Injectable shear-thinning hydrogel containing therapeutic agent for enhanced tumor treatment

Abstract

This invention provides compositions for drug delivery in cancer treatment and immunotherapy. [Solution] A composition is provided comprising polymer gelatin, silicate nanoparticles, and a therapeutic agent having a molecular weight of less than 1000 daltons, wherein the gelatin, the silicate nanoparticles, and the therapeutic agent form a shear-thinning hydrogel.

Description

Technical Field

[0001] The present invention relates to shear-thinning biomaterials containing bioactive agents, as well as methods for making and using them.

Background Art

[0002] Shear-thinning hydrogels are non-Newtonian materials that behave as viscous fluids under shear stress and then recover solid-like properties when the stress is removed [1]. Due to these properties, injectable shear-thinning biomaterials (STBs) have attracted attention as a group of self-healing materials that enable fluid injection and local equilibrium after approaching the final application site. In clinical applications, STBs can be delivered into the body by hand pressure using a needle or a general / micro catheter [2-4]. To optimize clinical applications, it is necessary to adjust the physical properties of STBs according to specific clinical situations. By changing the physical properties, hydrogels suitable for specific clinical applications (e.g., occluding blood vessels of a specific size, controlled drug release, and adjusting the stiffness of tissue engineering scaffolds) can be synthesized.

[0003] The physical properties of conventional STBs can be modulated by combinations of several carbon-based, polymer, and inorganic nanomaterials [5–8]. Several biomaterials, such as gelatin, hyaluronic acid, chitosan, collagen, and alginates, have been previously used in conjunction with inorganic components to form STBs [14–17]. Gelatin, in particular, demonstrates substantially improved hemocompatibility of STBs in vitro by limiting the adsorption of nonspecific proteins, enhancing hemolysis, and ultimately prolonging coagulation time

[18] . Furthermore, the application of gelatin in tissue engineering and regenerative medicine has been approved by the Food and Drug Administration (FDA) [19–21]. Conventional STBs are prepared by mixing gelatin with LAPONITE®, a synthetic clay nanoparticle, for hemostasis and intravascular embolization [18, 22]. These STBs exhibit strong shear-thinning behavior, as well as biocompatibility ranging from blood coagulation to minimal inflammatory response. Other researchers have expanded this study to implement STBs as embolizers

[23] , functionalized scaffolds [24, 25], 3D bioinks

[26] , and drug delivery systems

[27] . Unfortunately, however, synthetic clay nanoparticles such as LAPONITE are crystalline nanoparticles, and their size and surface chemistry are not easily controlled. In addition, the biocompatibility of LAPONITE in various in vivo applications needs further investigation, and this fact makes its use in clinical applications difficult.

[0004] For the reasons stated above, there is a need in the art for new shear-reducing materials and methods for their fabrication and use. [Overview of the Initiative]

[0005] As discussed below, the inventors have developed novel shear-thinning biomaterials using spherical silica nanoparticles, gelatin-based polymers, and small molecule therapeutic agents. In an exemplary embodiment, the inventors have developed a doxorubicin-loaded injectable shear-thinning biomaterial (STB) using silicate nanoplatelets (LAPONITE XLG) and a gelatin-based polymer. Shear-thinning biomaterial technology offers unique properties that allow internally loaded drugs to be easily and directly delivered to a target region through a needle or catheter. The inventors focused on the fact that shear-thinning biomaterials are 1) injectable and easy to apply, and 2) exhibit high localization due to high mechanical stability after injection. Accordingly, in this embodiment, the inventors loaded the shear-thinning biomaterial with doxorubicin, an anticancer agent, to treat solid tumors.

