressive activity, while low molecular weight HA may exhibit pro-inflammatory or immunostimulatory effects. For example, Gao et al. “A low molecular weight hyaluronic acid derivative accelerates excisional wound healing by modulating pro-inflammation, promoting epithelialization and neovascularization, and remodeling collagen” Int. J. Mol Sci (2019) 20:3722, Cyphert et al. “Size Matters: Molecular Weight Specificity of Hyaluronan Effects in Cell Biology.” Int. J. Cell Biol. (2015) 2015:563818, Dicker et al. “Hyaluronan: A simple polysaccharide with diverse biological functions” Acta Biomater. (2014) 10:1558-1570, Aya and Stern “Hyaluronan in wound healing:Rediscovering a major player.” Wound Repair Regen. (2014) 22:579-593, and Frenkel “The role of hyaluronan in See “wound healing” Int. Wound J. (2014) 11:159–163 (all the contents of each of these are incorporated herein by reference for the purposes described herein).Accordingly, in some embodiments, the HA or its variants that may be included in the provided polymer combination preparation may have a low molecular weight, for example, an average molecular weight of 500 kDa or less (e.g., including 450 kDa, 400 kDa, 350 kDa, 300 kDa, 250 kDa, 200 kDa, 150 kDa, 100 kDa, 50 kDa, or less). In some embodiments, the HA or its variants that may be included in the provided polymer combination preparation may have an average molecular weight of about 100 kDa to about 200 kDa. In some embodiments, the HA or its variants that may be included in the provided polymer combination preparation may have an average molecular weight of about 100 kDa to about 150 kDa. In some embodiments, the HA or its variants that may be included in the provided polymer combination preparation may have an average molecular weight of about 250 kDa to about 350 kDa. In some embodiments, the HA or its variants that may be contained in the provided polymer combination preparations may have an average molecular weight of about 300 kDa to about 400 kDa. In some embodiments, the polymer combination preparations described herein, which may contain poloxamers (e.g., those described herein) and low molecular weight HA or its variants in the absence of an immunomodulatory payload, may be useful in inducing innate immune agonism.

[0181] In some embodiments, the HA or variants that may be included in the provided polymer combination preparations may have high molecular weights, for example, above 500 kDa or more (e.g., including 550 kDa, 600 kDa, 650 kDa, 700 kDa, 750 kDa, 800 kDa, 850 kDa, 900 kDa, 950 kDa, 1 MDa, 1.1 MDa, 1.2 MDa, 1.3 MDa, 1.4 MDa, 1.5 MDa, 1.6 MDa, 1.7 MDa, 1.8 MDa, 1.9 MDa, 2 MDa, 2.5 MDa, 3 MDa, 3.5 MDa, 4 MDa, 4.5 MDa, or more). In some embodiments, the HA or variants that may be useful according to this disclosure may have an average molecular weight of about 600 kDa to about 900 kDa. In some embodiments, HA or its variants that may be useful according to this disclosure may have an average molecular weight of about 700 kDa to about 900 kDa. In some embodiments, HA or its variants that may be included in the provided polymer combination preparations may have an average molecular weight of about 500 kDa to about 800 kDa. In some embodiments, HA or its variants that may be included in the provided polymer combination preparations may have an average molecular weight of about 600 kDa to about 800 kDa. In some embodiments, HA or its variants that may be included in the provided polymer combination preparations may have an average molecular weight of about 700 kDa to about 800 kDa. In some embodiments, HA or its variants that may be useful according to this disclosure may have an average molecular weight of about 1 MDa to about 3 MDa. In some embodiments, polymer combination preparations described herein, which may include poloxamers (e.g., those described herein) and high molecular weight HA or its variants in the absence of an immunomodulatory payload, may be useful in dissipating inflammation (e.g., immunosuppressive inflammation).

[0182] In some embodiments, the polymer combination preparations provided include a hyaluronic acid variant. In some embodiments, the hyaluronic acid variant is water-soluble. In some embodiments, the hyaluronic acid variant may be a chemically modified hyaluronic acid, for example, in some embodiments, the hyaluronic acid is esterified. Examples of chemical modifications to hyaluronic acid include, but are not limited to, the addition of thiols, haloacetates, butanediols, diglycidyls, ethers, dihydrazides, aldehydes, glycans, and / or tyramine functional groups. Additional hyaluronic acid modifications and hyaluronic acid variants are known in the art. See, for example, Highley et al., “Recent advances in hyaluronic acid hydrogels for biomedical applications” Curr Opin Biotechnol (2016) Aug 40:35-40, Burdick & Prestwich, “Hyaluronic acid hydrogels for biomedical applications” Advanced Materials (2011), and Prestwich, “Hyaluronic acid-based clinical biomaterials derived for cell and molecule delivery in regenerative medicine” J.Control Release (2011) Oct 30;155(2):193-199 (each of these is incorporated herein by reference in whole for the purposes described herein).

[0183] In some embodiments, the provided polymer combination preparation comprises at least one poloxamer present in a concentration of 12.5% ​​(w / w) or less, and a second polymer component which may be or may contain hyaluronic acid or a variant thereof. In some such embodiments, HA or a variant thereof may be present in the provided polymer combination preparation in a concentration of about 10% (w / w) or less (e.g., including 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), 3% (w / w), 2% (w / w), or 1% (w / w), or less). In some embodiments, HA or its variants may be present in the provided polymer combination preparation at concentrations ranging from about 0.5% (w / w) to about 5% (w / w), for example, 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.5% (w / w), 2% (w / w), 2.5% (w / w), 3% (w / w), 3.5% (w / w), 4% (w / w), 4.5% (w / w), or 5% (w / w). In some embodiments, low molecular weight HA or its variants (such as those described herein) may be present in the provided polymer combination preparation at a concentration of at least about 1.5% (w / w) or more (e.g., including at least 2% (w / w), at least 2.5% (w / w), at least 3% (w / w), at least 4% (w / w), at least 5% (w / w), at least 6% (w / w), at least 7% (w / w), at least 8% (w / w), at least 9% (w / w), or more). In some embodiments, low molecular weight HA or its variants (such as those described herein) may be present in the provided polymer combination preparation at a concentration of about 1.5% (w / w) to about 5% (w / w). In some embodiments, low molecular weight HA or its variants (such as those described herein) may be present in the provided polymer combination preparation at a concentration of about 0.5% (w / w) to about 10% (w / w).In some embodiments, low molecular weight HA or its variants (such as those described herein) may be present in the provided polymer combination preparation at concentrations of about 1% (w / w) to about 10% (w / w) or about 1.5% (w / w) to about 10% (w / w). In some embodiments, low molecular weight HA or its variants (such as those described herein) may be present in the provided polymer combination preparation at concentrations of about 0.7% (w / w) to about 4% (w / w) or about 1.5% (w / w) to about 4% (w / w). In some embodiments, low molecular weight HA or its variants (such as those described herein) may be present in the provided polymer combination preparation at concentrations of about 3% (w / w) to about 7% (w / w). In some embodiments, high molecular weight HA or its variants (such as those described herein) may be present in the provided polymer combination preparation at concentrations of 2% (w / w) or less (e.g., including 1.5% (w / w), 1.25% (w / w), 1% (w / w), or less). In some embodiments, high molecular weight HA or its variants (such as those described herein) may be present in the provided polymer combination preparation at concentrations of about 0.5% (w / w) to about 3% (w / w).

[0184] (ii) Exemplary chitosan and its variants In some embodiments, the carbohydrate polymer contained in the polymer combination preparations provided, which include poloxamers (for example, as described herein), may be or may contain chitosan or its variants. Examples of chitosan and / or its variants that may be contained in the polymer combination preparations described herein include, but are not limited to, chitosan, chitosan salts (e.g., chitosan HCl, chitosan chloride, chitosan lactate, chitosan acetate, chitosan glutamate), alkyl chitosan, aromatic chitosan, carboxyalkyl chitosan (e.g., carboxymethyl chitosan), hydroxyalkyl chitosan (e.g., hydroxypropyl chitosan, hydroxyethyl chitosan), aminoalkyl chitosan, acylated chitosan, phosphorylated chitosan, thiolated chitosan, and quaternary ammonium chitosan (e.g., N-(2- Examples include hydroxyl)propyl-3-trimethylammonium chitosan chloride, guanidyl chitosan, chitosan oligosaccharides, glycated chitosan (e.g., N-dihydrogalactochitosan), chitosan poly(sulfonamide), chitosan-phenylsuccinic acid (e.g., phenylsuccinic anhydride or its variants (e.g., 2-phenylsuccinic anhydride, 2-phenylsuccinic acid derivatives, 2-O-acetyl-L-malic acid anhydride, etc.) and products formed by the reaction of chitosan) (e.g., chitosan phenylsuccinic acid hemiamide, which is a ring-opening amide carboxylic acid derivative), and their variants or combinations. In some embodiments, the carbohydrate polymer contained in the provided polymer combination preparations containing poloxamers (e.g., as described herein) may be or may contain carboxyalkyl chitosan (e.g., carboxymethyl chitosan).

[0185] Those skilled in the art will understand that, in some cases, chitosan and / or its variants can be produced by the deacetylation of chitin. In some embodiments, chitosan or its variants contained in polymer combination preparations containing poloxamers (such as those described herein) are characterized by a degree of deacetylation (i.e., a percentage of acetyl groups removed) of at least 70% (e.g., including at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more (up to 100%)). In some embodiments, chitosan or its variants are characterized by a degree of deacetylation of 99% or less, 95% or less, 90% or less, 85% or less, 80% or less, 75% or less, or less. Combinations of the above ranges are also possible. For example, chitosan or its variants may be characterized by a degree of deacetylation of 80% to 95%, 70% to 95%, or 75% to 90%. As will be understood by those skilled in the art, the degree of deacetylation (%DA) can be determined by various methods known in the art, for example, by NMR spectroscopy in some cases.

[0186] In some embodiments, the chitosan or its variant contained in a polymer combination preparation containing poloxamer (for example, as described herein) has a minimum of 5 kDa (for example, at least 10 kDa or more (for example, at least 20 kDa, at least 30 kDa, at least 40 kDa, at least 50 kDa, at least 60 kDa, at least 70 kDa, at least 80 kDa, at least 90 kDa, at least 100 kDa, at least 110 kDa, at least 120 kDa, at least 130 kDa, at least 140 kDa, at least 150 kDa) a) may have an average molecular weight including at least 160kDa, at least 170kDa, at least 180kDa, at least 190kDa, at least 200kDa, at least 210kDa, at least 220kDa, at least 230kDa, at least 240kDa, at least 250kDa, at least 260kDa, at least 270kDa, at least 280kDa, at least 290kDa, at least 300kDa, at least 350kDa, at least 400kDa, at least 500kDa, at least 600kDa, at least 700kDa, or more. In some embodiments, chitosan or its variants contained in polymer combination preparations containing poloxamer (for example, as described herein) may have an average molecular weight of 750 kDa or less (for example, including 700 kDa or less, 600 kDa or less, 500 kDa or less, 400 kDa or less, 300 kDa or less, 200 kDa or less, 100 kDa or less, 50 kDa or less, or less). Combinations of the above ranges are also possible. For example, in some embodiments, the chitosan or its variants contained in polymer combination preparations containing poloxamer (such as those described herein) are characterized by an average molecular weight of 10 kDa to 700 kDa, 20 kDa to 700 kDa, 30 kDa to 500 kDa, 150 kDa to 600 kDa, or 150 kDa to 400 kDa, 50 kDa to 150 kDa, or 10 kDa to 50 kDa.In some embodiments, the chitosan or its variants contained in polymer combination preparations containing poloxamers (for example, as described herein) are characterized by an average molecular weight of 20 kDa to 700 kDa or 30 kDa to 500 kDa. As described herein, the average molecular weight may be the number-average molecular weight, the weight-average molecular weight, or the peak-average molecular weight.

[0187] In some embodiments, the chitosan or its variants contained in polymer combination preparations containing poloxamer (for example, as described herein) are characterized by a molecular weight distribution in the range of 10 kDa to 700 kDa, 20 kDa, 700 kDa, 30 kDa to 500 kDa, 150 kDa to 600 kDa, 150 kDa to 400 kDa, 50 kDa to 150 kDa, or 10 kDa to 50 kDa. In some embodiments, the chitosan or its variants contained in polymer combination preparations containing poloxamer (for example, as described herein) are characterized by a molecular weight distribution in the range of 20 kDa to 700 kDa or 30 kDa to 500 kDa.

