Biocompatible polymers for tumor imaging and radiotherapy

Abstract

This document discloses a polymer for application at a treatment site to form a hydrogel, thereby physically separating / isolating target tissue for radiotherapy. The polymer comprises: a first monomer for binding water; a second monomer for imparting mechanical properties; optionally, a third monomer for binding to a natural or synthetic peptide or protein (NSPP); and a fourth monomer for imparting phase transition behavior. Preferably, the first monomer is OEGMA; the second monomer is PLA / HEMA; the third monomer is NAS; and the fourth monomer is NIPAAm. The polymer comprises: about 1 to about 15 mol% of OEGMA; 5 mol% to about 50 mol% of PLA / HEMA; 0 mol% to about 15 mol% of NAS; and up to about 85 mol% of NIPAAm. Preferably, the target tissue is a human prostate. Preferably, the polymer is applied in an aqueous solution, such as saline, at a concentration up to about 280 mg / mL.

Description

Related applications

[0001] This application claims Convention priority to Australian Provisional Patent Application No. 2023903450, filed on 27 October 2023. The contents of AU'450 are incorporated herein by reference in their entirety. Invention Field

[0002] This invention relates to biocompatible polymers, and the inventors have unexpectedly discovered that such polymers can be used as physical “spacers” and / or “water separation solutions” in tumor imaging and radiotherapy.

[0003] This invention also relates to the discovery that, at concentrations above about 100 mg / mL, the applicant's proprietary polymers PNPHO and PPHO can be used to create spaces between different organs by forming a hydrogel at the application site. Such observations have three main applications: 1) creating spaces to reduce the effects of therapeutic radiation on surrounding tissues; 2) filling gaps to reduce / normalize air pockets and thus improve the accuracy of dosing calculations; and 3) protecting tissues such as rectal tissue from direct radiation exposure.

[0004] The present invention also relates to the discovery that the applicant’s proprietary polymers PNPHO and PPHO, at concentrations between about 25 mg / mL and about 100 mg / mL, can be used as non-irritating solutions visible under ultrasound and / or CT scans for water separation of different tissues. Such observations have two main applications: (1) injection into tissues to separate target tissues; and (2) visibility under ultrasound and / or CT scans to facilitate more precise needle placement / water separation.

[0005] Therefore, this invention is intended to play a role in the medical field, and more specifically in oncology and related fields.

[0006] Although the invention will be described below with reference to its preferred embodiments, those skilled in the art will understand that the spirit and scope of the invention may be embodied in many other forms. Background of the Invention

[0007] Any discussion of prior art throughout the specification should not be construed as an admission that such prior art is well-known or constitutes part of common general knowledge in the art.

[0008] Despite recent advances in focused beam technology, radiation therapy for cancer inevitably involves the exposure of unaffected tissue. Therefore, patients may experience symptoms associated with damage to normal tissue during treatment, which can persist for weeks, months, or even years after treatment. Symptoms may be due to cell death induced within the irradiated tissue or wound healing and may be exacerbated by further damage or trauma. Many factors contribute to the risk and severity of reactions in normal tissue. These factors are site-specific and change over time after treatment.

[0009] Radiation therapy for cancer is based on the fact that rapidly dividing cells are more sensitive to radiation. Cancer is composed of rapidly dividing cells, so cancer cells are expected to be more sensitive to radiation than normal tissue. The main challenge of radiation therapy is to eradicate cancer without excessively damaging the surrounding normal tissue. Even today, the amount of radiation delivered to a tumor is still limited by collateral damage to nearby normal tissue.

[0010] Treatments are being developed to reduce the risk or severity of damage to normal tissues or to promote the healing of radiation injuries. This could significantly improve the quality of life for cancer patients. The severity and frequency of side effects on normal tissues can be reduced through modern, more precise therapies, such as particle therapy, which can be used to reduce the radiation dose to normal tissues to decrease side effects, or to improve tumor control through dose escalation.

[0011] The prostate gland is both an accessory gland of the male reproductive system and a muscular mechanical switch between urination and ejaculation. Anatomically, the prostate is located below the bladder, through which the urethra passes. It is also very close to the rectum, penis, testes, seminal vesicles, and lymph nodes.

[0012] Prostate cancer is one of the most common cancers affecting older men throughout the Western world. When deciding on a treatment, the two main options are prostatectomy (i.e., removal) or radiation therapy. Radiation can be administered in several ways, including brachytherapy (using a seed implanted in the patient's body) and external beam radiation therapy (projecting energy through the skin).

[0013] Given the location of the prostate as described above, the potential side effects of external beam radiotherapy for prostate cancer can be extensive and may include urinary frequency, difficulty or pain during urination, hematuria, urinary incontinence, abdominal cramps, diarrhea, painful defecation, rectal bleeding, rectal leakage, fatigue, sexual dysfunction (including decreased erectile function or reduced semen volume), skin reactions (similar to sunburn), and secondary cancer in the irradiated area.

[0014] In extreme cases, the potential for significant damage to adjacent cells or organs would preclude the use of radiation therapy in the treatment of prostate cancer. Therefore, any method to reduce the patient's risk profile must always be a goal for radiation oncologists and therapists (who may be called radiation technicians).

[0015] Hydrodissection is the use of a directed jet of water to separate tissue during surgery. It is commonly used to create tissue planes or divide soft tissue, resulting in less trauma compared to dissection using cutting instruments. By using appropriate pressure, tissue separation tends to follow the path of least resistance, close to the direction of the jet. For example, in placing hydrogel spacers, hydrodissection is used to create space in the perirectal fat before applying the hydrogel. Alternatively, in cataract surgery, hydrodissection is used to lift the capsule membrane from the lens by projecting a continuous stream of water through a cannula below the flap of the anterior capsule, thereby releasing the lens from its capsule. By guiding the water flow, the surgeon lifts the membranes surrounding the sides and back of the capsule until the lens is completely dislodged. Hydrodissection is also used in general surgery to release compressed nerves or reduce intraoperative blood loss, etc.

[0016] In various branches of the biomedical field, the applicant—Trimph IP Pty Ltd of Sydney, Australia—has been working for the past decade to patent a suite of biocompatible polymers for pharmaceutical applications. All patents and patent publications mentioned herein are incorporated herein by reference in their entirety.

[0017] WO 2013 / 091001 (PCT / AU2012 / 001566) relates to polymers, particularly polymers that can be used as hydrogels, and to the use of hydrogels for tissue repair or restoration. Specifically, the polymers and hydrogels of WO'001 can be used for the repair or restoration of cartilage, particularly articular cartilage. The polymer contains at least a monomer for binding water, a monomer for imparting mechanical properties, and a monomer for binding extracellular proteins. The hydrogel contains at least a polymer containing a monomer for binding water and a monomer for binding extracellular proteins. The polymer is cross-linked by binding extracellular matrix proteins, thereby forming the hydrogel.