[0006] The invention disclosed herein has many embodiments. Embodiments of the invention include, for example, compositions comprising polymer gelatin, silicate nanoparticles, and a therapeutic agent having a molecular weight of less than 1000 daltons. In such compositions, the amounts of gelatin, silicate nanoparticles, and therapeutic agent are selected to form a shear-thinning hydrogel. In a particular embodiment of the present invention, the composition comprises about 1% (w / w) to about 5% (w / w) of polymer gelatin (e.g., polymer gelatin in any of the ranges of about 1% (w / w) to about 2% (w / w) to about 3% (w / w) to about 4% (w / w) to about 5% (w / w)) (in other words, a range between any two of the above values), and about 1% (w / w) to about 5% (w / w) of silicate nanoparticles (e.g., silicate nanoparticles in any of the ranges of about 1% (w / w) to about 2% (w / w) to about 3% (w / w) to about 4% (w / w) to about 5% (w / w)).

[0007] In certain embodiments of the present invention, the composition comprises about 0.5% (w / w) to about 85% (w / w) of polymer gelatin and silicate nanoparticles (e.g., gelatin and silicate nanoparticles in any of the following ranges: about 0.5% (w / w) to about 1% (w / w) to about 2% (w / w) to about 5% (w / w) to about 10% (w / w) to about 25% (w / w) to about 50% (w / w) to about 75% (w / w) to about 85% (w / w)). In certain embodiments of the present invention, the ratio of silicate nanoparticles to polymer gelatin is about 1.0 to about 0.1 (e.g., in any of the following ranges: about 1.0 to about 0.9 to about 0.8 to about 0.7 to about 0.6 to about 0.5 to about 0.4 to about 0.3 to about 0.2 to about 0.1). In certain embodiments, the polymer gelatin is methacrylated gelatin (GelMA), acrylic gelatin, or thiolated gelatin. In certain embodiments, the composition contains about 0.5% (w / w) to about 99% (w / w) of water (for example, water in any of the following ranges: about 0.5% (w / w) to about 1% (w / w) to about 2% (w / w) to about 5% (w / w) to about 10% (w / w) to about 25% (w / w) to about 50% (w / w) to about 75% (w / w) to about 90% (w / w) to about 95% (w / w) to about 97.5% (w / w) to about 99% (w / w)). In certain embodiments, the simplest solution includes about 0.01% (w / w) to about 20% (w / w) of the therapeutic agent (for example, a therapeutic agent in any of the following ranges: about 0.01% (w / w) to about 0.02% (w / w) to about 0.5% (w / w) to about 1% (w / w) to about 2% (w / w) to about 5% (w / w) to about 10% (w / w) to about 15% (w / w) to about 20% (w / w)).

[0008] Typically, these compositions further include pharmaceutically acceptable excipients selected from the group consisting of preservatives, tonicity modifiers, surfactants, viscosity modifiers, sugars, and pH modifiers. In some embodiments of the present invention, the composition further includes human cancer cells. The compositions of the present invention include one or more small molecule therapeutic agents (e.g., anti-inflammatory agents, coagulation modifiers, antibiotics, chemotherapeutic agents, etc.). Exemplary therapeutic agents include alkaloids (e.g., paclitaxel, vinblastine, and vincristine), antimetabolites (e.g., gemcitabine, 5-fluorouracil, and methotrexate), antibiotics and antibiotic derivatives (e.g., doxorubicin, daunorubicin, and bleomycin), and hormonal antineoplastic agents (e.g., tamoxifen, diethylstilbestrol, and polyestradiol phosphate). In certain exemplary embodiments of the present invention, the therapeutic agent is doxorubicin.

[0009] In some embodiments of the present invention, the amount of the component is such that less than 15% or 20% of the drug is released from the shear-thinning hydrogel over a period of 15 days when placed in an environment having a pH of 7.4, and more than 15% or 20% is released from the shear-thinning hydrogel over a period of 15 days when placed in an environment having a pH of 5.0. In certain embodiments of the present invention, the shear-thinning hydrogel requires an injection force of at least 5 Newtons but less than 30 Newtons to extrude the shear-thinning hydrogel from a 0.8 mm (2.4 Fr) catheter / 1 mL (1 cc) syringe.