[0188] In some embodiments, chitosan or its variants contained in polymer combination preparations containing poloxamer (such as those described herein) may be characterized by a viscosity of 3,500 mPa·s or less (for example, including 3,000 mPa·s or less, 2,500 mPa·s or less, 2,000 mPa·s or less, 1,500 mPa·s or less, 1,000 mPa·s or less, 500 mPa·s or less, 250 mPa·s or less, 200 mPa·s or less, 150 mPa·s or less, 100 mPa·s or less, 75 mPa·s or less, 50 mPa·s or less, 25 mPa·s or less, 20 mPa·s or less, 15 mPa·s or less, 10 mPa·s or less, or less). In some embodiments, chitosan or its variants may be characterized by a viscosity of at least 5 mPa·s or higher (for example, including at least 10 mPa·s, at least 20 mPa·s, at least 30 mPa·s, at least 40 mPa·s, at least 50 mPa·s, at least 60 mPa·s, at least 70 mPa·s, at least 80 mPa·s, at least 90 mPa·s, at least 100 mPa·s, at least 125 mPa·s, at least 150 mPa·s, at least 175 mPa·s, at least 250 mPa·s, at least 500 mPa·s, at least 1,000 mPa·s, at least 1,500 mPa·s, at least 2,000 mPa·s, at least 2,500 mPa·s or higher). Combinations of the above ranges are also possible. For example, in some embodiments, such viscous polymer solutions of chitosan or its variants, or such viscous polymer solutions containing chitosan or its variants, may be characterized by a viscosity of 5 mPa·s to 3,000 mPa·s, or 5 mPa·s to 300 mPa·s, 5 mPa·s to 200 mPa·s, or 20 mPa·s to 200 mPa·s, or 5 mPa·s to 20 mPa·s. In some embodiments, the viscosity of the chitosan or its variants described herein is measured at 1% in 1% acetic acid at 20°C.

[0189] In some embodiments, polymer combination preparations containing poloxamer (for example, as described herein) include at least one (e.g., one, two, three, or more) chitosan and / or its variants (e.g., modified chitosan and / or salts of chitosan or modified chitosan, e.g., chloride salts or glutamates). For example, in some embodiments, chitosan and / or its variants (e.g., modified chitosan and / or salts of chitosan or modified chitosan, e.g., chloride salts or glutamates) may be characterized by a degree of deacetylation of 70% to 95%, or 75% to 90%, or 80% to 95%, or greater than 90%. In some embodiments, chitosan and / or its variants (e.g., modified chitosan and / or salts of chitosan or modified chitosan, e.g., chloride salts or glutamates) may be characterized by an average molecular weight of 10 kDa to 700 kDa, 20 kDa to 600 kDa, 30 kDa to 500 kDa, 150 kDa to 400 kDa, or 200 kDa to 600 kDa (e.g., measured as chitosan or a chitosan salt, e.g., chitosan acetate). In some embodiments, chitosan and / or its variants (e.g., modified chitosan and / or salts of chitosan or modified chitosan, e.g., chloride salts or glutamates) may be characterized by a molecular weight distribution in the range of 10 kDa to 700 kDa, 20 kDa to 600 kDa, 30 kDa to 500 kDa, 150 kDa to 400 kDa, or 200 kDa to 600 kDa (e.g., measured as chitosan or chitosan salts, e.g., chitosan acetate). In some embodiments, chitosan and / or its variants (e.g., salts thereof, e.g., chloride salts or glutamates) may be characterized by a viscosity in the range of 5 to 3,000 mPa·s or 5 to 300 mPa·s or 20 to 200 mPa·s.In some embodiments, such chitosan and / or its variants (e.g., including its salts, e.g., chloride salts or glutamates) may be or include PROTASAN® UltraPure Chloride Chitosan and / or Chitosan Glutamate (e.g., available from NovoMatrix®, a business unit of FMC Health and Nutrition (now part of DuPont; product numbers: CL 113, CL 114, CL 213, CL 214, G 113, G 213, G 214)). In some embodiments, such chitosan and / or its variants (e.g., including its salts, e.g., chloride salts or glutamates) may be or include chitosan, chitosan oligomers, and / or their variants (e.g., including chitosan HCl, carboxymethyl chitosan, chitosan lactate, and chitosan acetate) (e.g., Chitoceuticals® or Chitoscience®), which are available from, for example, Heppe Medical Chitosan GMBH.

[0190] In some embodiments, the chitosan or its variant contained in a polymer combination preparation containing poloxamer (for example, as described herein) is a carboxyalkyl chitosan (e.g., carboxymethyl chitosan) characterized by at least one or all of the following properties: (1) a degree of deacetylation of 80% to 95%, (ii) an average molecular weight of 30 kDa to 500 kDa, or a molecular weight distribution of 30 kDa to 500 kDa, and (iii) a viscosity in the range of 5 to 300 mPa·s.

[0191] In some embodiments, chitosan or its variants contained in polymer combination preparations containing poloxamer (for example, as described herein) are or include a variant of chitosan (for example, as described herein). In some embodiments, such a variant of chitosan may include one or more chemical modifications of one or more chemical moieties of the chitosan chain, e.g., hydroxyl and / or amino groups. In some embodiments, such a variant of chitosan may be or include modified chitosan (e.g., chitosan modified by adding one or more monosaccharide or oligosaccharide side chains to one or more of its free amino groups), such as glycated chitosan, for example, but not limited to these. Examples of glycated chitosans useful herein include, but are not limited to, those described in US5,747,475, US6,756,363, WO2013 / 109732, US2018 / 0312611, and US2019 / 0002594 (each of which is incorporated herein by reference for the purposes described herein).

[0192] In some embodiments, the chitosan or its variant contained in a polymer combination preparation containing poloxamer (for example, as described herein) is or contains chitosan conjugated with a polymer (for example, a hydrophilic polymer such as polyethylene glycol) that increases the solubility of chitosan in an aqueous environment.

[0193] In some embodiments, the chitosan or its variants contained in polymer combination preparations containing poloxamers (for example, as described herein) are thiolated chitosan or include thiolated chitosan. Various modifications of chitosan, such as, for example, carboxylation, pegylation, galactosylation (or other glycosylation), and / or thiolation, are known in the art, such as those described in Ahmadi et al. Res Pharm Sci., 10(1):1-16 (2015) (the contents of which are incorporated herein by reference for the purposes described herein), for example. Those skilled in the art who read this disclosure will understand that other modified chitosans may be useful for the specific applications in which the methods are carried out.

[0194] In some embodiments, the provided polymer combination preparation comprises at least one poloxamer present in a concentration of 12.5% ​​or less, and a second polymer component which may be or may contain a variant thereof. In some such embodiments, the chitosan or its variant may be present in the provided polymer combination preparation in a concentration of about 10% (w / w) or less (e.g., including 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.5% (w / w), 0.4% (w / w), 0.3% (w / w), 0.2% (w / w), 0.1% (w / w), or less). In some embodiments, chitosan or its variants may be present in polymer combination preparations provided at concentrations of 0.1% (w / w) to 10% (w / w), 0.1% (w / w) to 8% (w / w), 0.1% (w / w) to 5% (w / w), 1% (w / w) to 5% (w / w), or about 1% (w / w) to about 3% (w / w).

[0195] C. Exemplary payloads (e.g., therapeutic drugs) In some embodiments, the biomaterial preparation (e.g., the polymer combination preparation provided) may be administered without an additional payload. In some embodiments, such preparation may itself possess certain immunomodulatory properties. Alternatively or additionally, in some embodiments, the biomaterial preparation (e.g., the polymer combination preparation) may include one or more payload agents (e.g., therapeutic agents, e.g., immunomodulatory payloads, e.g., immunomodulators) and / or may be administered separately in combination therewith. That is, in some embodiments, the immunomodulatory composition may include or consist of the polymer combination preparation and one or more payload agents.

[0196] In some embodiments, the payload is or includes a therapeutic agent.

[0197] In some embodiments, the payload is or includes an immunomodulator.

[0198] In some embodiments, the payload is a drug approved by the Food and Drug Administration (e.g., a therapeutic agent) (for example, as described in Zhong et al., “A comprehensive Map of FDA-Approved Pharmaceutical Products.” Pharmaceutics, 2019 Dec;10(4):263 (the contents of which are incorporated herein by reference for the purposes described herein)).

[0199] In some embodiments, the payload is a drug (e.g., a therapeutic agent) that inhibits or reduces the level (e.g., expression and / or activity) of a target administered by a drug approved by the Food and Drug Administration (e.g., a therapeutic agent) (e.g., as described in Zhong et al., “A comprehensive Map of FDA-Approved Pharmaceutical Products.” Pharmaceuticals, 2019 Dec;10(4):263 (the contents of which are incorporated herein by reference for the purposes described herein)).

[0200] In some embodiments, the payload is a drug (e.g., a therapeutic agent) approved by the Food and Drug Administration (FDA) that induces or increases the level (e.g., expression and / or activity) of a target to be administered by the drug (e.g., a therapeutic agent) (e.g., as described in Zhong et al., “A comprehensive Map of FDA-Approved Pharmaceutical Products.” Pharmaceuticals, 2019 Dec;10(4):263 (the contents of which are incorporated herein by reference for the purposes described herein)).

[0201] In some embodiments, the payload is not a toxic agent (e.g., a cytotoxic agent or cell division inhibitor or other antiproliferative agent), but rather, for example, the payload is not a conventional chemotherapeutic agent that acts simply by killing cancer cells but does not promote immunogenic cell death to a clinically significant degree (e.g., Vacchelli et al., “Trial watch: Chemotherapy with immunogenic cell death inducers”, Oncoimmunology, March 1, 2013; Kepp et al., “Consensus guidelines for the detection of immunogenic cell death”, Oncoimmunology, December 13, 2014; Bloy et al., “Immunogenic stress and death of cancer cells: Contribution of antigenicity vs adjuvanticity to immunosurveillance”, Immunology Reviews, November 2017; Michaud et al., “Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice”, Science, December 16, 2011; Galluzzi et al. al., “Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018”, Cell Death Differentiation, March 2018, Galluzzi et al., “Immunogenic cell death in cancer and infectious disease”, Nature Reviews Immunology, October 2016, Galluzzi et al.See, “Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors”, Nature Reviews Clinical Oncology, August 5, 2020 (the contents of each of these are incorporated herein by reference for the purposes described herein). In some embodiments, whether such chemotherapeutic agents can promote a clinically significant degree of immunogenic cell death can be determined, for example, by evaluating the relative therapeutic effects of the chemotherapeutic agents after treatment of the same tumor model in immunodeficient mice versus healthy mice. Examples of conventional chemotherapeutic agents may be found in any of the various classes of anticancer agents, including, but not limited to, alkylating agents, antimetabolites, topoisomerase inhibitors, and / or mitotic inhibitors. In some embodiments, the polymer combination preparations described herein are substantially free of any conventional chemotherapeutic agents. In some embodiments, the polymer combination preparations are substantially free of cytotoxic agents or cell division inhibitors (or other antiproliferative agents).

[0202] In some embodiments, such payloads may be dispersed in a biomaterial preparation (e.g., a polymer combination preparation as described herein). In some embodiments, the disclosure provides, among other things, a composition comprising a polymer combination preparation and / or one or more payloads, wherein at least a portion of the payload(s) is dispersed in the polymer combination preparation. Examples of payloads, but not limited to, include nucleic acids, polypeptides, peptides, small molecules, lipids, sugars, metals, or combinations or complexes thereof.

[0203] In some embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) may be or include a therapeutic agent for the treatment and / or prevention of a disease, disorder, or condition. In some embodiments, the therapeutic agent contained in a biomaterial preparation (e.g., a polymer combination preparation provided) may be or include an agent for immunomodulation, wound healing, cancer treatment, and / or analgesia. In some embodiments, the therapeutic agent contained in a biomaterial preparation (e.g., a polymer combination preparation provided) may be useful for the treatment of cancer. In some embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) may be a chemotherapeutic agent, for example, in some embodiments, a chemotherapeutic agent that induces immunogenic cell death. As will be understood by those skilled in the art, chemotherapeutic agents suitable for use in accordance with this disclosure may be synthetic or natural compounds; a single molecule or a complex of different molecules. In some embodiments, preferred chemotherapeutic agents for inducing immunogenic cell death may belong to any of the various classes of compounds, including, but not limited to, small molecules, peptides, sugars, steroids, antibodies, fusion proteins, nucleic acid agents (e.g., antisense polynucleotides, ribozymes, and small interfering RNAs), peptide mimetic compounds, and the like. Similarly, preferred chemotherapeutic agents may be found in any of the various classes of anticancer agents, including, but not limited to, alkylating agents, antimetabolites, topoisomerase inhibitors, and / or mitotic inhibitors.