[0018] The preferred polymer disclosed in WO'001 is poly(NIPAAm-co-NAS-co-(PLA / HEMA)-co-OEGMA), i.e., "PNPHO". The polymer PNPHO preferably comprises: about 1 mol% to about 15 mol% of OEGMA, about 5 mol% to about 50 mol% of PLA / HEMA, up to 15 mol% of NAS, and the balance to make up 100% of the polymer composition, for example, about 50 mol% to about 85 mol% of NIPAAm. For clarity, the percentages refer to the final polymer composition, not the feed amounts used to form the polymer.

[0019] The preferred form of polymer PNPHO is a polymer of formula (I) shown below. Furthermore, x is 1-1000, y is 1-1000, and m, n, p, and q are 1-20. Those skilled in the art will recognize that monomers A, B, C, and D can be present in the polymer in any order, as long as the desired water-binding, reinforcing, and / or crosslinking capabilities are achieved.

[0020] WO 2017 / 035587 (PCT / AU2016 / 050817) discloses biocompatible materials that can be used for tissue regeneration and repair, wherein the bioactive polymer can be in the form of a hydrogel, such as a thermoresponsive hydrogel. The bioactive polymer of WO'587 and the resulting hydrogel can be used for bone tissue regeneration. Therefore, this reference teaches a method for treating bone defects in mammals, comprising applying a therapeutically effective amount of a hydrogel formed from a bioactive polymer to the mammal to treat the bone defect.

[0021] WO 2017 / 015703 (PCT / AU2016 / 050653) discloses a polymer comprising at least one antiseptic / analgesic / anti-inflammatory monomer unit in combination with at least three other monomer units, said three other monomer units causing properties selected from the group consisting of: temperature activation, water solubility, mechanical strength, protein / polysaccharide binding capacity, and combinations thereof. Specifically, WO'703 discloses a polymer wherein the water-soluble monomer unit is a hydrophilic ethylene glycol (OEGMA) moiety; the monomer unit imparting mechanical strength is polylactide-co-2-hydroxy-ethyl methacrylate (PLA / HEMA); the protein-reactive monomer unit is an N-acryloyloxysuccinimide (NAS) moiety; and the thermosetting monomer unit is an N-isopropylacrylamide (NIPAAm) moiety. The antibacterial / analgesic / anti-inflammatory monomer unit comprises a methacrylate derivative of salicylic acid (5-HMA or 4-HMA, or a combination thereof).

[0022] WO 2021 / 119727 (PCT / AU2020 / 051332) teaches compositions comprising a polymer and a natural or synthetic peptide or protein (NSPP) (such as thymosin β-4). The polymer comprises a first monomer for binding water, a second monomer for imparting mechanical properties, a third monomer for binding with the NSPP, and a fourth monomer for imparting phase transition behavior. Specifically, the composition forms a viscous and flowable hydrogel upon application to the body or to a body surface, thereby facilitating tissue repair and regeneration. Therefore, WO'727 discloses a method for tissue repair and / or regeneration comprising applying the composition by injection or by application of an aerosol, thereby forming a hydrogel at mammalian body temperature.

[0023] Finally, WO 2023 / 201397 (PCT / AU2023 / 050329) discloses a new polymer “PPHO”, namely, poly(N-isopropylacrylamide-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric(ethylene glycol) / poly(NIPAAm-co-(PLA / HEMA)-co-OEGMA)).

[0024] The polymer PPHO preferably comprises: about 1 mol% to about 15 mol% of OEGMA, about 5 mol% to about 50 mol% of PLA / HEMA, and the balance to make up 100% of the polymer composition, for example, about 50 mol% to about 85 mol% of NIPAAm. In a preferred embodiment, PPHO comprises about 1 mol% to 15 mol% of OEGMA, and / or about 15 mol% to 50 mol% of PLA / HEMA, and / or about 50 mol% to 85 mol% of NIPAAM. As mentioned above, the percentages stated herein refer to the composition of the final polymer, not the amount of feed used to form the polymer.

[0025] The purpose of this invention is to overcome or improve at least one of the disadvantages of the prior art, or to provide a useful alternative.

[0026] There is a general need in this field for new methods to mitigate damage to surrounding cells / tissues caused by radiotherapy used to treat diseases such as prostate cancer.

[0027] There is a general need in the field for new methods to reduce damage to tissues separated during water separation procedures.

[0028] It is against this backdrop that the present invention was developed. Various embodiments of the present invention can satisfy one or more of the aforementioned general needs.

[0029] Specifically, the present invention has been found to be useful for establishing safe, non-irritating, CT-scan-visible, and injectable physical spacers between irradiated organs (e.g., prostate) and surrounding cells / tissues / organs (e.g., rectum).

[0030] Furthermore, the present invention has been found to be useful for developing safe, non-irritating, ultrasound-visible, and injectable solutions for hydrolysis of various tissues (e.g., perirectal fat).

[0031] Although the invention will be described with reference to specific embodiments, those skilled in the art will understand that the invention may be embodied in many other forms. Summary of the Invention

[0032] In a broader sense, this invention relates to the application of polymers to treatment sites at or near target tissue (e.g., the human prostate), whereby the polymer forms a hydrogel at body temperature. Such hydrogels can have various applications for radiation oncology and broader medical purposes, including: 1) application as a non-irritating solution, visualized by ultrasound, for precise hydroaspiration (e.g., for perirectal fat). This hydroaspiration is facilitated by precisely injecting a solution of the polymer of the invention to prevent side effects such as rectal wall infiltration during the application of the separator; 2) providing a physical separation between tissue and nearby cells / tissues / organs (e.g., the human rectum). This physical separation / isolation of the prostate and rectum allows radiotherapy to be focused on the separated target tissue without substantially affecting the cells / tissues / organs separated from it by the polymer hydrogel; and 3) use as a space-filler to reduce the presence of balloons / cavities in targeted radiotherapy (e.g., after breast mass resection and MammoSite treatment). The hydrogel filler of the present invention for removing airbags / air cavities can reduce the inhomogeneity of airbags / air cavities in targeted radiotherapy (e.g., MammoSite), and thereby reduce dose errors in tissues located near the air / tissue interface due to the lack of attenuation and inverse square correction.

[0033] According to a first aspect of the invention, a polymer is provided for application at a treatment site to form a hydrogel, the hydrogel physically spaced / isolated target tissue for radiotherapy and / or hydrolyzed tissue / organ and / or physically spaced / isolated target tissue for radiotherapy and / or filled a site to reduce air pockets, the polymer comprising: The first monomer used for binding water; The second monomer used to impart mechanical properties; Optionally, a third monomer for binding to natural or synthetic peptides or proteins (NSPPs); and The fourth monomer used to impart phase transition behavior.