[0010] A further embodiment of the present invention is a method for preparing a shear-thinning biocompatible composition disclosed herein, comprising combining spherical silica nanoparticles, gelatin, and small therapeutic molecules such as doxorubicin, and optionally pharmaceutically acceptable excipients, to form a shear-thinning biocompatible composition. In specific embodiments of these methods, the surface properties of the spherical silica nanoparticles, the median diameter of the spherical silica nanoparticles, the relative amount of the spherical silica nanoparticles, and / or the relative amount of gelatin, etc., are selected to adjust or modulate one or more rheological properties or therapeutic release profile of the shear-thinning biocompatible composition. By adjusting the mechanical properties of the composition of the present invention in this manner, embodiments of the present invention can be adapted for use in a variety of different clinical applications.

[0011] Another embodiment of the present invention is a method for delivering a shear-thinning biocompatible composition disclosed herein to a pre-selected site (e.g., an in vivo site including cancer cells). Typically, such a method includes the steps of: placing the composition in a container (e.g., a catheter) having a first end and a second end including an opening; applying a force to the second end of the container, such that the force is sufficient to liquefy the composition; and then delivering the composition from the container through the opening to the pre-selected site. In some embodiments, the container includes a syringe loaded with the composition, and the syringe is configured to be in fluid communication with a needle and / or catheter tube. Embodiments of such a method include therapeutic regimens that use a shear-thinning biocompatible composition disclosed herein to deliver a therapeutic agent. In certain embodiments, the disclosure covers a method for treating a solid tumor in a subject requiring it, comprising the step of administering to the subject a therapeutically effective amount of a shear-thinning biocompatible composition disclosed herein. In certain embodiments, the solid tumor is selected from vascular tumors, brain tumors (e.g., meningioma or glioblastoma), spinal cord tumors, carotid body tumors, liver cancer, lung cancer, neuroendocrine tumors, kidney tumors, pancreatic tumors, or prostate tumors. In certain embodiments, the solid tumor is selected from skin cancers (e.g., melanoma, mast cell tumors, squamous cell carcinoma, or basal cell tumors), breast cancer, sarcomatous tumors (e.g., fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, or chondrosarcoma), and lymphomatous tumors. In certain embodiments, the composition is administered to a local area requiring treatment. In certain embodiments, the composition provides sustained release of a therapeutically effective amount of the therapeutic agent to the local area. In certain embodiments, the local area includes a solid tumor. In certain embodiments, the composition provides tumor embolization and sustained release of a therapeutically effective amount of the therapeutic agent to the tumor.

[0012] Other objects, features, and advantages of the present invention will become apparent to those skilled in the art from the following detailed description. However, it should be understood that the detailed description and specific examples illustrate, but are not limiting, some embodiments of the present invention. Many changes and modifications can be made within the scope of the present invention without departing from the spirit of the invention, and the present invention includes all such modifications. [Brief explanation of the drawing]

[0013] [Figure 1] Figures 1A, 1B, and 1C show release profile data from various compositions of doxorubicin-loaded STB under different pH conditions. [Figure 2] Figures 2A, 2B, and 2C show injection power data from various compositions of STB. [Figure 3] Figures 3A, 3B, and 3C show the rheological properties of various compositions of STB. [Figure 4] Figure 4A shows photographs of various doxorubicin-loaded STBs. Figure 4B provides a schematic diagram of an in vitro study to evaluate the direct contact anticancer effect of doxorubicin-loaded STBs. Figure 4C provides a schematic diagram of an in vitro study to evaluate the anticancer effect of doxorubicin-loaded STBs by transwell release. [Figure 5] Figures 5A, 5B, and 5C show data from in vitro anticancer efficacy evaluations of doxorubicin-loaded STBs via direct contact. [Figure 6] Figures 6A, 6B, and 6C show data from the evaluation of in vitro anticancer efficacy by Transwell release of doxorubicin-loaded STBs. [Figure 7] Figure 7A shows data from an in vivo anticancer efficacy study of DOX-STB for melanoma. Figure 7B shows data from tumor growth curves of melanoma-carrying mice with doxorubicin-loaded STBs. Figure 7C shows data from a tumor weight study on the day of slaughter. [Modes for carrying out the invention]