[0204] In some embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is one or more nucleic acid agents. Such nucleic acid agents may have enzymatic activity (e.g., ribozyme activity), gene expression inhibitory activity (e.g., antisense RNA agents or interfering RNA agents), polypeptide encoding function, immunomodulatory activity, and / or other activities. In some embodiments, the nucleic acid agents that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) may act to modulate one or more aspects of the immune response or may encode modulators of one or more aspects of the immune response.

[0205] In certain embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is or contains an antibiotic. Examples of antibiotics, but are not limited to, include: afavicin (Debio 1450), amikacin, amoxicillin, ampicillin, amprolium, apramycin (EBL-1003), ARV-1801 (sodium fusidate), azithromycin, bacitracin, benapenem, BOS-228, brilacidine, BV100, cefaclor, cefdinir, cefepime, cefilavancin, cefotaxime, ceftazidime, ceftibutene, ceftriaxone, cefuroxime, CG-549, chlortetra Cycline, cilastatin, ciprofloxacin, clarithromycin, clavulanate, clindamycin, clopidol, contezolid (MRX-I) / contezolidacefosamil (MRX-4), CRS3123, dalbavancin, decoquinate, delpazolid (LCB01-0371), demeclocycline, diclazuril, dicloxacillin, DNV3837 / DNV3681, doripenem, doxycycline, durobactam, EMROK / EMROK O, Enmetazobactam, Elavacycline, Ertapenem, Erythromycin, ETX0282CPDP / ETX1317, Fenbendazole, Finafloxacin, Gentamicin, Gepotidacin (GSK2140944), Halifuginone, Hygromycin B, Ibezapolstat, Imipenem, KBP-7072, Rhydromicin, Lasaroside, Levofloxacin, Lincomycin, Rubabegron, Melengestrol, Melengestrol Acetate, Meropenem, MGB-BP-3, Minocycline, Monensin, Moxifloxacin, MRX-8, Nacbactam (OP0595), Nafithromycin (WCK4873), Neomycin, Omadacycline, OMNIVance (QPX7728), Oritabancin, Olmethoprim, Oxacillin, Oxytetracycline, Penicillin V potassium, Pyrantel, Ractopamine, Ridinirazole, Lobenidin, Salinomycin, Senduramycin, SPR206, SPR741, Sulbactam, Sulfadimethoxine, Sulfamethoxazole, Sulfaquinoxaline, Sulfasalazine, Sulfisoxazole, Sulopenem / Sulopenem etozadroxil-Probenecid, T -4288 (Solithromycin), Taigexyn (Nemonoxacin), Tanivolbactam, Tebipenem / Tebipenem pivoxil hydrobromide, Teravancin, Tetracycline, TNP-2092, Tobramycin, TP-271, TP-6076, Trimethoprim, TXA709 / TXA707, Tylosin, Vancomycin, Virginiamycin, VNRX-7145, XNW4107, Zevtera (Ceftoviprole), Didebactam, Zilpaterol, Zoarene, Zoliflodacin (ETX0914), and combinations thereof.

[0206] In certain embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is or contains an antibody. Examples of antibodies, but are not limited to, include: adalimumab, alemtuzumab, alirocumab, atezolizumab, avelumab, belimumab, benralizumab, bevacizumab, bezlotoxumab, blinatumomab, brentuximab vedotin, brodalumab, brolucizumab, brosumab, canakinumab, semiprimab, and cell Tolizumab, cetuximab, daratumumab, denosumab, dinutuximab, dupilumab, durvalumab, elotuzumab, emapalumab, emicizumab, erenumab, evolocumab, fremanezumab, galcanezumab, gemtuzumab ozogamicin, golimumab, guselkumab, ibalizumab, ibritumomab tiuxetan, idarucizumab, Infliximab, Inotuzumab Ozogamicin, Ipilimumab, Ixekizumab, Lanadermab, Mepolizumab, Mogamulizumab, Moxetumomab, Natalizumab, Necitumumab, Nivolumab, Oviltoxaximab, Obinutuzumab, Ocrelizumab, Ofatumumab, Oraratumab, Omalizumab, Palivizumab, Panitumumab, Pembron Lizumab, pertuzumab, polatuzumab, ramucirumab, ranibizumab, ravulizumab, reslizumab, risankizumab, rituximab, romosozumab, sarilumab, secukinumab, siltuximab, tildrakizumab, tocilizumab, trastuzumab, trastuzumab, ustekinumab, vedolizumab, and combinations thereof (see, for example, Lu et al., Development of therapeutic antibodies for the treatment of diseases. Journal of Biomedical Science, 2020).

[0207] In certain embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is or contains an analgesic. Examples of various types of analgesics include, but are not limited to, anticonvulsants, antidepressants, anxiolytics, corticosteroids, COX-2 inhibitors, fibromyalgia medications, opioid antagonists, muscle relaxants, nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, or combinations thereof.In some embodiments, analgesics that may be included in a biomaterial preparation (e.g., a polymer combination preparation provided) include acetaminophen, acetaminophen-codeine combination, alprazolam, amitriptyline, aspirin, baclofen, buprenorphine, bupropion, butorphanol, carbamazepine, carisoprodol, celecoxib, chlorzoxazone, clonazepam, cortisone, cyclobenzaprine, dantrolene, and decibels. Pramin, Dexamethasone, Diazepam, Diclofenac, Diflunisal, Duloxetine, Etodolac, Fenoprofen, Fentanyl, Fluoxetine, Flurbiprofen, Gabapentin, Hydrocodone, Hydrocodone / Ibuprofen combination, Hydrocodone / Acetaminophen combination, Hydromorphone, Ibuprofen, Imipramine, Indomethacin, Ketoprofen, Ketrolac, Lamotrigine, Lorazepam, Mefenamic acid, Mero Xicam, meperidine, metaxalon, methadone, methocarbamol, methylprednisolone, milnacipran, morphine, nabumetone, nalbuffine, naproxen, orphenadrine, oxaprozine, oxycodone, oxycodone / acetaminophen combination, oxycodone / aspirin combination, oxycodone / ibuprofen combination, oxymorphone, pentazocine, pentazocine / naloxone, piroxicam, prednisolone, predni Zon, pregabalin, propoxifen / acetaminophen combination, propoxifen / aspirin combination, rofecoxib, sulindac, tapentadol, tapentadol ER, thiagabine, tizanidine, tolmetine, topiramate, tramadol, tramadol hydrochloride, tramadol / acetaminophen combination, triamcinolone, triazolam, valdecoxib, venlafaxine, or any combination thereof, or containing them.

[0208] In certain embodiments, the payload that may be included in a biomaterial preparation (e.g., a polymer combination preparation provided) is or includes an anticoagulant. In some embodiments, the anticoagulant that may be included in a biomaterial preparation (e.g., a polymer combination preparation provided) is or includes apixaban, betrixaban, dabigatran, dalteparin sodium, dalexaban, edoxaban, eribaxaban, retaxaban, rivaroxaban, warfarin, or a combination thereof.

[0209] In certain embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is or contains a coagulant. In some embodiments, the coagulant that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is or contains coagulation factor VIIa (e.g., recombinant coagulation factor VIIa, e.g., NovoSeven or NovoSevenRT), coagulation factor IX (e.g., recombinant coagulation factor IX, e.g., Alprolix, Benefix, Ixinity, or Rixubis), albumin-fused coagulation factor IX (e.g., albumin-fused recombinant coagulation factor IX, e.g., Idelvion), glycopegylated coagulation factor IX (e.g., glycopegylated recombinant coagulation factor IX, e.g., Rebinyn), coagulation factor XIII A subunit (e.g., recombinant coagulation factor XIII A subunit, e.g., Tretten), coagulation factor X (e.g., recombinant coagulation factor X), or a combination thereof.

[0210] In certain embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is or contains an antiemetic. Examples of various types of antiemetics include, but are not limited to, anticholinergics, cannabinoids, corticosteroids, dopamine receptor antagonists, H-1 antihistamines, neurokinin-1 inhibitors, serotonin receptor antagonists, or combinations thereof. In some embodiments, antiemetics that may be included in a biomaterial preparation (e.g., a polymer combination preparation provided) are aprepitant, bismuth subsalicylate, cyclidine, dexamethasone, dimenhydrinate, diphenhydramine, drasetron, doxylamine / pyridoxine, dronabinol, droperidol, granisetron, lorazepam, meclizine, methylprednisolone, metoclopramide, nabilone, netupitant / palonosetron, ondansetron, orthophosphate, palonosetron, prochlorperazine, prochlorperazine maleate, promethazine, pyridoxine, lorapitant, scopolamine, or a combination thereof.

[0211] In certain embodiments, the payload that may be contained in a biomaterial preparation (e.g., a provided polymer combination preparation) is or includes a wound healing agent. In some such embodiments, the agents that promote wound healing include acesulfame K, acetamide MEA (monoethanolamine), acetic acid, activated charcoal, African palm oil, alcohol, allantoin, almond meal, aloe vera, aluminum hydroxide, magnesium aluminum hydroxide stearate, aluminum oxide, aluminum powder, aluminum sulfate, ammonium phosphate, Angelica species wheat extract, arachidyl alcohol, ascorbyl palmitate (vitamin C ester), ascorbyl tetraisopalmitate (vitamin C ester), avocado oil, bacitracin, beeswax, behenyl alcohol (docosanol, Abreva), benzalkonium chloride, benzocaine, benzoic acid, benzyl alcohol, betaine (various forms), bisabolol (chamomile oil), bismuth subgallate, bismuth tribromyl carbonate, borneol, butylated hydroxytoluene (BHT), butylene glycol, and Butyrospermum parkii, cadexomer iodine, calamine, calcium, calcium carbonate, calcium chloride, calcium oxide, calcium sulfate, Camellia sinensis, candelilla wax, capryloyl glycine, carvacrol, Centella asiatica, ceramide, ceteareth-10 phosphate, cetearyl alcohol (cetostearyl alcohol), ceteth-20, cetyl alcohol, cetyl dimethicone copolyol, cetyl palmitate, chlorhexidine, chlorine dioxide, chlorophyllin copper complex sodium, cholesterol, chromium chloride, citric acid, CitrisGrandis extract, cobalt chloride, cocoamphodiacetate, colloidal silica, conjugated linoleic acid, copper, copper chloride (cupric chloride), crystal violet, cupuacu butter, cyclodextrin, cyclomethicone, DEA cetyl phosphate, decanoic acid (capric acid), dehydroacetic acid, dialkylcarbamoyl chloride, diazolidinyl urea, dicetyl phosphate, diisopropyl adipate, dimethicone, dipolyhydroxystearate, dissolved oxygen, DMDM ​​hydantoin, EDTA, ethanol, ethoxydiglycol, ethylene glycol monostearate, ethylhexylglycerin, ethylhexyl palmitate, eucalyptus oil, eugenol, licorice extract (deglycyrrhetinic acid), ferric chloride hexahydrate, ferric oxide, fruit extract, fumed silica, gentian violet, Germaben II II) Glycerin (glycerol), glyceryl monolaurate, glyceryl monostearate, glyceryl stearate, glycyrrhetinic acid (licorice extract), guar gum (Cyaiuopsis letragonolobus), frankincense, hectorite clay, hexyl laurate, hydrochloric acid, hydrocortisone, hydrogen peroxide, hydrogenated castor oil, hydrogenated lecithin, hydroquinone, hydrolyzed lanolin, hydroxypropyl bispalmitamide MEA (ceramide), hydroxypropyl guar gum, hypochlorous acid, iodine, iodoform, iron (various forms), ferrous sulfate, isohexadecane, isopropyl alcohol, isopropyl myristate, isopropyl sorbate, kaolin, karaya gum, keratin, konjac powder, lactic acid, lavender, lecithin, lemon, L-glutamic acid, lidocaine, diesel fuel, Liquid GermallPlus (propylene glycol, diazolidinyl urea, iodide propynyl butylcarbamate), lyophilized porcine plasma preparation, aluminum magnesium silicate, magnesium oxide, magnesium stearate, magnesium sulfate, malic acid, maltodextrin, manganese chloride, manganese oxide, mannitol, meadowsweet extract, menthol, methyl salicylate, methyltriethoxysilane (MTES), methylal, methylene blue, mineral oil, molybdenum chloride, myristyl myristate, Myrtill US extract, oak bark extract, oat glucan, o-cymen-5-ol (Biosol), olive oil, ozone, palm glyceride, palmitamide MEA, palmitic acid, FCC grade panthenol (a form of vitamin B), parabens (various forms), paraffin, pentaline-H (pentaerythritol ester of rosin), pentylene glycol, petrolatum, phenoxyethanol, phosphoric acid, phosphorus pentoxide, piroctone olamine, polyaminopropyl biguanide (PAPB), Polygonum Cuspidatum, polyhexamethylene biguanide (PHMB, polyhexanide), polymyxin B sulfate, polyricinoleate, polyvinylpyrrolidone iodine, potassium ironate, potassium iodide, potassium iron oxyphosphate, potassium sorbate, povidone-iodine, USP grade povidone (Plasdone K-29 / 32), propyl gallate, propylene glycol, pyroglutamic acid, quaternium-15, RADA-16 peptide, rubidium chloride, saccharin, salicylic acid, sandalwood oil, sarcosine, shea butter, silver (various forms), silver sulfadiazine, sodium benzoate, sodium citrate, sodium fluoride, sodium lactate, sodium metabisulfite, sodium selenite, sodium sulfate, sodium tetraborate (borax), Solanum Lycopersicum (tomato) extract, sorbic acid, sorbitan sesquioleate (Arlacel C), sorbitol, soy protein, squalane, steareth-10, stearic acid, Styrax genus, sucralfate (sucrose octasulfate, aluminum hydrochloride), sucrose, sucrose laurate, sulfur dioxide, tara gum, tartaric acid, tea tree oil, thermestain, TheobromaGrandiflorum seed oil, thrombin, thymol, titanium dioxide, titanium dioxide, Tonalin FFA 80, trans-cinnamaldehyde, triethanolamine (TEA), triglycerol (polyglycerol-3), triiodine resin, trolamine, USP grade tromethamine, Vaccinium (blueberry), vegetable oil, vitamin C (ascorbic acid), vitamin E (tocopherol), Vitis vinifera (grape), white petrolatum, wintergreen fragrance, wood pulp core, xanthan gum, xylitol, zinc (various forms), zirconium oxide, or a combination thereof, or containing them.