[0034] According to a second aspect of the invention, a polymer is provided for application at a treatment site to form a hydrogel that physically hydrolyzes two or more adjacent tissues, the polymer comprising: The first monomer used for binding water; The second monomer used to impart mechanical properties; Optionally, a third monomer for binding to natural or synthetic peptides or proteins (NSPPs); and The fourth monomer used to impart phase transition behavior.

[0035] The preferred embodiments outlined below are applicable to the first and second aspects of the invention, unless otherwise stated.

[0036] In the implementation scheme, the polymer is poly(NIPAAm-co-NAS-co-(PLA / HEMA)-co-OEGMA), i.e., "PNPHO". The polymer PNPHO preferably comprises: about 1 mol% to about 15 mol% of OEGMA, about 5 mol% to about 50 mol% of PLA / HEMA, up to 15 mol% of NAS, and the balance to make up 100% of the polymer composition, for example, about 50 mol% to about 85 mol% of NIPAAm.

[0037] In the embodiments, the polymer is poly(N-isopropylacrylamide-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric (ethylene glycol) / poly(NIPAAm-co-(PLA / HEMA)-co-OEGMA), i.e., "PPHO". The polymer PPHO preferably comprises: about 1 mol% to about 15 mol% of OEGMA, about 5 mol% to about 50 mol% of PLA / HEMA, and the balance of NIPAAm to make up 100% of the polymer composition, for example, about 50 mol% to about 85 mol%).

[0038] In the implementation scheme, the first monomer is selected from: polyether, polyvinyl alcohol (PVA); poly(vinylpyrrolidone) (PVP); poly(amino acid) and dextran.

[0039] In the implementation scheme, the polyether is selected from: polyethylene glycol (PEG), oligomeric (ethylene glycol) (OEG), polyethylene oxide (PEO), polyethylene oxide-co-propylene oxide (PPO), copolymerized ethylene oxide blocks or random copolymers thereof.

[0040] In the implementation scheme, the first monomer is oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA).

[0041] In the embodiments, the second monomer is a methacrylate or a random copolymer containing a methacrylate.

[0042] In the implementation scheme, the second monomer is selected from: hydroxyethyl methacrylate (HEMA), hydroxyethyl methacrylate poly(lactic acid) copolymer (PLA / HEMA), poly(lactic acid), poly(caprolactone), poly(glycolic acid), poly(glycolic acid), poly(glycolic acid-co-glycolic acid), or poly(glycolic acid-co-caprolactone).

[0043] In the implementation scheme, the second monomer is hydroxyethyl methacrylate poly(lactic acid) (PLA / HEMA).

[0044] In the implementation scheme, the third monomer has an electrophilic functional group for binding with NSPP.

[0045] In the embodiments, the third monomer is selected from: N-hydroxysulfosuccinimide (SNHS), N-hydroxyethoxysuccinimide (ENHS) and N-acryloyloxysuccinimide (NAS).

[0046] In the implementation scheme, the third monomer is N-acryloyloxysuccinimide (NAS).

[0047] In the implementation scheme, the fourth monomer has a low critical solution temperature (LCST) of less than about 37°C.

[0048] In the embodiments, the fourth monomer is selected from homopolymers and copolymers of poly(ethylene oxide) / poly(propylene oxide) and poly(N-isopropylacrylamide) (PNIPAAm).

[0049] In the implementation scheme, the fourth monomer is (N-isopropylacrylamide) (NIPAAm).

[0050] In the implementation scheme, the polymer contains a first monomer in an amount of about 1 mol% to about 15 mol%.

[0051] In the implementation scheme, the polymer contains a second monomer in an amount of about 5 mol% to about 50 mol%.

[0052] In the implementation scheme, the polymer contains a third monomer in an amount of about 0 mol% to about 15 mol%.

[0053] In the implementation scheme, the polymer contains about 50 mol% to about 85 mol% of a fourth monomer.

[0054] In the embodiments, the polymer comprises: a first monomer in an amount of about 1 mol% to about 15 mol%; a second monomer in an amount of about 5 mol% to about 50 mol%; a third monomer in an amount of 0 mol% to about 15 mol%; and a fourth monomer in an amount that makes up the balance of the polymer to 100%.

[0055] In the implementation scheme, the first monomer is OEGMA; the second monomer is PLA / HEMA; the third monomer is NAS; and the fourth monomer is NIPAAm. The polymer comprises: about 1 mol% to about 15 mol% of OEGMA; 5 mol% to about 50 mol% of PLA / HEMA; 0 mol% to about 15 mol% of NAS; and up to about 85 mol% of NIPAAm.

[0056] In the implementation scheme, in order to apply the polymer to the treatment site, it is dissolved or dispersed in an aqueous solution at a polymer concentration greater than about 100 mg / mL.

[0057] Regarding the first aspect, the polymer concentration is greater than approximately 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 mg / mL.

[0058] Regarding the first aspect, in one embodiment, in order to apply the polymer to the treatment site, it is dissolved or dispersed in an aqueous solution at a polymer concentration greater than about 280 mg / mL.

[0059] In an embodiment of the first aspect, the target tissue for radiotherapy is the human prostate gland. In other embodiments, the target tissue for radiotherapy is the human head and neck, chest and breast, abdomen and gastrointestinal organs, pelvis, genitourinary system and colorectal organs, limbs, or skin.

[0060] In an embodiment of the first aspect, the polymer is applied to the treatment site by injection. Alternatively, the polymer may be applied transdermally or via implantation.

[0061] In an embodiment of the first aspect, where the prostate is the target tissue, a polymer is injected between the patient's rectum and the prostate to provide temporary space between the organs, thereby reducing the radiation dose delivered to the rectum.

[0062] Regarding a second aspect of the invention, in order to apply the polymer to the treatment site, it is dissolved or dispersed in an aqueous solution at a polymer concentration of about 25 mg / mL to about 100 mg / mL.

[0063] In an embodiment of the second aspect, the concentration of the polymer in the aqueous solution is about 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, or about 100 mg / mL.

[0064] In the second aspect of the implementation, the polymer is applied to the treatment site by injection.

[0065] In the implementation scheme, the first monomer is OEGMA; the second monomer is PLA / HEMA; the third monomer is NAS; and the fourth monomer is NIPAAm.

[0066] In the embodiments, the polymer comprises: about 1 mol% to about 15 mol% of OEGMA; 5 mol% to about 50 mol% of PLA / HEMA; 0 mol% to about 15 mol% of NAS; and up to about 85 mol% of NIPAAm.