[0014] The description of embodiments may refer to accompanying drawings illustrating specific embodiments that form part of this specification and can carry out the invention. It should be understood that other embodiments may be used and structural modifications may be made without departing from the scope of the invention. Unless otherwise defined, all technical terms, notations, and other scientific or technical terms used herein are intended to have meanings generally understood by those skilled in the art to which the invention pertains. In some cases, terms having generally understood meanings are defined herein for clarity and / or for ease of reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a substantial difference from those generally understood in the art. Many of the aspects of techniques and procedures described or referenced herein are well understood and commonly used by those skilled in the art. The following text describes various embodiments of the invention.

[0015] Shear-thinning biomaterial (STB) technology offers unique properties that allow internally loaded solid polymers and drugs to be easily delivered directly to a target region by means such as catheters. Considering this, the inventors have developed a novel class of shear-thinning biomaterials using silica nanoparticles and gelatin-based polymers. Embodiments of the present invention include, for example, shear-thinning biocompatible compositions comprising silica nanoparticles and gelatin. Among inorganic composite compositions, silica is considered one of the most biocompatible materials, classified as "Generally Recognized As Safe (GRAS)" by the FDA. Considering this, silicate nanoparticles have been used in the pharmaceutical, cosmetic, and food industries as active ingredients or rheological modifiers due to their uniform particle size and surface charge and bioactive properties [9, 10]. In addition, the size, structure, and surface properties of silica nanoparticles can be easily controlled, and these properties allow silica nanoparticles to provide a class of useful materials for a wide variety of biomedical applications.

[0016] The compositions of the present invention may comprise further components (e.g., further polymers, excipients, therapeutic agents, etc.). For example, the compositions of the present invention may comprise one or more FDA-approved polymers or cell-compatible polymers. Examples of such polymers include alginates, chitosan, collagen, hyaluronic acid (HA), chondroitin sulfate (ChS), dextrin, gelatin, fibrin, peptides, and silk. Synthetic polymers (e.g., poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), poloxamer (Pluronic®) (PEO-PPO-PEO), polyoxamine (Tetronic®) (PEO-PPO), poly(vinyl alcohol) (PVA), poly(lactic acid-co-glycolic acid) (PLGA), poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polycaprolactone (PCL), poly(L-glutamic acid) (PLga), polyanhydride, poly(N-isopropylacrylamide) (PNIPAAm), polyaniline, etc.) may also be included in the compositions of the present invention. As is known in the art, hydrogel preparations may be made to include materials that are crosslinked either chemically or physically.

[0017] Certain embodiments of the compositions of the present invention include, for example, pharmaceutically active ingredients (selected from the group consisting of, for example, preservatives, tonicity modifiers, surfactants, viscosity modifiers, sugars, and pH modifiers). For compositions suitable for administration to humans, the term “excipients” means, but is not limited to, the components described in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2006) (the contents of which are incorporated herein by reference).

[0018] If necessary, the compositions of the present invention include one or more small molecule therapeutic agents (i.e., those having a molecular weight of less than 1,000 daltons) (e.g., anti-inflammatory agents, coagulation modulators, antibiotics, chemotherapeutic agents, etc.). In embodiments of the present invention disclosed herein, the small molecule therapeutic agent is doxorubicin. The compositions of the present invention can be formulated for use as carriers or scaffolds for therapeutic agents such as drugs, cells, proteins, and bioactive molecules (e.g., enzymes). As carriers, such compositions can incorporate drugs and deliver them to desired sites in the body for the treatment of various pathological conditions. Pathological conditions include, for example, infectious and inflammatory diseases (e.g., Parkinson's disease, bacterial and antimicrobial infections, diabetes, etc.), as well as cancers (e.g., colon cancer, lung cancer, breast cancer, ovarian cancer, lymphoma, etc.). Furthermore, as scaffolds, the compositions of the present invention can provide flexible retention spaces for cells and other agents for use in tissue repair and regeneration of desired tissues (e.g., repair of cartilage, bone, retina, brain, and nerve tissue, vascular regeneration, wound healing, etc.). Furthermore, embodiments of the present invention may include, for example, immunomodulators useful in immunotherapy to enhance components of the immune system. Specific exemplary materials and methods suitable for use in such embodiments of the present invention can be found, for example, in Hydrogels: Design, Synthesis and Application in Drug Delivery and Regenerative Medicine 1st Edition, Singh, Laverty and Donnelly Eds; and Hydrogels in Biology and Medicine (Polymer Science and Technology) UK ed. Edition by J. Michalek et al.