[0212] In some embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is or includes a photosensitizer used in photodynamic therapy (PDT). In PDT, the photosensitizer is administered topically or systemically to the patient, followed by irradiation of the tissue or organ being treated with light absorbed by the photosensitizer. Light absorption by the photosensitizer generates reactive species (e.g., radicals) that are harmful to cells. For maximum efficacy, the photosensitizer must be in a form suitable for administration, and preferably in a form that readily undergoes intracellular translocation at the target site with some degree of selectivity compared to normal tissue.

[0213] In some embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is or contains a radiosensitizer. A radiosensitizer is typically a molecule, compound, or drug that makes target cells more sensitive to radiotherapy. Administration of a biomaterial preparation containing a radiosensitizer (e.g., a polymer combination preparation provided) to a patient undergoing radiotherapy may concentrate the function of the radiosensitizer on the target cells, thereby enhancing the effect of the radiotherapy.

[0214] In some embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is or contains a radioisotope. Examples of suitable radioisotopes include any α-emitters, β-emitters, or γ-emitters that, when localized to a target site, cause cell disruption, for example, but are not limited to . Examples of such radioisotopes include, but are not limited to, iodine-131, iodine-125, bismuth-212, bismuth-213, astatine-211, rhenium-186, rhenium-188, phosphorus-32, yttrium-90, samarium-153, and lutetium-177.

[0215] In some embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is, for example, a prodrug activating enzyme for a directed enzyme prodrug therapeutic approach, or includes such enzyme. For example, in some embodiments, a biomaterial preparation containing a prodrug activating enzyme (e.g., a polymer combination preparation provided) and a prodrug may be administered to a subject, where the biomaterial preparation is formed in situ at the target site, and the prodrug activating enzyme contained therein converts the prodrug delivered to the target site / surrounding the target site into an active drug. The prodrug may be converted into an active drug (by the prodrug activating enzyme) in one step or in two or more steps.

[0216] In some embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is or contains an anti-angiogenic agent. Examples of anti-angiogenic agents suitable for use in accordance with this disclosure include any molecule, compound, or factor that inhibits, suppresses, delays, or reduces the process of angiogenesis or the process by which new blood vessels are formed from existing blood vessels. Such molecules, compounds, or factors may inhibit angiogenesis by inhibiting, suppressing, delaying, or reducing any of the steps involved in angiogenesis, which include (1) the step of dissolution of the membrane of the originating blood vessel, (2) the step of migration and proliferation of endothelial cells, and (3) the step of formation of the tubular structure of the new blood vessel by the migrating cells. Examples of anti-angiogenic agents include, but are not limited to, bevacizumab (Avastin®), celecoxib (Celebrex®), endostatin, anti-VEGF antibodies, interferon-α, squalamine, cisplatin, combretastatin A-4, and Neovastat.

[0217] In some embodiments, the payload that may be contained in a biomaterial preparation (e.g., a polymer combination preparation provided) is or includes an immunomodulatory agent payload. In some embodiments, the immunomodulatory agent payload is included in a biomaterial preparation (e.g., a polymer combination preparation provided) as a monotherapy. In some embodiments, the immunomodulatory agent payload is or includes an inflammation modulator. As will be understood by those skilled in the art, inflammation can be immunostimulative or immunosuppressive depending on the biological context. Accordingly, in some embodiments, the immunomodulatory agent payload is or includes an immunostimulatory inflammation modulator. In some embodiments, the immunomodulatory agent payload is or includes an immunosuppressive inflammation modulator. In some embodiments, the immunomodulatory agent payload is or includes an innate and / or adaptive immune modulator. In some such embodiments, the innate and / or adaptive immune modulator is or includes an innate and / or adaptive immune agonist.

[0218] In some embodiments, the immunomodulatory payload is or contains a granulocyte modulator. Granulocytes are a category of leukocytes in the innate immune system characterized by the presence of granules in the cytoplasm. Granulocytes may be referred to as polymorphonuclear leukocytes or polymorphonuclear neutrophils (PMN, PML, or PMNL) due to the various shapes of their nuclei, which are usually lobed into three segments. This distinguishes them from mononuclear agranulocytes. Examples of granulocytes include, but are not limited to, neutrophils, eosinophils, basophils, and / or mast cells.

[0219] In some embodiments, the immunomodulatory payload is or includes an agranulocyte modulator. As will be understood by those skilled in the art, agranulocytes, also known as nongranulocytes or mononuclear leukocytes, are characterized by the absence of granules in their cytoplasm, thereby distinguishing them from granulocytes. Examples of agranulocytes include, but are not limited to, lymphocytes, monocytes, and / or macrophages. As will be understood by those skilled in the art, lymphocytes typically include, but are not limited to, B cells, T cells, natural killer T cells, and / or natural killer (NK) cells.

[0220] In some embodiments, the immunomodulatory payload is or includes a modulator of myeloid cells and / or lymphoid cells. In some embodiments, the immunomodulatory payload is or includes a modulator of neutrophils, eosinophils, basophils, lymphocytes, and / or monocytes. In some embodiments, the immunomodulatory payload is or includes a modulator of hematopoietic stem cells, common myeloid progenitor cells, megakaryocytes, platelets, erythrocytes, mast cells, myeloblasts, basophils, neutrophils, eosinophils, monocytes, macrophages, dendritic cells, common lymphoid progenitor cells, natural killer cells, T lymphocytes, B lymphocytes, and / or plasma cells.

[0221] In some embodiments, the immunomodulatory payload is an immunomodulator as described in International Patent Publication WO2018 / 045058 (examples include, but are not limited to, activators of innate immune responses, activators of adaptive immune responses, immunomodulatory cytokines, and modulators of macrophage effector function) and WO2019 / 183216 (examples include, but are not limited to, inhibitors of immunosuppressive inflammation mediated by, for example, the p38-mitogen-activated protein kinase (MAPK) pathway), the contents of each of these are incorporated herein by reference for the purposes described herein. In some embodiments, the immunomodulatory payload is or includes an activator of the innate immune response, for example, in some embodiments the activator of the innate immune response may be or include an interferon gene-stimulating factor (STING) agonist, a Toll-like receptor (TLR) agonist, and / or an activator of the innate immune response as described in International Patent Publication WO2018 / 045058 (the contents of which are incorporated herein by reference for the purposes described herein). In some embodiments, the immunomodulatory payload is or includes an inhibitor of immunosuppressive inflammation, for example, in some embodiments the inhibitor of immunosuppressive inflammation may be or include a COX2 inhibitor or an inhibitor of immunosuppressive inflammation mediated by the p38-mitogen-activated protein kinase (MAPS) pathway as described in International Patent Publication WO2019 / 183216 (the contents of which are incorporated herein by reference for the purposes described herein).

[0222] In some embodiments, the immunomodulatory payload is or includes a Toll-like receptor 7 and 8 (TLR7 / 8) agonist (e.g., as described in International Patent Publication WO2018 / 045058). In some embodiments, the exemplary TLR7 / 8 agonist is or includes regiquimod (R848) or a variant thereof.

[0223] In some embodiments, the immunomodulatory payload is or includes an inhibitor of a COX1 and / or COX2-mediated signaling pathway. In some embodiments, an exemplary inhibitor of a COX1 and / or COX2-mediated signaling pathway is a nonsteroidal anti-inflammatory drug (NSAID). In some embodiments, the immunomodulatory payload is or includes a nonsteroidal anti-inflammatory drug (NSAID) (e.g., as described in International Patent Publication WO2019 / 183216). In some embodiments, the NSAID is or includes ketorolac (e.g., ketrolactromethamine). Ketorolac has traditionally been used for short-term pain management and is therefore not usually prescribed for longer than 5 days due to toxicity. Systemic exposure to ketorolac can cause nephrotoxicity and cardiotoxicity as well as gastrointestinal bleeding. In some embodiments, this disclosure understands that topical retention of ketorolac may be desirable. For example, in some embodiments, the ketorolac used in this disclosure is released from a polymer combination preparation (as described herein) for at least two days, for example, at least three days, at least four days, at least five days, at least six days, at least seven days, at least eight days, at least nine days, at least ten days, or longer, so that the immune system is regulated (for example, immunosuppressive inflammation induced by tumor resection surgery is inhibited or reduced). Ketorolac may be administered as a racemic mixture or as individual enantiomers, for example, S-enantiomers. In some embodiments, the NSAID comprises lornoxicam. In some embodiments, the NSAID comprises sodium meclofenamate.

[0224] In some embodiments, the immunomodulatory payload is or includes a resolvin (e.g., as described in International Patent Publication WO2019 / 183216). In some embodiments, an exemplary resolvin is or includes RvD2. RvD2 is a resolvin that acts as a specific inflammatory convergence mediator (SPM) involved in a coordinated convergence program that can prevent excessive inflammation and / or resolve acute inflammation.

[0225] In some embodiments, the immunomodulatory payload is or includes a modulator of an adenosine-related pathway (e.g., adenosine metabolism and / or recognition pathway). In certain embodiments, the inhibitor of an adenosine-related pathway may be an inhibitor of the A2A and / or A2B receptor. In certain embodiments, the inhibitor of A2A and / or A2B may be or include etrmadenant (also known as AB928).

[0226] In some embodiments, the immunomodulatory payload is or includes an inhibitor of Bruton's tyrosine kinase (BTK). In certain embodiments, the BTK inhibitor may be or include zanubrutinib (also known as Brukinsa or BGB-3111).

[0227] In some embodiments, the immunomodulatory payload is or includes an inhibitor of CXCR4 / CXCL12-mediated signaling. In certain embodiments, the inhibitor of CXCR4 / CXCL12-mediated signaling may be, but is not limited to, prelixafor.

[0228] In some embodiments, the immunomodulatory payload is or includes a NOD1 and / or NOD2 agonist (for example, as described in International Patent Publication WO2018 / 045058). In some embodiments, the exemplary NOD1 and / or NOD2 agonist may be or include L-Ala-γ-D-Glu-mDAP (TriDAP). Tri-DAP is typically present in peptidoglycans (PGNs) of Gram-negative bacteria and certain Gram-positive bacteria. In some embodiments, Tri-DAP is recognized by the intracellular sensor NOD1, which triggers a signaling cascade that leads to NF-κB activation and / or the production of inflammatory cytokines. In some embodiments, the exemplary NOD1 and / or NOD2 agonist may be or include MurNAc-L-Ala-γ-D-Glu-mDAP (M-TriDAP). Similar to TriDAP, M-TriDAP is a peptidoglycan (PGN) degradation product found primarily in Gram-negative bacteria. M-TriDAP is typically recognized by the intracellular sensor NOD1 (CARD4) and, to a lesser extent, by NOD2 (CARD15). Recognition of M-TriDAP by NOD1 / NOD2 interacts with IKK, thereby triggering a signaling cascade involving serine / threonine RIP2 (RICK, CARDIAK) kinase, which leads to NF-κB activation and / or production of inflammatory cytokines, such as TNF-α and IL-6. In some embodiments, M-TriDAP induces NF-κB activation at a similar level to Tri-DAP.