[0067] In the implementation plan, the target tissue for radiotherapy is the human prostate gland; and In the implementation scheme, the polymer is present at a concentration of approximately 280 mg / mL.

[0068] According to a third aspect of the invention, a method for physically separating / isolating target tissue for radiotherapy is provided, the method comprising administering an effective concentration of a polymer as defined in the first aspect of the invention to a subject in need at or near the target tissue.

[0069] According to a fourth aspect of the invention, a method is provided for physically hydrolyzing two or more adjacent tissues at a treatment site, the method comprising administering an effective concentration of a polymer as defined in a second aspect of the invention to a subject in need at or near the treatment site.

[0070] The preferred embodiments outlined below are applicable to the third and fourth aspects of the invention, unless otherwise stated.

[0071] In an embodiment, the polymer comprises: a first monomer for binding water; a second monomer for imparting mechanical properties; optionally, a third monomer for binding with natural or synthetic peptides or proteins (NSPPs); and a fourth monomer for imparting phase transition behavior.

[0072] In the embodiments, the polymer comprises: about 1 mol% to about 15 mol% of OEGMA; 5 mol% to about 50 mol% of PLA / HEMA; 0 mol% to about 15 mol% of NAS; and up to about 85 mol% of NIPAAm.

[0073] In the implementation plan, the medication is applied at or near body temperature.

[0074] In this implementation, application is performed by injection. Alternatively, the polymer may be applied transdermally or via implantation.

[0075] In one implementation, the target tissue for radiotherapy is the human prostate gland. In other implementations, the target tissue for radiotherapy is the human head and neck, chest and breast, abdomen and gastrointestinal organs, pelvis, genitourinary system and colorectal organs, limbs, or skin.

[0076] In an embodiment of the third aspect, in order to apply the polymer to the treatment site, it is dissolved or dispersed in an aqueous solution at a polymer concentration greater than about 100 mg / mL.

[0077] Regarding the third aspect, the polymer concentration is greater than approximately 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 mg / mL.

[0078] In an embodiment of the third aspect, in order to apply the polymer to the treatment site, it is dissolved or dispersed in an aqueous solution at a polymer concentration of about 280 mg / mL.

[0079] Regarding the third aspect, the polymer concentration is greater than approximately 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 or 500 mg / mL.

[0080] Regarding the third aspect, in cases where the prostate is the target tissue, a polymer is injected between the patient's rectum and prostate to provide temporary space between the organs, thereby reducing the radiation dose delivered to the rectum.

[0081] Regarding a fourth aspect of the invention, in order to apply the polymer to the treatment site, it is dissolved or dispersed in an aqueous solution at a polymer concentration of about 25 mg / mL to about 100 mg / mL.

[0082] In an embodiment of the fourth aspect, the polymer concentration in the aqueous solution is about 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, or about 100 mg / mL.

[0083] In the fourth aspect of the implementation, the polymer is applied to the treatment site by injection.

[0084] According to a fifth aspect of the invention, the use of a polymer as defined in the first aspect of the invention is provided in the preparation of a medicament for physically separating / isolating target tissues for radiotherapy.

[0085] According to a sixth aspect of the invention, the use of a polymer as defined in a second aspect of the invention is provided in the preparation of a medicament for physically separating two or more adjacent tissues at a therapeutic site.

[0086] The preferred embodiments outlined below are applicable to the fifth and sixth aspects of the invention, unless otherwise stated.

[0087] In an embodiment, the polymer comprises: a first monomer for binding water; a second monomer for imparting mechanical properties; optionally, a third monomer for binding with natural or synthetic peptides or proteins (NSPPs); and a fourth monomer for imparting phase transition behavior.

[0088] In the embodiments, the polymer comprises: about 1 mol% to about 15 mol% of OEGMA; 5 mol% to about 50 mol% of PLA / HEMA; 0 mol% to about 15 mol% of NAS; and up to about 85 mol% of NIPAAm.

[0089] In the implementation plan, the medication is applied at or near body temperature.

[0090] In this implementation, application is performed by injection. Alternatively, the polymer may be applied transdermally or via implantation.

[0091] In one implementation, the target tissue for radiotherapy is the human prostate gland. In other implementations, the target tissue for radiotherapy is the human head and neck, chest and breast, abdomen and gastrointestinal organs, pelvis, genitourinary system and colorectal organs, limbs, or skin.

[0092] In an embodiment of the fifth aspect, in order to apply the polymer to the treatment site, it is dissolved or dispersed in an aqueous solution at a polymer concentration greater than about 100 mg / mL.

[0093] Regarding the fifth aspect, the polymer concentration is greater than approximately 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 mg / mL.

[0094] In an embodiment of the fifth aspect, in order to apply the polymer to the treatment site, it is dissolved or dispersed in an aqueous solution at a polymer concentration of about 280 mg / mL.

[0095] Regarding the fourth aspect of the invention, the polymer concentration is preferably greater than about 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 or 500 mg / mL.

[0096] In a fifth embodiment, where the prostate is the target tissue, a polymer is injected between the patient's rectum and prostate to provide temporary space between the organs, thereby reducing the radiation dose delivered to the rectum.

[0097] According to a seventh aspect of the invention, a kit is provided for physically separating / isolating target tissue for radiotherapy, the kit comprising: a polymer as defined in a first aspect of the invention; a means for applying the polymer; and instructions for applying the polymer at or near the target tissue.

[0098] In an embodiment, the polymer comprises: a first monomer for binding water; a second monomer for imparting mechanical properties; optionally, a third monomer for binding with natural or synthetic peptides or proteins (NSPPs); and a fourth monomer for imparting phase transition behavior.

[0099] In the embodiments, the polymer comprises: about 1 mol% to about 15 mol% of OEGMA; 5 mol% to about 50 mol% of PLA / HEMA; 0 mol% to about 15 mol% of NAS; and up to about 85 mol% of NIPAAm.

[0100] In the implementation plan, the medication is applied at or near body temperature.

[0101] In this implementation, application is performed by injection. Alternatively, the polymer may be applied transdermally or via implantation.

[0102] In one implementation, the target tissue for radiotherapy is the human prostate gland. In other implementations, the target tissue for radiotherapy is the human head and neck, chest and breast, abdomen and gastrointestinal organs, pelvis, genitourinary system and colorectal organs, limbs, or skin.

[0103] In the implementation scheme, in order to apply the polymer to the treatment site, it is dissolved or dispersed in an aqueous solution at a polymer concentration of about 280 mg / mL.

[0104] Preferably, the polymer concentration is greater than about 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 or 500 mg / mL.