[0019] Embodiments of the present invention include, for example, compositions comprising polymer gelatin, silicate nanoparticles, and a therapeutic agent having a molecular weight of less than 1000 daltons. In such compositions, the amounts of gelatin, silicate nanoparticles, and therapeutic agent are selected to form a shear-thinning hydrogel. In certain embodiments of the present invention, the composition comprises about 1% to about 5% polymer gelatin and about 1% to about 5% silicate nanoparticles. Typically, these compositions further include pharmaceutically active ingredients selected from the group consisting of preservatives, tonicity modifiers, surfactants, viscosity modifiers, sugars, and pH modifiers. In some embodiments of the present invention, the composition further comprises human cancer cells. In exemplary embodiments of the present invention, the therapeutic agent is doxorubicin.

[0020] In some embodiments of the present invention, the composition is placed in a container (e.g., a catheter) selected for its ability to facilitate the user's adjustment of one or more rheological properties of the composition. Specific exemplary materials and methods that may be adapted for use in embodiments of the present invention can be found, for example, in Biomedical Hydrogels: Biochemistry, Manufacture and Medical Applications (Woodhead Publishing Series in Biomaterials) 1st Edition; Steve Rimmer (Editor). As shown in Figures 3A-3C, which represent exemplary embodiments of the present invention, the components of the composition are selected to provide desired rheological properties.

[0021] Another embodiment of the present invention is a method for delivering a shear-thinning biocompatible composition disclosed herein to a pre-selected site (e.g., an in vivo site where an individual has experienced trauma or injury, or exhibits a lesion such as cancer). Typically, such a method includes the steps of: placing the composition in a container (e.g., a catheter) having a first end and a second end including an opening; applying a force to the second end of the container, such that the force is sufficient to liquefy the composition; and then delivering the composition from the container through the opening to the pre-selected site. Embodiments of such a method include, for example, therapeutic regimens using the shear-thinning biocompatible composition disclosed herein to deliver a therapeutic agent, as shown in Figures 4A-4C.

[0022] Yet another embodiment of the present invention is a method of making a shear-thinning biocompatible composition disclosed herein, the method comprising combining silica nanoparticles and gelatin, a small molecule therapeutic agent, and optionally a pharmaceutical excipient together to form a shear-thinning biocompatible composition. In certain embodiments of these methods, surface properties of the silica nanoparticles, the median diameter of the silica nanoparticles, the relative amount of silica nanoparticles, and / or the relative amount of gelatin, etc. are selected to adjust or regulate one or more rheological properties of the shear-thinning biocompatible composition. By adjusting the mechanical properties of the compositions of the present invention in this manner, embodiments of the present invention can be adapted for use in a variety of different clinical applications. In this regard, for example, U.S. Patent Application Publication Nos. 20050227910, 20100120149, 20120315265, 20140302051, and 20190290804; as well as Lee, Biomaterials Research volume 22, Article number: 27 (2018); Thambi et al., J Control Release. 2017 Dec 10; 267: 57-66. doi: 10.1016 / j.jconrel.2017.08.006. Epub 2017 Aug 4; and Gianonni et al., Biomater. Sci., 2016 (the contents of which are incorporated by reference), and a variety of other materials and methods recognized in the art can be adapted for use in embodiments of the present invention.