[0229] In some embodiments, the immunomodulatory payload is or includes a modulator of the effector function, survival, and / or recruitment of immune cells. In some embodiments, the immunomodulatory payload is or includes a modulator of the effector function, survival, and / or recruitment of monocytes. In some embodiments, the immunomodulatory payload is or includes a modulator of the effector function, survival, and / or recruitment of macrophages. In some embodiments, the immunomodulatory payload is or includes a modulator of the effector function, survival, and / or recruitment of myeloid-derived suppressor cells (MDSCs). In some embodiments, the immunomodulatory payload is or includes a modulator of the function, survival, and / or recruitment of neutrophils. In some embodiments, the immunomodulatory payload is or includes a modulator of the effector function, survival, and / or recruitment of natural killer cells. Examples of modulators affecting the effector function, survival, and / or recruitment of immune cells include, but are not limited to, adenosine A2A receptor (A2AR) inhibitors, chemokines (e.g., CCL1, CCL2, CCL3, CCL4, CCL5, CCL17, CCL19, CCL21, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL16, and / or CX3CL1), angiopoietin 2 (ANG2) inhibitors, arginase-1 (ARG1) inhibitors, colony-stimulating factor 1 (CSF1) inhibitors, granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibitors, and colony-stimulating factor 1 inhibitors. CSF1R inhibitors, ectonucleotide triphosphate diphosphohydrolase (ENTPD1, ​​also known as CD39) inhibitors, tumor necrosis factor receptor superfamily member 5 (CD40) agonists, OX40 agonists, 4-1BB agonists, CD160 agonists, DNAM agonists, NKG2D agonists, NKG2A inhibitors, TIGIT inhibitors, LILRB1 inhibitors, LILRB2 inhibitors, leukocyte surface antigen CD47 (CD47) inhibitors, signal regulatory protein α (SIRP) inhibitors, 5'-nucleotidase (NT5E, also known as CD73) inhibitors, prostaglandin endoperoxide synthase 2 (PTGS2,Also known as cyclooxygenase-2 (COX-2) inhibitors, prostaglandin E2 (PGE2) inhibitors, PGE2 receptor 2 (EP2) inhibitors, PGE2 receptor 4 (EP4) inhibitors, inducible nitric oxide synthase (iNOS) inhibitors, fibroblast growth factor 1 (FGF) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, and Class II inhibitors. HDAC inhibitors (e.g., HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10), Ig-like transcript 2 (ILT2) inhibitors, S100A8 / A9 inhibitors, RAGE inhibitors, interleukin-8 (IL-8, also known as CXCL8) inhibitors, CXC chemokine receptor type 1 (CXCR-1) inhibitors, CXC chemokine receptor type 2 (CXCR-2) inhibitors, interleukin-10 (IL-10) inhibitors, interleukin-2 (and its variants), interleukin-12 subunit α (IL-1 2a, also known as IL-12) (and its variants), interleukin-15 (and its variants), interleukin-18 (and its variants), leukotriene B4 (LTB4) inhibitors, resolbin family (e.g., RvD1, RvD2, RvD3, RvD4, RvD5, RvD6, 17R-RvD1, 17R-RvD2, 17R-RvD3, 17R-RvD4, 17R-RvD5, 17R-RvD6, RvEl, 18S-RvE1, RvE2, RvE3, RvTl, RvT2, RvT3, RvT4, RvDl, n -3, RvD2 n -3 and / or RvD5 n-3) Specific anti-inflammatory mediators (SPMs), lipoxin family (e.g., LxA4, LxB4, 15-epi-LxA4, and / or 15-epi-LxB4) SPMs, protectin / neuroprotection (e.g., DHA-derived protectin / neuroprotectin and / or n-3 DPA-derived protectin / neuroprotectin) SPMs, maresin (e.g., DHA-derived maresin and / or n-3 DPA-derived maresin) SPMs, phosphoinositide 3 kinase γ (PI3Kγ) inhibitors, transforming growth factor β (TGF-β) inhibitors, transforming growth factor β receptors (TGF-βR family, e.g., ALK1, ALK2, ALK3, ALK4, TGF-βR1, ALK6, ALK7, TGF-βR 2) Inhibitors of the vascular endothelial growth factor family (VEGF, e.g., VEGF-A, VEGF-B, VEGF-C, and / or VEGF-D), inhibitors of the vascular endothelial growth factor receptor family (VEGFR, e.g., VEGFR-1, VEGFR-2, and / or VEGFR-3), JAK / STAT inhibitors, and / or combinations thereof may be used.

[0230] Those skilled in the art will understand that the human immune system is complex, and that a strict classification of a particular drug as a single category of immunomodulator (e.g., as an agonist of innate immunity or an agonist of adaptive immunity, and / or as a modulator of macrophage effector function, such as granulocytes, myeloid cells, and / or lymphoid cells) is not always useful, necessary, or even possible. Those skilled in the art will understand, based on the description herein, the metes and bounds of relevant drugs useful in the embodiments described herein in the context. For example, in some embodiments, a particular immunomodulator that may be useful as an activator of adaptive immune response in one context may also be effective in modulating the survival, recruitment, and / or effector function of one or more immune cell types, including, for example, macrophages, monocytes, myeloid suppressor cells, and / or natural killer cells.

[0231] In some embodiments, the immunomodulatory payload is released from a polymer combination preparation and taken up by immune cells. In some embodiments, the immune cells that take up the immunomodulatory payload exhibit at least one of the following biological activities: expressing an immunomodulatory polypeptide in response to the immunomodulatory payload; showing increased expression of type 1 interferon in response to innate immune stimulation induced by the immunomodulatory payload; and / or showing changes in the level and / or activity of the immunomodulatory polypeptide.

[0232] In some embodiments, the immunomodulatory payload is a polynucleotide drug. In some embodiments, the polynucleotide drug is a non-coding polynucleotide that is not translated into polypeptides. In some embodiments, the non-coding polynucleotide is a dsRNA, siRNA, miRNA, shRNA, or another RNA that induces RNA interference reactions. In some embodiments, the polynucleotide is a guide RNA suitable for resulting in gene editing. In some embodiments, the polynucleotide drug is a coding polynucleotide that can be translated into polypeptides. In some embodiments, a biomaterial preparation contained in a polymer combination preparation is characterized in that the polynucleotide drug is released from the biomaterial preparation and taken up by local cells, resulting in at least a subset of local immune cells expressing an immunomodulatory polypeptide encoded by the polynucleotide drug. In some embodiments, the polymer combination preparation is characterized in that the expression of type 1 interferon in at least a subset of local immune cells increases in response to innate immune stimulation induced by the polynucleotide drug. In some embodiments, the polymer combination preparation is characterized in that the level and / or activity of the immunomodulatory polypeptide in at least a subset of local immune cells changes in response to the polynucleotide drug.

[0233] In some embodiments, the target cells may include myeloid cells and / or plasmacytoid dendritic cells. In some embodiments, the target cells may include non-immune cells, such as fibroblasts and / or endothelial cells.

[0234] D. Solvent System In some embodiments, the polymer combination preparation, or the individual components of the polymer combination preparation, are prepared in or present in a suitable solvent system. For example, in some embodiments, such a solvent system has a pH in the range of 4.5 to 8.5. In certain embodiments, the polymer combination preparation, or the individual components of the polymer combination preparation, are prepared in or present in a suitable solvent system having a pH of 7 to 9. In certain embodiments, the polymer combination preparation, or the individual components of the polymer combination preparation, are prepared in or present in a suitable solvent system having a pH of 7 to 7.5 (e.g., pH 7.4). In certain embodiments, the polymer combination preparation, or the individual components of the polymer combination preparation, are prepared in or present in a suitable solvent system having a pH of 7.5 to 8.5. In certain embodiments, a polymer combination preparation, or the individual components of a polymer combination preparation, are prepared in a suitable solvent system having a pH of 8, or are present in a suitable solvent system having a pH of 8.

[0235] In certain embodiments, the polymer combination preparation, or the individual components of such a polymer combination preparation, are prepared in or present in water. In some embodiments, the polymer combination preparation, or the individual components of such a polymer combination preparation, are prepared in or present in an aqueous buffer system. In some embodiments, such an aqueous buffer system may contain one or more salts (e.g., sodium phosphate and / or sodium bicarbonate, but not limited to these). In some embodiments, such a solvent system is an aqueous buffer system having a higher buffering capacity than 10 mM phosphate buffer. In some embodiments, such a solvent system is an aqueous buffer system having a higher buffering capacity than 20 mM phosphate buffer. In certain embodiments, the polymer combination preparation, or the individual components of such a polymer combination preparation, are prepared in or present in a phosphate buffer, e.g., phosphate-buffered saline (PBS). In certain embodiments, the polymer combination preparation, or the individual components of such a polymer combination preparation, are prepared in or present in a bicarbonate buffer. In some embodiments, polymer combination preparations and / or their individual components are prepared in or present in an aqueous buffer system having a concentration range of 1 mM to 500 mM, 5 mM to 250 mM, 10 mM to 150 mM, 1 mM to 50 mM, 5 mM to 50 mM, 5 mM to 100 mM, or 50 mM to 100 mM. In certain embodiments, a suitable aqueous buffer (e.g., a phosphate buffer) is prepared at a concentration of 10 mM to 50 mM. In certain embodiments, a suitable aqueous buffer (e.g., a phosphate buffer) is prepared at a concentration of 10 mM to 30 mM. In certain embodiments, a suitable aqueous buffer (e.g., a bicarbonate buffer) is prepared at a concentration of 100 mM to 200 mM. In certain embodiments, the polymer combination preparation or its individual components are prepared in or present in sodium phosphate buffer at concentrations of 10 mM to 50 mM or 10 mM or 30 mM.In some embodiments, the aqueous buffer system may contain 0.9% physiological saline.

[0236] E. Any additives In some embodiments, the polymer combination preparation may contain one or more additives. In some embodiments, such additives may be or may contain thickeners. As will be understood by those skilled in the art, such thickeners may improve emulsification, increasing the suspension of components or the stability of the combination. In some embodiments, such thickeners may be useful in preventing, reducing, or delaying phase separation of individual polymer components in the polymer combination preparation. Examples of thickeners, but not limited to, include cellulose derivatives, starch, pectin, xanthan gum, and / or any combination thereof.

[0237] II. Certain properties and / or characteristics of the polymer combination preparations or compositions containing them provided. The polymer combination preparations or compositions containing them provided may be characterized by one or more (e.g., one, two, three or more) of certain properties and / or features described herein. Those skilled in the art who read this disclosure will understand that the polymer combination preparations or compositions containing them provided may be configured to provide material properties and / or features suitable for a particular application. For example, in some embodiments, the material properties and / or features suitable for a particular application may be determined based, for example, on the properties of the tissue surrounding the tumor, the route of administration, the site of administration, and / or the desired duration of immunomodulation in which the method is performed.

[0238] A. Immunomodulatory properties In some embodiments, the polymer combination preparations provided may be non-immunomodulatory. In some such embodiments, the polymer combination preparations and / or compositions comprising them may include an immunomodulatory payload (e.g., as described herein) such that the resulting composition or preparation is immunomodulatory.

[0239] In some embodiments, the polymer combination preparations provided, comprising poloxamer, may include a second polymer component or additional polymer components such that the resulting polymer combination preparation itself can be immunomodulatory in the absence of an immunomodulatory payload. For example, in some embodiments, such a resulting polymer combination preparation itself may be useful in inducing innate immune agonism. In some embodiments, such a resulting polymer combination preparation itself may be useful in resolving or reducing inflammation that may be or may include immunosuppressive inflammation. In some embodiments, such polymer combination preparations may not only substantially lack an immunomodulatory payload, but compositions or preparations comprising such polymer combination preparations of the Disclosure may not necessarily require the inclusion of at least one (e.g., at least two, at least three) types of immunomodulatory payloads, including, for example, innate immune immunomodulatory payloads, adaptive immunomodulatory payloads, immunomodulatory cytokines, immunomodulatory chemotherapeutic agents, immunomodulatory therapeutic agents, and / or combinations thereof. In some embodiments, the immunomodulatory compositions of the Disclosure include the polymer combination preparations provided in the absence of an immunomodulatory payload.