[0105] In one implementation, where the prostate is the target tissue, a polymer is injected between the patient's rectum and prostate to provide temporary space between the organs, thereby reducing the radiation dose delivered to the rectum.

[0106] In another embodiment, in order to apply the polymer to the treatment site, it is dissolved or dispersed in an aqueous solution at a polymer concentration of about 25 mg / mL to about 100 mg / mL.

[0107] In the embodiments, the concentration of the polymer in the aqueous solution is about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 mg / mL.

[0108] Definition and naming In describing and claiming protection for this invention, the following terms will be used in accordance with the definitions listed below. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0109] Unless the context explicitly requires otherwise, throughout the specification and claims, the words “comprising”, “including”, etc., shall be interpreted as having a inclusive meaning, the opposite of an exclusive or exhaustive meaning; in other words, meaning “including but not limited to”.

[0110] The terms "preferred" and "ideally" refer to embodiments of the invention that may provide specific benefits in certain circumstances. However, other embodiments may also be preferred in the same or other circumstances. Furthermore, the description of one or more preferred embodiments does not imply that other embodiments are unavailable, nor is it intended to exclude other embodiments from the scope of the invention.

[0111] As used herein, the wording defining a range or length limit, such as “1 to 5”, refers to any integer from 1 to 5, i.e., 1, 2, 3, 4, and 5. In other words, any range defined by two explicitly mentioned integers is intended to include and disclose any integer that defines the limit, as well as any integer contained within that range.

[0112] Except as described in the working examples or otherwise, all figures used herein to indicate the amount of an ingredient or reaction condition should be understood to be modified by the term “about” in all cases. The examples are not intended to limit the scope of the invention. Unless otherwise stated below, “%” will mean “weight %”, “ratio” will mean “weight ratio”, and “parts” will mean “parts by weight”.

[0113] Although the numerical ranges and parameters illustrating the broad scope of the invention are approximate, the values ​​described in the specific embodiments are reported as precisely as possible. However, any numerical value inherently contains some error, which is necessarily caused by the standard deviation present in their respective test measurements.

[0114] The following abbreviations are used in this instruction manual: Attached Figure Description

[0115] Preferred embodiments of the invention will now be described by way of example only with reference to the accompanying drawings, in which: Injected PNPHO and / or PPHO aqueous solutions form hydrogels at body temperature. Figure 1 The simulation tests shown confirm that the polymer hydrogel has a CT-Henry unit (HU) of 10 to 60, which is similar to the equivalent values ​​of water and soft tissue, and is therefore suitable for ensuring accurate radiation oncology by obtaining the relationship between HU and the electron density of the structure exposed to the radiation beam. Figure 1 The setup for obtaining CT-Henness units of the polymer hydrogel is shown (simulated at 37°C). The simulation was performed using 280 mg / mL PNPHO hydrogel and daily quality assurance (QA) LAP Wike Phantom. Visualization of the polymer hydrogel is indicated by yellow arrows.

[0116] Figure 2 This indicates that the injected one or more polymers form a hydrogel at body temperature, which in turn provides structure / space for at least 6 weeks. Subcutaneous injection of the hydrogel in a mouse model confirmed that the product physically provides structure / space for at least 6 weeks after injection. Thus, the results confirm that the injected PHPHO and / or PPHO aqueous solution forms a hydrogel at body temperature at the application site, thereby creating space to (i) reduce the effects of therapeutic radiation on surrounding tissues; (ii) fill gaps to reduce air sacs / restore air sacs to normal, and thus improve the accuracy of dosing calculations; and (iii) protect tissues (e.g., dermis) from direct radiation exposure.

[0117] Figure 3 The ultrasound measurement of the injected hydrogel after injection is shown. The results confirm that the hydrogel is clearly visible at the application site. The measurement was completed, and the calculated volume of the hydrogel (~0.27 mL) is similar to the actual injected volume (0.25 mL). Distance 1 = 9.9 mm; distance 2 = 5.1 mm; and distance 3 = 10.3 mm; calculated volume = 0.27 mL.

[0118] Figure 4 shows the Heinz unit output of TL150-IOPXX (defined below) in the subcutaneous injection model. Figure 4a It is TL150-IOP20 (i.e., containing 20 mg I / mL iohexol in 150 mg / mL PPHO); and Figure 4b It is TL150-IOP40 (i.e., 40 mg I / mL iohexol in 150 mg / mL PPHO). The results confirmed that the PPHO formulation in iohexol is radiopaque.

[0119] Figure 5 Product visibility during and after gelation of TL150-IOP40 (i.e., 40 mg I / mL iohexol in 150 mg / mL PPHO) is shown by TRUS (transrectal ultrasound) visibility measurement (confirmed by topup, increasing the initial volume of product injection).

[0120] Figure 6 The volume formation after gelation is shown and is visible on CT. The spacer spans observed were 13.7 mm (487 HU) and 11.85 mm (385 HU).

[0121] Figure 7 The space generated at the injection site is shown after water separation and injection of 2 × 6 mL TL150-IOP40. Detailed Implementation

[0122] The invention will now be described more fully with reference to the accompanying embodiments and drawings. However, it should be understood that the following description is illustrative only and should not be construed in any way as limiting the generality of the invention described above.

[0123] Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with embodiments, it should be understood that the invention is not limited to these embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined in the claims.

[0124] Those skilled in the art will recognize that many methods and materials similar to or equivalent to those described herein can be used in the practice of this invention. This invention is by no means limited to the methods and materials described.

[0125] It should be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more individual features mentioned or obvious from the text or drawings. All these different combinations constitute various alternative aspects of the invention.

[0126] This article broadly discloses the use of biocompatible polymers applied to or near target tissues at therapeutic sites, whereby the polymer forms a hydrogel at body temperature to provide a physical separation between the tissue and nearby cells / tissues / organs (e.g., the human rectum). This physical separation / isolation of the prostate and rectum allows radiotherapy to be focused on the isolated target tissue without substantially affecting the cells / tissues / organs separated from it by the polymer hydrogel.

[0127] polymer As used herein, the term "polymer" refers to a macromolecule (high molecular weight polymer) composed of repeating structural units (monomers). These subunits are typically linked by covalent chemical bonds. The polymer can be a linear or branched polymer. Preferably, the polymer of the present invention is a copolymer comprising three or more different monomers. For example, in one embodiment, the polymer of the present invention comprises: a first water-binding monomer, a second monomer capable of imparting mechanical properties to the polymer, and a third monomer having functional groups for binding with NSPP.

[0128] As used herein, the term "monomer" refers to a structural unit that can be combined to form a polymer, but it can also be a polymer itself, or a derivative of a monomer or polymer. The latter type of monomer is also referred to herein as a "macromonomer." In this context, a "macromonomer" is a polymer or oligomer whose molecules each have an end group that acts as a monomer molecule, such that each polymer or oligomer molecule contributes only a single monomer unit to the chain of the product polymer.