[0023] Exemplary Materials and Methods of the Present Invention As an exemplary embodiment of the present invention, the inventors developed a doxorubicin-loaded injectable shear-thinning biomaterial (STB) using silicate nanoplates (LAPONITE XLG) and gelatin-based polymers. Shear-thinning biomaterial technology provides unique properties that enable the drug loaded inside to be easily delivered directly to the target area through a needle or catheter. The inventors focused on the fact that the shear-thinning biomaterial is 1) injectable and easy to apply, and 2) exhibits high localization due to its high mechanical stability after injection. Therefore, the inventors loaded the anti-cancer drug doxorubicin into the shear-thinning material to treat solid tumors.

[0024] The inventors tested three different STB compositions (gelatin 4.5% / LAPONITE 1.5% [6NC25]; gelatin 3.0% / LAPONITE 3.0% [6NC50]; gelatin 1.5% / LAPONITE 4.5% [6NC75]) for doxorubicin-loaded biomaterials. The release profiles were analyzed for 30 days under three pH conditions (pH 5.0, 6.0, 7.4) (Figures 1A, 1B, 1C). Gelatin released doxorubicin within 3 days regardless of the pH condition, while LAPONITE released less than 20% of doxorubicin only under acidic conditions. Interestingly, all three STB compositions showed high release of doxorubicin under acidic conditions of pH 5, but little release at 7.4, the normal physiological pH. It was also observed that the higher the LAPONITE ratio, the lower the release of doxorubicin. Injection force measurements showed that all three compositions tested by the inventors could be delivered via a 0.8 mm (2.4 Fr) microcatheter and a 1.66 mm (5 Fr) general catheter (Figures 2A, 2B, 2C). All STB compositions were within the preferred injection force range (<30 N), but the injection force was higher with a higher LAPONITE content. Rheology measurements showed that all STB compositions exhibited shear-thinning properties (non-Newtonian behavior, viscosity decreases as shear rate increases), and the storage modulus was found to be higher with a higher LAPONITE content (Figures 3A, 3B, 3C).

[0025] The inventors prepared two types of STBs by mixing gelatin polymer and LAPONITE, and then added a doxorubicin solution to create doxorubicin-loaded STBs (DOX-STBs) (Figure 4A). To determine the in vitro anticancer efficacy of DOX-STBs, the inventors devised two types of in vitro tests. First, to analyze the anticancer efficacy of DOX-STBs in contact with tumors, B16F10 melanoma cells were seeded on culture plates, and then two STBs loaded with four ranges of doxorubicin were applied (Figure 4B). Other in vitro models were identified using a Transwell-release anticancer efficacy model to analyze the anticancer efficacy of doxorubicin released from DOX-STBs rather than in direct contact (Figure 4C). Both direct contact and Transwell-release in vitro models were analyzed for anticancer efficacy by performing viability staining 1, 3, and 7 days after DOX-STB application. Direct contact in vitro anticancer efficacy analysis showed that STB itself did not exhibit anticancer effects, while most tumor cells were killed at doxorubicin concentrations of 10 ug / g or higher (Figures 5A, 5B, 5C). Similarly, indirect Transwell release results showed that tumor cells were killed at DOX-STB concentrations of 10 ug / g or higher (Figures 6A, 6B, 6C).

[0026] Finally, the in vivo anticancer efficacy of DOX-STB was analyzed in a melanoma tumor model created by subcutaneously injecting B16F10 melanoma tumor cells into C57Bl / 6J mice (Figure 7A). Generally, as in in vitro experiments, STB itself did not show anticancer efficacy, but tumor size decreased in all groups treated with doxorubicin (DOX, DOX-6NC25, DOX-6NC75). Tumor growth curves measured every two days by calypsoas showed that both doxorubicin-treated groups inhibited melanoma growth (Figure 7B). Interestingly, the median tumor weights for DOX-6NC25 and DOX-6NC75 were lower than those for DOX (Figure 7C).

[0027] In summary, our DOX-STB exhibits the following characteristics: 1) pH-dependent doxorubicin release (doxorubicin release at acidic pH), 2) DOX release is adjustable according to changes in the STB composition, 3) doxorubicin released directly and / or from the DOX-STB can kill tumor cells, and 4) the DOX-STB can inhibit tumor growth in animal models.