[0240] In some embodiments, the polymer combination preparations provided and / or compositions or preparations comprising the polymer combination preparations provided may indirectly or directly activate one or more pattern recognition receptors of one or more types of cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, and / or natural killer (NK) cells, so as to induce at least one or more innate immune responses (as described herein, for example). Examples of such pattern recognition receptors are or include type C lectin receptors (CLRs), nucleotide-binding oligomerized domain-like receptors (NOD-like receptors or NLRs), retinoic acid-inducible gene I-like receptors (RLRs), and / or Toll-like receptors (TLRs). In some embodiments, the provided polymer combination preparations and / or compositions or preparations comprising the provided polymer combination preparations may directly or indirectly activate at least one type C lectin receptor (CLR) of a number of different cells of the innate immune system (e.g., dendritic cells, macrophages, etc.), including, for example, mannose receptors and / or asialoglycoprotein receptor families (e.g., Dectin 1, Dectin 2, macrophage-inducible type C lectin (Minkle), dendritic cell-specific ICAM3-binding nonintegrin (DC-SIGN), and DC NK lectin group receptor 1 (DNGR-1)). In some embodiments, the provided polymer combination preparations and / or compositions or preparations comprising the provided polymer combination preparations may directly or indirectly activate at least one NOD-like receptor (NLR) of different types of leukocytes (e.g., lymphocytes, macrophages, dendritic cells), such as NLRA (e.g., CIITA), NLRB (e.g., NAIP), NLRC (e.g., NOD1, NOD2, NLRC3, NLRC4, NLRC5, NLRX1), and / or NLRP (e.g., NLRP1, NLRP2, NLRP3, NLRP4, NLRP5, NLRP6, NLRP7, NLRP8, NLRP9, NLRP10, NLRP11, NLRP12, NLRP13, NLRP14).In some embodiments, the provided polymer combination preparations and / or compositions or preparations comprising the provided polymer combination preparations may directly or indirectly activate at least one RIG-I-like receptor (RLR) on, for example, myeloid cells, such as RIG-I, MDA5, and / or LGP2. In some embodiments, the provided polymer combination preparations and / or compositions or preparations comprising the provided polymer combination preparations may directly or indirectly activate at least one Toll-like receptor (TLR) on different types of leukocytes (e.g., dendritic cells, myeloid dendritic cells, monocytes, macrophages, and / or neutrophils), such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, and / or TLR10.

[0241] In some embodiments, the polymer combination preparations provided and / or compositions or preparations comprising the polymer combination preparations provided may indirectly or directly activate or induce (e.g., increase the level and / or activity of) inflammasomes in myeloid cells, for example, so as to induce at least one or more innate immune responses (and / or one or more features of innate immune responses) (e.g., as described herein). In some embodiments, inflammasomes are typically multiprotein complexes that activate one or more inflammatory responses, for example, one or more inflammatory cytokines, for example, interleukin 1β and / or interleukin 18, which promote maturation and / or secretion. In some embodiments, the polymer combination preparations provided and / or compositions or preparations comprising the polymer combination preparations provided may indirectly or directly activate or induce (e.g., increase the level and / or activity of) inflammasomes containing Absent in Melanoma 2 (AIM2)-like receptors ("AIM2 inflammasomes"). In some embodiments, the polymer combination preparations provided and / or compositions or preparations comprising the polymer combination preparations provided may indirectly or directly activate or induce (e.g., increase the level and / or activity of) an inflammasome containing one or more NLRs, such as NLRP1 (e.g., NALP1b), NLRP3 (e.g., NALP3), and / or NLRC4 (e.g., IPAF).

[0242] In some embodiments, the provided polymer combination preparations and / or compositions or preparations comprising the provided polymer combination preparations may directly or indirectly activate one or more components involved in the cGAS-STING pathway (e.g., the cGAS-STING pathway and / or its components, as described in Chen et al., “Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing” Nature Immunology (2016) 17:1142-1149 (which is incorporated herein by reference in its entirety for the purposes described herein)) so as to induce innate immunity. In some embodiments, the polymer combination preparations provided and / or compositions or preparations comprising the polymer combination preparations provided may directly or indirectly induce the activity and / or levels of NFκB and / or other components related to the NFκB pathway (e.g., NFκB activation during innate immune responses, as described in Dev et al., “NF-κB and innate immunity” Curr.Top.Microbiol.Immunol.(2011)349:115-43 (which is incorporated herein by reference in its entirety for the purposes described herein)). In some embodiments, the polymer combination preparations provided and / or compositions or preparations comprising the polymer combination preparations provided may directly or indirectly induce the generation of reactive oxygen species during innate immune responses, for example.

[0243] As will be apparent to those skilled in the art by reading this disclosure, in some embodiments, the polymer combination preparations provided and / or compositions or preparations comprising the polymer combination preparations provided may directly or indirectly activate one or more components and / or pathways (e.g., those described herein) related to the activation of innate immunity. For example, in some embodiments, the polymer combination preparations provided and / or compositions or preparations comprising the polymer combination preparations provided may directly or indirectly activate one or more pattern recognition receptors (e.g., those described herein) of one or more types of cells of the innate immune system, and may also activate or induce inflammasomes in myeloid cells (e.g., they may also increase their levels and / or activity).

[0244] B. Viscosity In some embodiments, the polymer combination preparations described herein (e.g., a polymer network state such as a precursor state or a viscous solution) have a pressure of 25,000 mPa·s or less or less (e.g., 24,000 mPa·s or less, 23,000 mPa·s or less, 22,000 mPa·s or less, 21,000 mPa·s or less, 20,000 mPa·s or less, 19,000 mPa·s or less, 18,000 mPa·s or less, 17,000 mPa·s or less, 16,000 mPa·s or less, 15,000 mPa·s or less, 14,000 mPa·s or less, 13,000 mPa·s or less, 12,000 mPa·s or less, 11,000 mPa·s or less, 10,000 mPa·s or less) It may be characterized by viscosity of s or less, including 9,000 mPa·s or less, 8,000 mPa·s or less, 7,000 mPa·s or less, 6,000 mPa·s or less, 5,000 mPa·s or less, 4,000 mPa·s or less, 3,500 mPa·s or less, 3,000 mPa·s or less, 2,500 mPa·s or less, 2,000 mPa·s or less, 1,500 mPa·s or less, 1,000 mPa·s or less, 500 mPa·s or less, 250 mPa·s or less, 200 mPa·s or less, 150 mPa·s or less, 100 mPa·s or less, 75 mPa·s or less, 50 mPa·s or less, 25 mPa·s or less, 20 mPa·s or less, 15 mPa·s or less, 10 mPa·s or less, or less.In some embodiments, the polymer combination preparations described herein (e.g., a polymer network state such as a precursor state or a viscous solution) have a pressure of at least 5 mPa·s or more (e.g., at least 10 mPa·s, at least 20 mPa·s, at least 30 mPa·s, at least 40 mPa·s, at least 50 mPa·s, at least 60 mPa·s, at least 70 mPa·s, at least 80 mPa·s, at least 90 mPa·s, at least 100 mPa·s, at least 125 mPa·s, at least 150 mPa·s, at least 175 mPa·s, at least 250 mPa·s, at least 500 mPa·s, at least 1,000 mPa·s, at least 1,500 mPa·s, at least 2,000 mPa·s, at least 2,500 mPa·s, at least 3,000 mPa·s, and less At least 4,000 mPa·s, at least 5,000 mPa·s, at least 6,000 mPa·s, at least 7,000 mPa·s, at least 8,000 mPa·s, at least 9,000 mPa·s, at least 10,000 mPa·s, at least 11,000 mPa·s, at least 12,000 mPa·s, at least 13,000 mPa·s, at least 14,000 mPa·s, at least 15 It may be characterized by viscosity (including, but not limited to, 1,000 mPa·s, at least 16,000 mPa·s, at least 17,000 mPa·s, at least 18,000 mPa·s, at least 19,000 mPa·s, at least 20,000 mPa·s, at least 21,000 mPa·s, at least 22,000 mPa·s, at least 23,000 mPa·s, at least 24,000 mPa·s, or higher). Combinations of the above ranges are also possible. For example, in some embodiments, the polymer combination preparations described herein (e.g., a precursor state or a polymer network state such as a viscous solution) may be characterized by a viscosity of 5 mPa·s to 10,000 mPa·s, or 10 mPa·s to 5,000 mPa·s, or 5 mPa·s to 200 mPa·s, or 20 mPa·s to 100 mPa·s, or 5 mPa·s to 20 mPa·s, or 3 mPa·s to 15 mPa·s.In some embodiments, the polymer combination preparations described herein (e.g., a precursor state or a polymer network state such as a viscous solution) may be a viscous solution having a viscosity comparable to that of honey (e.g., having a viscosity of about 2,000 to 10,000 mPa·s and / or centipoise, e.g., about 2,000 to 10,000 mPa·s). In some embodiments, the polymer combination preparations described herein (e.g., a precursor state or a polymer network state such as a viscous solution) may be a viscous solution having a viscosity comparable to that of natural syrups (e.g., sap-derived syrups, molasses-derived syrups, etc.) (e.g., having a viscosity of about 15,000 to 20,000 mPa·s and / or centipoise, e.g., about 15,000 to 20,000 mPa·s). In some embodiments, the polymer combination preparations described herein (e.g., a precursor state or a polymer network state such as a viscous solution) may be a viscous solution having a viscosity comparable to ketchup (e.g., mPa·s and / or centipoise, e.g., about 5,000 to 20,000 mPa·s, comparable to ketchup, e.g., tomato ketchup). Those skilled in the art reading this disclosure will understand that, in some cases, the viscosity of the polymer combination preparations described herein may be selected or adjusted based on, for example, the route of administration (e.g., injection or implantation), the injection volume and / or injection time, and / or the duration of the effect of innate immune stimulation. Also, as will be understood by those skilled in the art, the viscosity of a polymer depends, for example, on temperature and the concentration of the polymer in the experimental sample. In some embodiments, the viscosity of the polymer combination preparations described herein may be, for example, 1000 s. -1 This can be measured at 20°C with a shear rate of .

[0245] In some embodiments, polymer combination preparations containing poloxamers (e.g., as described herein) (e.g., precursor states or polymer network states such as viscous solutions) may be characterized by a viscosity of 3,500 mPa·s or less or less (e.g., including 3,000 mPa·s or less, 2,500 mPa·s or less, 2,000 mPa·s or less, 1,500 mPa·s or less, 1,000 mPa·s or less, 500 mPa·s or less, 250 mPa·s or less, 200 mPa·s or less, 150 mPa·s or less, 100 mPa·s or less, 75 mPa·s or less, 50 mPa·s or less, 25 mPa·s or less, 20 mPa·s or less, 15 mPa·s or less, 10 mPa·s or less, or less). In some embodiments, polymer combination preparations containing poloxamers (e.g., as described herein) (e.g., precursor states or polymer network states such as viscous solutions) may be characterized by a viscosity of at least 5 mPa·s or higher (e.g., including at least 10 mPa·s, at least 20 mPa·s, at least 30 mPa·s, at least 40 mPa·s, at least 50 mPa·s, at least 60 mPa·s, at least 70 mPa·s, at least 80 mPa·s, at least 90 mPa·s, at least 100 mPa·s, at least 125 mPa·s, at least 150 mPa·s, at least 175 mPa·s, at least 250 mPa·s, at least 500 mPa·s, at least 1,000 mPa·s, at least 1,500 mPa·s, at least 2,000 mPa·s, at least 2,500 mPa·s, or higher). Combinations of the above ranges are also possible. For example, in some embodiments, such viscous polymer solutions (e.g., precursor states or polymer network states such as viscous solutions) may be characterized by viscosities of 5 mPa·s to 3,000 mPa·s, or 5 mPa·s to 300 mPa·s, 5 mPa·s to 200 mPa·s, or 20 mPa·s to 200 mPa·s, or 5 mPa·s to 20 mPa·s. In some embodiments, the viscosity of the polymer combination preparations described herein may be, for example, 1,000 mPa·s. -1 This can be measured at 20°C with a shear rate of .

[0246] In particular, this disclosure understands that hydrogel technologies, including certain crosslinking techniques (e.g., certain chemical crosslinking techniques, ultraviolet light, etc.), may generate toxic byproducts and / or adversely affect the stability or efficacy of drugs (e.g., therapeutic agents) that may be combined with polymer combination preparations.