[0129] The polymer of the present invention comprises: a first monomer for binding water; a second monomer for imparting mechanical properties to the polymer; optionally, a third monomer for binding to natural or synthetic peptides or proteins (NSPPs); and a fourth monomer for imparting phase transition behavior.

[0130] First monomer: Water-bound monomer As described above, the advantages of the polymers of the present invention can be attributed at least in part to the specific components constituting the polymers. A particularly advantageous property of the polymers of the present invention is their water-binding capacity. The presence of water in the polymers of the present invention provides both an environment similar to the natural environment of damaged tissue (which facilitates tissue regeneration) and provides the polymer with the required compressive strength.

[0131] Therefore, the preferred polymers used herein should contain monomers or units capable of binding water to achieve the ability to form malleable structures when the polymer is hydrated. Furthermore, the resulting structures should possess the required compressive strength and resilience.

[0132] Those skilled in the art will understand that the water-binding monomers need to be present in the polymers of the present invention in proportions sufficient to produce polymers that meet these requirements. Typically, the molar ratio of water-binding monomers in the polymer is about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:10, about 1:20, about 1:30, about 1:40, or about 1:50. In practice, the water-binding monomers not only need to make the polymer hydrophilic, but also need to impart a much greater water-binding capacity to the polymer. Therefore, the polymers according to the present invention will have a water-binding capacity of about 70% to about 500%, about 80% to about 400%, about 90% to 300%, or about 100% to 200%. For example, the water-binding capacity of the polymer of the present invention is about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, about 310%, about 320%, about 330%, about 340%, about 350%, about 360%, about 370%, about 380%, about 390%, about 400%, about 410%, about 420%, about 430%, about 440%, about 450%, about 460%, about 470%, about 480%, about 490%, or about 500%.

[0133] Suitable examples of water-binding monomers include those that can be synthesized into polymers, such as polyethers (e.g., polyalkylene oxides such as polyethylene glycol (PEG), oligomeric (ethylene glycol) (OEG), polyethylene oxide (PEO), polyethylene oxide-co-propylene oxide (PPO), copolymers of ethylene oxide block or random copolymers, polyvinyl alcohol (PVA)), polyvinylpyrrolidone (PVP), poly(amino acids), and dextran. Polyethers, and more specifically oligomeric (olefin oxides) (e.g., OEG), are particularly preferred because they possess the necessary water-binding capacity, are readily synthesized and / or available, and are inert, i.e., they elicit minimal or no immune response in the tissue in which they are placed.

[0134] Furthermore, any of a variety of hydrophilic functional groups can be used to make monomers (and thus polymers formed from such monomers) water-soluble. For example, water-soluble functional groups such as phosphates, sulfates, quaternary ammonium groups, hydroxyl groups, amines, sulfonates, and carboxylates can be introduced into monomers to make them water-soluble.

[0135] Monomers can also react with other compounds to form "macromonomers". Therefore, the first monomer can optionally be a macromonomer.

[0136] The preferred first monomer for macromolecular monomers is oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA), which is a hydrophilic monomer composed of two hydrophilic monomers, ethylene glycol and methacrylate.

[0137] Preferably, the polymer comprises a first monomer in an amount of about 1 mol% to about 15 mol%. In various embodiments, the first monomer may be present in the form of about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, or about 15 mol%. In various embodiments, the first monomer may be present in the form of about 1 mol% to about 15 mol%, about 2 mol% to about 14 mol%, about 3 mol% to about 13 mol%, about 4 mol% to about 12 mol%, about 5 mol% to about 11 mol%, about 6 mol% to about 10 mol%, about 7 mol% to about 9 mol%, or about 8 mol%.

[0138] Second monomer: The monomer that imparts mechanical properties As described above, the advantageous properties of the polymers of the present invention can be attributed in part to the specific components constituting the polymers of the present invention. In some embodiments, the polymers of the present invention are able to provide additional mechanical properties and adhesiveness to the polymers of the present invention.

[0139] Those skilled in the art will understand that monomers capable of imparting mechanical properties to polymers need to be present in the polymers of the present invention in proportions sufficient to produce polymers with the desired mechanical properties. Typically, the proportion of “mechanical” monomers in the polymer is a water-bound monomer to mechanical strength monomer molar ratio of about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:10, about 1:20, about 1:30, about 1:40, or about 1:50. Suitable examples of monomers capable of imparting mechanical properties (e.g., compressive strength) to polymers include acrylates (e.g., hydroxyethyl methacrylate (HEMA)), polyesters (e.g., poly(lactic acid), poly(caprolactone), poly(glycolic acid)) and their random copolymers (e.g., poly(glycolic acid-co-lactide) and poly(glycolic acid-co-caprolactone)).

[0140] Monomers can also react with other compounds to form "macromonomers". A preferred second monomer as a macromonomer is poly(lactic acid) hydroxyethyl methacrylate (PLA / HEMA).

[0141] Preferably, the polymer contains a second monomer in an amount of about 1 mol% to about 50 mol%. In various embodiments, the second monomer can be in the form of 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 It exists in mol%, about 42 mol%, about 43 mol%, about 44 mol%, about 45 mol%, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, or about 50 mol%.

[0142] In various embodiments, the second monomer can be in the range of about 1 mol% to about 15 mol%, about 2 mol% to about 49 mol%, about 3 mol% to about 48 mol%, about 4 mol% to about 47 mol%, about 5 mol% to about 46 mol%, about 6 mol% to about 45 mol%, about 7 mol% to about 44 mol%, about 8 mol% to about 43 mol%, about 9 mol% to about 42 mol%, about 10 mol% to about 41 mol%, about 11 mol% to about 40 mol%, about 12 mol% to about 39 mol%, about 13 mol% to about 38 mol%, about 14 mol% to about 37 mol%, about 15 mol% to about 36 mol%, about 16 mol% to about 35 mol%, about 17 mol% to about 34 mol%, about 18 mol% to about 33 mol%, about 19 mol% to about 34 mol%, about 20 mol% to about 33 mol%, about 21 mol% to about 30 mol%. It exists in mol%, about 22 mol% to about 29 mol%, about 23 mol% to about 28 mol%, about 24 mol% to about 27 mol%, or about 25 mol% to about 26 mol%.

[0143] Those skilled in the art will understand that the amount of the second monomer is more extensive than that of the other monomers, because mechanical strength and adhesion are key factors in this invention.

[0144] Third monomer: NSPP-binding monomer As described above, the polymers used in this invention can optionally be formed by combining the polymer with NSPP. For efficient combination of the polymer with NSPP, preferably, the polymer contains monomers or units with crosslinking capabilities.