[0028] In summary, the inventors have developed novel shear-thinning biomaterials having composites of doxorubicin, gelatin, and biocompatible silica nanoparticles with various properties. By adjusting the properties of the silica nanoparticles, such as the particle size and composition of the gelling / silica nanoparticles, the mechanical and rheological properties can be carefully tuned to meet different requirements. All compositions used in these experiments are injectable through catheters of different sizes. Rheological tests showed rapid recovery and mechanical stability due to the shear-thinning properties. Gelatin-silica nanoparticle-based STBs exhibit excellent biological stability, thermogenic extrusion, shear-thinning behavior, and rapid network recovery. These attractive physicochemical properties are advantageous for easy in vivo administration, and gelatin-silica nanoparticle-based STBs may hold great potential for drug delivery, intravascular embolization, tissue regeneration, bioprinting, and other biomedical applications.

[0029] References

[0030] [Table 1-1]

[0031] [Table 1-2]

[0032] [Table 1-3]

[0033] All publications referenced herein (for example, the references listed numerically above, and U.S. Patent Application Publication No. 20180104059) are incorporated herein by reference to disclose and describe aspects, methods, and / or materials in relation to the cited publications.

[0034] The appendices included in this provisional application provide a disclosure of the invention formatted for publication in a journal. This disclosure illustrates various aspects and embodiments of the invention. These appendices are incorporated herein by reference.

Claims

1. Polymer gelatin and, Silicate nanoparticles and A therapeutic agent having a molecular weight of less than 1000 daltons, A composition comprising the gelatin, the silicate nanoparticles, and the therapeutic agent, which form a shear-thinning hydrogel.

2. Approximately 1% to 5% polymer gelatin, Approximately 1% to 5% silicate nanoparticles, The composition according to claim 1, comprising:

3. 7. When placed in an environment with a pH of 4, less than 15% or 20% of the drug is released from the shear-thinning hydrogel over a period of 15 days. The composition according to claim 2, wherein when placed in an environment having a pH of 5.0, 15% or more than 20% is released from the shear-thickened hydrogel over a period of 15 days.

4. The composition according to claim 3, wherein the therapeutic agent is doxorubicin.

5. The composition according to claim 1, wherein the shear-thinning hydrogel requires an injection force of at least 5 Newtons but less than 30 Newtons to extrude the shear-thinning hydrogel from a 0.8 mm (2.4 Fr) catheter / 1 mL (1 cc) syringe.

6. The composition according to claim 1, further comprising human cancer cells.

7. The composition according to claim 1, further comprising a pharmaceutically acceptable excipient selected from the group consisting of preservatives, tonicity adjusters, surfactants, viscosity modifiers, sugars, and pH adjusters.

8. The composition according to claim 1, wherein the composition is placed inside a catheter.

9. The composition according to claim 1, wherein the silicate nanoparticles include LAPONITE.

10. A method for delivering a composition according to any one of claims 1 to 9 to a pre-selected site, The steps include placing the composition in a container having a first end and a second end, which include an opening, A step of applying force to the second end of the container, wherein the force is sufficient to liquefy the composition, The steps include delivering the composition from the container to the pre-selected portion through the opening, Methods that include...

11. The method according to claim 10, wherein the aforementioned site is an in vivo site.

12. The method according to claim 11, wherein the aforementioned site is located in vivo and contains cancer cells.

13. The method according to claim 10, wherein the container is a catheter.

14. A method for preparing the composition according to any one of claims 1 to 9, comprising combining silica nanoparticles, gelatin, a therapeutic agent having a molecular weight of less than 1,000 daltons, and optionally a pharmaceutical excipient to form a shear-thinning biocompatible composition.

15. The method according to claim 14, wherein the relative amounts of silica nanoparticles and / or gelatin are selected to adjust or modulate one or more rheological properties of the composition and / or the release profile of the therapeutic agent from the shear-thinning hydrogel.

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