[0247] Alternatively or additionally, the Disclosure understands that in some embodiments, certain advantages can be achieved by administering the components(s) of a polymer combination preparation so that they form during and / or when the immunomodulatory composition described herein is administered, compared to pre-forming the polymer biomaterial (e.g., by crosslinking) before introduction to the target. For example, administration of a pre-formed biomaterial requires a corresponding incision and / or surgical intervention to facilitate administration. For example, the Disclosure understands that in some embodiments, such pre-formation results in a material with a distinct size and / or structure, which may limit the administration options because the dimensions of the pre-formed material may differ from the dimensions of the target site (e.g., excised cavity). In some embodiments, a hydrogel may be formed during and / or when administered. In some embodiments, the polymer combination preparation administered to the target site may include a pre-formed hydrogel of the polymer combination preparation.

[0248] In some embodiments, this disclosure recognizes that polymer combination preparations useful for administration to target sites as described herein may be viscous solutions. For example, in some embodiments, a liquid polymer combination preparation may be introduced to a target site such that, upon administration to the target site, it forms an immunomodulatory composition as described herein in the form of a viscous solution (e.g., a solution having a viscosity of about 5,000 to 15,000 centipoise at body temperature, e.g., a solution having a viscosity of about 10,000 centipoise at body temperature).

[0249] In some embodiments, this disclosure understands that polymer combination preparations useful for administration to a target site as described herein may be viscous solutions that can be substantially retained at the target site for a certain period of time after administration. In some embodiments, such viscous liquid polymer combination preparations have a viscosity that is low enough to be injectable (e.g., through a syringe tip or catheter and / or syringe needle) but high enough to be substantially retained at the target site for a certain period of time after administration. In some embodiments, such viscous liquid polymer combination preparations may have a viscosity of about 500 to 10,000 centipoise at room temperature. In some embodiments, such viscous liquid polymer combination preparations may have a viscosity of about 500 to 3,000 centipoise at room temperature. In some embodiments, such viscous liquid polymer combination preparations may have a viscosity of about 1,000 to 8,000 centipoise at room temperature. In some embodiments, such viscous liquid polymer combination preparations may have a viscosity of about 2,000 to 6,000 centipoise at room temperature. In some embodiments, such a polymer combination preparation of a viscous liquid may have a viscosity of about 3,000 to 7,000 centipoise at room temperature. In some embodiments, such a polymer combination preparation of a viscous liquid may have a viscosity of about 4,000 to 8,000 centipoise at room temperature. In some embodiments, such a polymer combination preparation of a viscous liquid may have a viscosity of about 5,000 to 9,000 centipoise at room temperature. In some embodiments, such a polymer combination preparation of a viscous liquid may have a viscosity of about 6,000 to 10,000 centipoise at room temperature.

[0250] In some embodiments, this disclosure recognizes that there may be viscosity requirements and / or limitations in the injectability of liquid polymer combination preparations. For example, in some embodiments, an injectable polymer combination preparation may feature a viscosity suitable for filling and controlling release through a series of gauge needles (e.g., 14-20 gauge needles, e.g., 16-18 gauge needles). Alternatively, in some embodiments, an injectable polymer combination preparation may feature a viscosity suitable for filling and controlling release through a series of diameter syringe tips (i.e., without a connected needle or with a catheter). In some embodiments, a polymer combination preparation contained in an immunomodulatory composition (e.g., as described herein) filled into a syringe may further contain a plasticizer.

[0251] This disclosure provides technologies that include specific polymer combination preparations, as well as administration methods that enable interventions that may be less invasive than transplantation and / or less toxic than systemic administration. In some such embodiments, preparations having improved administration properties may be administered in liquid form. In some embodiments, they may be administered in a pre-formed gel state characterized by flexible space-filling properties. In some embodiments, they may be administered subcutaneously. In some embodiments, they may function as proximal depots for sustained release of immunomodulatory payloads (e.g., those described herein). In some embodiments, they may enable reprogramming of tissues (e.g., tumors and / or sentinel lymph nodes and / or inflow area lymph nodes). In some embodiments, they may be administered before or concurrently with tumor resection surgery. In some embodiments, they may be administered ipsilaterally when compared to the tumor resection site and / or primary tumor site. In some embodiments, they may be administered contralaterally when compared to the tumor resection site and / or primary tumor site. In some embodiments, they may be administered to patients with metastatic cancer, disseminated cancer and / or recurrent cancer. In some such embodiments, the preparation provided is composed of a suitable material in particle form (for example, such that the preparation comprises a plurality of particles characterized by a size distribution and / or other parameters as described herein).

[0252] C. Storage modulus: Polymer network state In some embodiments, when the polymer combination preparation described herein is in the form of a polymer network, such polymer network state is at least 100 Pa, at least 200 Pa, at least 300 Pa, at least 400 Pa, at least 500 Pa, at least 600 Pa, at least 700 Pa, at least 800 Pa, at least 900 Pa, at least 1,000 Pa, at least 1,100 Pa, at least 1,200 Pa, at least 1,300 Pa, at least 1,400 Pa, at least 1,500 Pa, at least 1,600 Pa, at least 1,700 Pa, at least 1,800 Pa, at least 1,900 Pa, at least 2,000 Pa, at least 2,100 Pa, It may feature a storage modulus of at least 2,200 Pa, at least 2,300 Pa, at least 2,400 Pa, at least 2,500 Pa, at least 2,600 Pa, at least 2,700 Pa, at least 2,800 Pa, at least 2,900 Pa, at least 3,000 Pa, at least 3,500 Pa, at least 4,000 Pa, at least 4,500 Pa, at least 5,000 Pa, at least 6,000 Pa, at least 7,000 Pa, at least 8,000 Pa, at least 9,000 Pa, at least 10,000 Pa, at least 11,000 Pa, at least 12,000 Pa, at least 13,000 Pa, at least 14,000 Pa, at least 15,000 Pa, or higher. In some embodiments, the polymer network state of the provided polymer combination preparation may be characterized by a storage modulus of 15 kPa or less, 14 kPa or less, 13 kPa or less, 12 kPa or less, 11 kPa or less, 10 kPa or less, 9 kPa or less, 8 kPa or less, 7 kPa or less, 6 kPa or less, or less. Combinations of the above ranges are also possible. For example, in some embodiments, the polymer network state of the provided polymer combination preparation may be characterized by a storage modulus of 100 Pa to 15 kPa, or 100 Pa to 10 kPa, or 100 Pa to 7.5 kPa, or 200 Pa to 5,000 Pa, or 300 Pa to 2,500 Pa, or 500 Pa to 2,500 Pa, or 100 Pa to 500 Pa.In some embodiments, the polymer network state of the provided polymer combination preparation may be characterized by a storage modulus of 1,000 Pa to 10,000 Pa, 2,000 Pa to 10,000 Pa, 3,000 Pa to 10,000 Pa, 4,000 Pa to 10,000 Pa, 5,000 Pa to 10,000 Pa, or 6,000 Pa to 10,000 Pa. Those skilled in the art will understand that various fluid characterization methods (such as those described, for example, in Weng et al., “Rheological Characterization of in situ Crosslinkable Hydrogels Formulated from Oxidized Dextran and N-Carboxyethyl Chitosan” Biomacromolecules, 8:1109-1115 (2007)) can be used to measure the storage modulus of a substance, and that, in some cases, the storage modulus of a substance can be measured by rheometer and / or dynamic mechanical analysis (DMA). Those skilled in the art will also understand that the fluidic characterization may vary with respect to ambient conditions, such as temperature and / or pH. Accordingly, in some embodiments, the polymer combination preparations provided are characterized by a storage modulus (as described herein, for example) measured at the body temperature of the subject (e.g., a human subject at 37°C) and at, for example, pH 5-8 or physiological pH (e.g., pH 7). As will be apparent to those skilled in the art by reading this disclosure provided herein, for example, the storage modulus of a polymer combination preparation provided in particulate form refers to the bulk storage modulus of the particle population.

[0253] In some embodiments, the polymer network state of the polymer combination preparations provided herein may be characterized by a storage modulus less than that of an 18% wt% poloxamer hydrogel. For example, in some embodiments, the polymer network state of the polymer combination preparations provided herein may be characterized by a storage modulus, measured at 37°C, that is reduced by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or more) compared to the storage modulus of an 18% (w / w) poloxamer hydrogel.

[0254] In some embodiments, the polymer network state of the polymer combination preparations provided herein may be characterized by a storage modulus (such as those described herein) that is maintained substantially the same (e.g., within 20%, 10%, or 5%) when stored at a suitable temperature for a certain period of time. For example, in some embodiments, the polymer network state of the polymer combination preparations provided herein may be characterized by a storage modulus (such as those described herein) measured at 37°C that is maintained substantially the same (e.g., within 20%, 10%, or 5%) when stored at a temperature of 4°C to 10°C (e.g., 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or 10°C) for a certain period of time, for example, at least one week or more (e.g., including at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least two months, at least three months, at least four months, at least five months, at least six months, or longer). In some embodiments, the polymer network state of the polymer combination preparations provided herein may be characterized by a storage modulus (e.g., as described herein) measured at 37°C, which is maintained substantially the same (e.g., within 20%, 10%, or 5%) when stored at room temperature (e.g., 20°C to 25°C) for a certain period, e.g., at least one week (e.g., including at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least two months, at least three months, at least four months, at least five months, at least six months, or longer).

[0255] D. Phase angle: Polymer network state In some embodiments, the polymer network state of the provided polymer combination preparation may be characterized by phase angles indicating that it is a viscoelastic material. For example, in some embodiments, the polymer network state of the provided polymer combination preparation may be characterized by phase angles of 1° to 50°, or 2° to 45°, or 3° to 40°, or 3° to 35°, 3° to 30°, or 3° to 25°, or 5° to 30°, or 10° to 30°, 15° to 25°, or 20° to 35°. In some embodiments, the polymer network state of the provided polymer combination preparation may be characterized by phase angles of 10° to 30° or 15° to 25°. In some embodiments, the polymer network state of the provided polymer combination preparation may be characterized by phase angles of 5° to 15° or 10° to 20°. As those skilled in the art will understand, the phase angle of polymer biomaterials can be determined by dynamic mechanical analysis, such as frequency sweep analysis, which includes, for example, determining the shear storage modulus and shear loss modulus of the sample. Those skilled in the art will understand that the storage modulus or modulus of a substance can be determined based on its stored energy and represents the elastic properties of the substance, while the loss modulus or viscosity can be determined based on the energy dissipated as heat and represents the viscous properties of the substance. The phase angle (δ) is the arctangent of the ratio of the storage modulus to the loss modulus, and its value indicates whether the substance is more elastic or more viscous. Typically, a phase angle greater than 45° indicates that viscous properties are dominant and the substance behaves more like a solution. As the phase angle approaches 0°, elastic (solid or gel-like) properties become dominant. For example, a substance with a large storage modulus and a small phase angle indicates that it is a stronger (more elastic) gel compared to one with a smaller storage modulus and phase angle. In some embodiments, the phase angle of a polymer combination preparation provided (e.g., as described herein) in a polymer network state can be determined by frequency sweep analysis performed at a temperature corresponding to the body temperature of the object being treated. In some embodiments, the frequency sweep analysis can be performed over a frequency range of 0.1 to 10 Hz while applying a constant 0.4% strain.

[0256] E. Dissolution / degradation rate The polymer combination preparations described herein are typically biocompatible. In some embodiments, at least one polymer component in the provided polymer combination preparation may be biodegradable in vivo. In some embodiments, at least one polymer component in the provided polymer combination preparation may exhibit resistance to biodegradation (e.g., by enzymatic and / or oxidative mechanisms). In some embodiments, at least one polymer component in the provided polymer combination preparation may be chemically oxidized. Thus, in some embodiments, the polymer combination preparation may be chemically and / or biologically degraded within a physiological environment, e.g., within the body of the subject, e.g., at a target site of the subject. Those skilled in the art reading this disclosure will understand that the degradation rate of the provided polymer combination preparation may vary, for example, based on the type of poloxamer and / or the selection of a second polymer (e.g., in some embodiments, a carbohydrate polymer such as hyaluronic acid and / or chitosan as described herein) and their material properties and / or concentrations (e.g., as described herein). For example, the half-life of the provided polymer combination preparation (the time it takes for 50% of the polymer combination preparation to decompose into monomers and / or other non-polymeric parts) may be approximately several days, weeks, months, or years. In some embodiments, the polymer combination preparations described herein may be biologically degraded, for example, by enzymatic activity or cellular mechanisms, for example, by exposure to lysozyme (e.g., having a relatively low pH), or by simple hydrolysis. In some examples, the provided polymer combination preparations may be decomposed into monomers (e.g., monomers of polymers) and / or non-polymeric parts that are non-toxic to cells. As will be understood by those skilled in the art, the provided polymer combination preparations have a longer residual time at the target site (e.g., tumor resection site) upon administration if such a provided polymer combination preparation has a slower degradation rate in vivo.