[0145] This crosslinking ability means that the polymer can bind to NSPP, and in doing so, crosslink the NSPP to form a polymer containing NSPP. Alternatively, through a similar mechanism, NSPP acts as a crosslinking agent, thereby causing the polymer to crosslink to form a polymer.

[0146] In order to produce a polymer capable of binding with NSPP, those skilled in the art will understand that the monomers capable of binding with NSPP need to be present in the polymer of the present invention in a proportion sufficient to crosslink with NSPP such that a polymer can be formed in the presence of water. Typically, the ratio of "crosslinked" monomers in the polymer is about 15:1, about 10:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:10, or about 1:15 of crosslinked monomer:water-bound monomer.

[0147] Monomers that can bind to NSPP typically have electrophilic or nucleophilic functional groups, such that, for example, the nucleophilic functional group on the NSPP can react with the electrophilic functional group on the monomer to form a covalent bond.

[0148] Therefore, for example, if NSPP has a nucleophilic functional group such as an amine, the polymer can have an electrophilic functional group such as N-hydroxysuccinimide (NHS). Other electrophilic functional groups suitable for the present invention are N-hydroxysulfosuccinimide (SNHS) and N-hydroxyethoxysuccinimide (ENHS). An example of this type of monomer is N-acryloyloxysuccinimide (NAS). On the other hand, if NSPP has an electrophilic functional group, the polymer can have a nucleophilic functional group such as an amine or a thiol group.

[0149] Preferably, the polymer contains up to 15 mol% of a third monomer. In various embodiments, the third monomer may be present in the form of about 0 mol%, about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, or about 15 mol%. In various embodiments, the third monomer may be present in the form of about 0 mol% to about 1 mol%, about 1 mol% to about 15 mol%, about 2 mol% to about 14 mol%, about 3 mol% to about 13 mol%, about 4 mol% to about 12 mol%, about 5 mol% to about 11 mol%, about 6 mol% to about 10 mol%, about 7 mol% to about 9 mol%, or about 8 mol%.

[0150] Those skilled in the art will understand that polymers can be formed from hydrophobic compositions, and therefore a third monomer is optional in the polymer.

[0151] Fourth monomer: Phase change monomer In another embodiment of the invention, the polymer may further comprise a fourth monomer capable of imparting phase change properties to the polymer, thereby ensuring post-application stability. Furthermore, these phase change properties allow the polymers of the present invention to form polymers whose various properties (e.g., viscosity) can be altered by changing factors such as pH and temperature. The polymers are designed such that the low critical solution temperature (LCST) is below body temperature. A variety of thermally responsive and injectable polymers comprising poly(ethylene oxide) / poly(propylene oxide) and poly(N-isopropylacrylamide) (PNIPAAm) copolymers are suitable for use in the present invention.

[0152] Typically, the ratio of phase change monomers in the polymer is at least about 3:1 molar ratio of phase change monomer to water-bound monomer. This ratio can be increased to, for example, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, about 16:1, about 17:1, about 18:1, about 19:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, and about 85:1 molar ratios of phase change monomer to water-bound monomer.

[0153] Preferably, the polymer comprises a fourth monomer in an amount that makes up the 100% balance of the polymer group. In embodiments, the mol% of the fourth monomer can be up to about 85%, preferably about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85 mol%.

[0154] Other polymer properties Those skilled in the art will understand that by combining different types of monomers, polymers with a range of different properties can be produced. Furthermore, the properties of a polymer can be altered by introducing specific monomers or functional groups into a pre-existing polymer. For example, copolymerization of HEMA monomer with other monomers (e.g., methyl methacrylate) can be used to modify properties such as swelling and mechanical properties. Monomers can also react with other compounds to form macromonomers (as defined above), which are then included in the polymers of the present invention. For example, HEMA can react with lactide to form a HEMA-polylactic acid polymer (PLA / HEMA), which itself can be used as a monomer in the polymers of the present invention. Furthermore, the monomer itself can be a combination of monomer units that are then introduced into the polymer. An example of this type of monomer is oligomeric (ethylene glycol) monomethyl ether methacrylate (OEGMA), a hydrophilic monomer composed of two hydrophilic monomers, ethylene glycol and methacrylate.

[0155] The preferred polymers of the present invention can also be modified with one or more moieties and / or functional groups. Any moieties or functional groups can be used according to the present invention. In some embodiments, the polymer can be modified with polyethylene glycol (PEG), with carbohydrates, and / or with acyclic polyacetals derived from polysaccharides. Furthermore, as described above, hydrophilic groups can be introduced into the monomer (and thus the polymer) to increase the polymer's water-binding capacity.

[0156] In terms of sequence, the copolymer can be any of the aforementioned and other polymers, including block copolymers, graft copolymers, random copolymers, blends, mixtures, and / or adducts. Typically, the polymers according to the invention are organic polymers. Preferably, the polymers of the invention are biocompatible. In some embodiments, the polymer is biodegradable. In other embodiments, the polymer is both biocompatible and biodegradable.

[0157] The preferred polymers of the present invention may also contain other monomers in their structure. For example, the monomers may be polymers such as polyvinyl alcohol (PVA), polyesters, acrylic polymers and ionomers, or monomers thereof.

[0158] If a biodegradable or absorbable polymer is desired, one or more monomers having a biodegradable linkage can be used. Alternatively or additionally, monomers that produce biodegradable linkages as reaction products can be selected. For each method, monomers and / or linkages that cause the resulting biodegradable polymer to degrade or be absorbed within a desired time period (e.g., from about 6 hours to about 6 months) can be selected. Preferably, the monomers and / or linkages are selected such that when the polymer degrades under physiological conditions, the resulting products are non-toxic.

[0159] Biodegradable linkers can be chemically or enzymatically hydrolyzable or absorbable. Exemplary chemically hydrolyzable biodegradable linkers include polymers, copolymers, and oligomers of glycolide, lactide, caprolactone, dioxane, and trimethylene carbonate. Exemplary enzymatically hydrolyzable biodegradable linkers include peptide linkers that can be cleaved by metalloproteinases and collagenases. Other exemplary biodegradable links include polymers and copolymers of poly(hydroxy acids), poly(orthocarbonates), poly(anhydrides), poly(lactones), poly(amino acids), poly(carbonates), and poly(phosphonates).

[0160] In this invention, the chemical hydrolysis of lactide leads to an increase in the low critical solution temperature (LCST) of the polymer (by reducing the overall hydrophobicity of the polymer), and thus results in an increase in its bioavailability.