[0257] In some embodiments, the polymer combination preparations provided herein remain substantially homogeneous (e.g., without detectable phase separation) when stored at a temperature of 4°C to 10°C (e.g., 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or 10°C) for a certain period of time, for example, at least one week (e.g., including at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least two months, at least three months, at least four months, at least five months, at least six months, or longer). In some embodiments, the polymer combination preparations provided herein remain substantially homogeneous (e.g., without detectable phase separation) when stored at room temperature for a certain period of time, for example, at least one week (e.g., including at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least two months, at least three months, at least four months, at least five months, at least six months, or longer).

[0258] In some embodiments, the polymer combination preparations provided herein may be characterized by the fact that, when stored at a temperature of 4°C to 10°C (e.g., 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or 10°C) for a certain period of time, for example, at least one week (e.g., including at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least two months, at least three months, at least four months, at least five months, at least six months, or longer), 20% or less of the polymer combination preparation (e.g., including 15% or less, 10% or less, 8% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less) is degraded (e.g., by biodegradation or chemical degradation). In some embodiments, the polymer combination preparations provided herein may be characterized in that, when stored at room temperature for a certain period of time, for example, at least one week or more (e.g., including at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least two months, at least three months, at least four months, at least five months, at least six months, or longer), 20% or less (e.g., including 15% or less, 10% or less, 8% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or less) of the polymer combination preparation is degraded (e.g., by biodegradation or chemical degradation).

[0259] In some embodiments, when the provided polymer combination preparations are evaluated in vivo by administration to a target site under test (e.g., a tumor resection site) (e.g., as described herein), at least 10% (e.g., including at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) of such provided polymer combination preparations remain at the target site in vivo two days or more after administration. In some embodiments, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, or less of such provided polymer combination preparations remain at the target site in vivo two days or more after administration. Combinations of the above are also possible. For example, in some embodiments, the provided polymer combination preparations are characterized in that, when evaluated in vivo by administration to a target site under test (e.g., a tumor resection site) (e.g., as described herein), 30% to 80% or 40% to 70% of such provided polymer combination preparations remain at the target site in vivo at least two days after administration.

[0260] In some embodiments, when the provided polymer combination preparations are evaluated in vivo by administration to a target site under test (e.g., a tumor resection site) (e.g., as described herein), at least 10% (e.g., including at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) of such provided polymer combination preparations remain at the target site in vivo at least 3 days after administration. In some embodiments, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, or less of such provided polymer combination preparations remain at the target site in vivo at least 3 days after administration. Combinations of the above are also possible. For example, in some embodiments, the provided polymer combination preparations are characterized in that, when evaluated in vivo by administration to a target site under test (e.g., a tumor resection site) (e.g., as described herein), 30% to 80% or 40% to 70% of such provided polymer combination preparations remain at the target site in vivo at least 3 days after administration.

[0261] In some embodiments, when the provided polymer combination preparations are evaluated in vivo by administration to a target site under test (e.g., a tumor resection site) (e.g., as described herein), at least 10% (e.g., including at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more) of such provided polymer combination preparations remain at the target site in vivo at least 5 days after administration. In some embodiments, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, or less of such provided polymer combination preparations remain at the target site in vivo at least 5 days after administration. Combinations of the above are also poss...

Claims

1. A polymer combination preparation comprising at least first and second polymer components, wherein the first polymer component is a poloxamer, the second polymer component is a carbohydrate polymer, and the polymer combination preparation transitions from a liquid precursor state to a gelled polymer network state in response to the body temperature of the subject. The gelled polymer network state includes crosslinks that are not present in the liquid precursor state. The aforementioned crosslinking is intramolecular crosslinking, intermolecular crosslinking, or both, or includes the same. The first polymer component is present in the polymer combination preparation at a concentration of at least 5% (w / w) and less than 12.5% ​​(w / w), A preparation comprising the polymer combination preparation, wherein the second polymer component is present in the polymer combination preparation at a concentration of at least 1% (w / w) and less than 10% (w / w).

2. The preparation according to claim 1, wherein the crosslinking does not include crosslinking by covalent bonds.

3. The preparation according to claim 1 or 2, wherein the polymer combination preparation comprises a polymer in a total content of at least 10% (w / w).

4. The preparation according to any one of claims 1 to 3, wherein the critical gelation weight ratio of the first polymer component to the second polymer component is 1:1 to 14:1 or 1:1 to 10:

1.

5. The preparation according to any one of claims 1 to 4, wherein the polymer network state is a viscous solution or colloid.

6. The preparation according to any one of claims 1 to 4, wherein the polymer network state is a hydrogel.

7. The preparation according to claim 6, characterized in that when the polymer network state is tested in vitro at 37°C, the polymer combination preparation releases the lipophilic agent incorporated therein at a rate equivalent to that of a hydrogel formed from a P407 solution having a concentration of 18% (w / w).

8. The preparation according to any one of claims 1 to 7, characterized in that when the polymer network state is tested in vitro at 37°C, more than 60% of the lipophilic agent incorporated in the polymer combination preparation can be retained therein for at least 24 hours.

9. The preparation according to any one of claims 1 to 7, characterized in that when the polymer network state is tested in vitro at 37°C, 40% or less of the lipophilic agent incorporated in the polymer combination preparation can be released therefrom within 24 hours.

10. The preparation according to any one of claims 1 to 9, characterized in that when the polymer network state is tested in vitro at 37°C, the polymer combination preparation releases the hydrophilic agent incorporated therein at a rate equivalent to or faster than the rate at which a hydrogel formed from a P407 solution having a concentration of 18% (w / w).

11. The preparation according to any one of claims 1 to 10, characterized in that when the polymer network state is tested in vitro at 37°C, the polymer combination preparation releases the hydrophilic agent incorporated therein at a faster rate (e.g., at least 20% faster within 48 hours) compared to a chemically crosslinked hyaluronic acid hydrogel.

12. The preparation according to claim 11, wherein the chemically crosslinked hyaluronic acid hydrogel is a hydrogel formed by mixing thiol-modified hyaluronic acid (Glycosil®) with a thiol-reactive PEGDA crosslinking agent (Extralink®) under conditions that cause gelation.

13. The preparation according to any one of claims 1 to 12, characterized in that when the polymer network state is tested in vitro at 37°C, at least 40% of the hydrophilic agent incorporated in the polymer combination preparation is released therefrom within 12 hours.

14. The preparation according to claim 1, wherein the carbohydrate polymer in the polymer combination preparation is present at a concentration of less than about 5% (w / w).

15. The preparation according to claim 1 or 14, wherein the carbohydrate polymer is hyaluronic acid or comprises the same.

16. The preparation according to claim 15, wherein the hyaluronic acid has a molecular weight of about 50 kDa to about 2 MDa.

17. The preparation according to claim 16, wherein the hyaluronic acid has a low molecular weight of about 100 to 500 kDa, about 100 to 400 kDa, about 125 to 375 kDa, or about 100 to 200 kDa.

18. The preparation according to claim 16, wherein the hyaluronic acid has a high molecular weight of about 500 to 1,500 kDa or about 600 to 800 kDa.

19. The preparation according to claim 1 or 14, wherein the carbohydrate polymer is chitosan or modified chitosan, or comprises the same.

20. The preparation according to claim 19, wherein the modified chitosan is carboxymethyl chitosan or comprises the same.

21. The polymer network state is a. Storage modulus in the range of 100 Pa to approximately 10,000 Pa, measured at 37°C and pH 5 to 8. b. A storage modulus at least 40% lower than that of a hydrogel formed from a solution containing poloxamer at a solution concentration of 18% (w / w), and c. The preparation according to any one of claims 1 to 20, characterized by one or more material properties selected from the storage modulus measured at 37°C (or, when measured at 37°C, 20% or less of the polymer combination preparation decomposes over a period of one month), wherein the precursor state is maintained substantially the same after being stored at 2 to 8°C for one month.

22. The preparation according to any one of claims 1 to 21, wherein the polymer combination preparation has a pH of 4.5 to 8.

5.

23. The preparation according to any one of claims 1 to 22, wherein the polymer combination preparation has a pH of 7 to 8 (for example, a pH of 7.4).

24. The preparation according to any one of claims 1 to 23, wherein the polymer combination preparation has a higher buffering capacity than a 10 mM phosphate buffer.

25. The preparation according to any one of claims 1 to 24, wherein the poloxamer is poloxamer 407 or comprises the same.

26. The preparation according to any one of claims 1 to 25, further comprising a therapeutic agent.

27. The preparation according to claim 26, wherein the therapeutic agent is an analgesic, an antibiotic, an anticoagulant, an antiemetic, a coagulant, or a wound healing agent, or comprises the same.

28. The preparation according to claim 26, wherein the therapeutic agent is an immunomodulatory agent payload or comprises one.

29. The preparation according to claim 28, wherein the immunomodulatory agent payload is or comprises a modulator of innate immunity.

30. The preparation according to claim 28 or 29, wherein the immunomodulatory payload is a modulator of myeloid cell function or comprises the same.

31. The preparation according to any one of claims 28 to 30, wherein the immunomodulatory payload is or comprises an adaptive immunity modulator.

32. The preparation according to any one of claims 28 to 30, wherein the immunomodulatory payload is or comprises an inflammation modulator.

33. The preparation according to claim 32, wherein the immunomodulatory agent payload is a TLR7 / 8 agonist or comprises a TLR7 / 8 agonist.

34. The preparation according to claim 32, wherein the immunomodulatory agent payload is or comprises regiquimod.

35. The preparation according to claim 32, wherein the immunomodulatory agent payload is a COX2 inhibitor or comprises one.

36. The preparation according to claim 32, wherein the immunomodulatory agent payload is an NSAID (e.g., ketorolac) or comprises the same.

37. The preparation according to any one of claims 1 to 36, wherein, when the polymer combination preparation includes an immunomodulatory agent payload, the polymer combination preparation has a higher survival rate than a comparable group of test animals having the polymer combination preparation without the immunomodulatory agent payload at the tumor resection site when evaluated two months after administration of the polymer combination preparation.

38. The preparation according to claim 37, wherein the polymer combination preparation in a polymer network state is delivered to the tumor resection site by administering a preparation containing the polymer combination preparation pre-formed in a polymer network state to the tumor resection site during surgery.

39. The preparation according to claim 37, wherein the polymer combination preparation in the polymer network state transitions to the polymer network state at the tumor resection site after administration, and the preparation containing the polymer combination preparation in the precursor state is delivered to the tumor resection site by administering the preparation to the tumor resection site during surgery.

40. The preparation according to any one of claims 1 to 39, wherein the first polymer component is present in the polymer combination preparation at a concentration of 11% (w / w) or less.

41. The preparation according to any one of claims 1 to 39, wherein the first polymer component is present in the polymer combination preparation at a concentration of 10.5% (w / w) or less.

42. The preparation according to any one of claims 1 to 39, wherein the first polymer component is present in the polymer combination preparation at a concentration of 10% (w / w) or less.

43. The preparation according to any one of claims 1 to 42, wherein the first polymer component is present in the polymer combination preparation at a concentration of at least 6% (w / w).

44. A preparation according to any one of claims 1 to 43, for administration to a subject that requires administration.

45. The preparation according to claim 44, wherein the subject requiring administration is a subject suffering from cancer.

46. The preparation according to claim 45, wherein the subject requiring the administration is suffering from or is susceptible to recurrent or disseminated cancer.

47. The preparation according to any one of claims 44 to 46, wherein the subject requiring the administration is a subject of tumor resection surgery.

48. The preparation according to claim 47, characterized in that the preparation is administered to the tumor resection site or within 2 cm thereof.

49. The preparation according to any one of claims 46 to 48, characterized in that the administration is by transplantation.

50. The preparation according to claim 49, characterized in that the preparation comprising the polymer combination preparation in the polymer network state is administered by transplantation.

51. The preparation according to any one of claims 46 to 48, characterized in that the administration is by injection.

52. The preparation according to claim 51, characterized in that the preparation containing the polymer combination preparation in the precursor state is administered by injection, and the precursor state transitions to the polymer network state upon administration.

53. The preparation according to any one of claims 46 to 52, characterized in that the administration is performed simultaneously with or after the laparoscopy.

54. The preparation according to any one of claims 46 to 52, characterized in that the administration is performed simultaneously with or after minimally invasive surgery.

55. The preparation according to any one of claims 46 to 52, characterized in that the administration is performed simultaneously with or after robotic surgery.

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