[0161] Preferred polymers The polymer preferably contains a first monomer in an amount of about 1 mol% to about 15 mol%. In various embodiments, the first monomer may be present in the form of about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, or about 15 mol%. Preferably, the first monomer is OEGMA.

[0162] The polymer preferably contains a second monomer in an amount of about 5 mol% to about 50 mol%. In various embodiments, the second monomer may be in the form of about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, about 45 mol%, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%. It may be present at approximately 50 mol%. Preferably, the second monomer is PLA / HEMA.

[0163] The polymer preferably contains a third monomer in an amount of up to 15 mol%. In various embodiments, the third monomer may be present in the form of about 0 mol%, about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, or about 15 mol%. Preferably, the third monomer is NAS.

[0164] The polymer preferably contains a fourth monomer in an amount that makes up the 100% balance of the polymer composition, for example, about 50 mol% to about 85 mol%. In embodiments, the mol% of the fourth monomer can be up to about 85%, preferably about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85 mol%. Preferably, the fourth monomer is NIPAAm.

[0165] The percentages mentioned in this article refer to the composition of the final polymer, not the amount of feed used to form the polymer.

[0166] In one embodiment, the polymer preferably comprises: a first monomer in an amount of about 1 to about 15 mol%; a second monomer in an amount of about 5 to about 50 mol%; a third monomer in an amount of up to 15 mol%; and a fourth monomer in an amount of up to about 85 mol%.

[0167] Preferably, the first monomer is OEGMA, the second monomer is PLA / HEMA, the third monomer is NAS, and the fourth monomer is NIPAAm.

[0168] In another embodiment, the polymer preferably comprises: about 7 mol% of a first monomer; about 30 mol% of a second monomer; about 7 mol% of a third monomer; and about 53 mol% of a fourth monomer.

[0169] Preferably, the first monomer is OEGMA, the second monomer is PLA / HEMA, the third monomer is NAS, and the fourth monomer is NIPAAm.

[0170] In one embodiment, the polymer of the present invention is a polymer of formula (Ia): (Ia) in A is the first monomer (water-bound monomer), for example, OEGMA; B is the second monomer (a monomer that can impart mechanical properties to the polymer), for example, PLA / HEMA; C is a third monomer (a monomer with a functional group that binds to NSPP), for example, NAS; and D is the fourth monomer (a monomer that can impart phase change properties to a polymer), for example, NIPAAm.

[0171] In various implementations, m is an integer from 1 to 20; n is an integer from 1 to 20; p is an integer from 0 to 20; and q is an integer from 1 to 20.

[0172] An exemplary polymer of the present invention is represented by the following formula (I): (I) Where A is the water-bound monomer OEGMA, B is the reinforcing monomer PLA / HEMA, C is the crosslinking agent NAS, D is the phase change monomer NIPAAm, and m, n, p, q, x, and y are as defined above.

[0173] Those skilled in the art will recognize that monomers A, B, C, and D can exist in the polymer in any order, as long as the desired water binding, reinforcement, and / or crosslinking capabilities are achieved.

[0174] It has also been found that certain monomers (e.g., PLA / HEMA, polyesters (e.g., poly(lactic acid), poly(caprolactone), poly(glycolic acid)) and their random copolymers (e.g., poly(glycolic acid-co-lactide) and poly(glycolic acid-co-caprolactone)), as well as other biodegradable and biocompatible polymers, can enhance the LCST of the preferred polymers used in this invention during the in vivo degradation of the biodegradable segment (e.g., PLA), thereby leading to the bioabsorption of the polymer. This provides another advantage: the polymers used in this invention can be designed to be biodegradable in vivo.

[0175] The overall size of the preferred polymers used in this invention can vary, depending on factors such as the type of monomers introduced into the polymer, the type of NSPP sought to form the polymer, and the conditions under which the protein is coupled to the polymer. However, typically, the preferred polymers used in this invention can be molecules of about 1 kDa to about 100 kDa, about 5 kDa to about 60 kDa, or about 30 kDa. In various embodiments, the polymers of the invention can be about 1 kDa, 2 kDa, 3 kDa, 4 kDa, 5 kDa, 6 kDa, 7 kDa, 8 kDa, 9 kDa, 10 kDa, 11 kDa, 12 kDa, 13 kDa, 14 kDa, 15 kDa, 16 kDa, 17 kDa, 18 kDa, 19 kDa, 20 kDa, 21 kDa, 22 kDa, 23 kDa, 24 kDa, 25kDa, 26 kDa, 27 kDa, 28 kDa, 29 kDa, 30 kDa, 31 kDa, 32 kDa, 33 kDa, 34 kDa, 35 kDa, 36kDa, 37 kDa, 38 kDa, 39 kDa, 40 kDa, 41 kDa, 42 kDa, 43 kDa, 44 kDa, 45 kDa, 46 kDa, 47kDa, 48 kDa, 49 kDa, 50 kDa, 51 kDa, 52 kDa, 53 kDa, 54 kDa, 55 kDa, 56 kDa, 57 kDa, 58kDa, 59 kDa, 60 kDa, 61 kDa, 62 kDa, 63 kDa, 64 kDa, 65 kDa, 66 kDa, 67 kDa, 68 kDa, 69kDa, 70 kDa, 71 kDa, 72 kDa, 73 kDa, 74 kDa, 75 kDa, 76 kDa, 77 kDa, 78 kDa, 79 kDa, 80kDa, 81 kDa, 82 kDa, 83 kDa, 84 kDa, 85 kDa, 86 kDa, 87 kDa, 88 kDa, 89 kDa, 90 kDa, 91kDa, 92 kDa, 93 kDa, 94 kDa, 95 kDa, 96 kDa, 97 kDa, 98 kDa, 99 A molecule of kDa or about 100 kDa.

[0176] PNPHO, for example, formula (I) The preferred polymer of the present invention is poly(NIPAAm-co-NAS-co-(PLA / HEMA)-co-OEGMA), i.e., "PNPHO". The polymer PNPHO preferably comprises: about 1 mol% to about 15 mol% of OEGMA, about 5 mol% to about 50 mol% of PLA / HEMA, up to 15 mol% of NAS, and the balance to make up 100% of the polymer composition, for example, about 50 mol% to about 85 mol% of NIPAAm.

[0177] The percentages mentioned in this article refer to the composition of the final polymer, not the amount of feed used to form the polymer.

[0178] In one embodiment, preferably, the polymer comprises: OEGMA, in amounts of about 3 mol% to about 8 mol% (e.g., about 4 to about 6 mol%); HEMA-PLA, in an amount of about 5 mol% to about 9 mol% (e.g., about 6 to about 8 mol%); NAS, in an amount of at least about 7 mol%; and NIPAAm, in an amount of up to about 85 mol% (e.g., up to about 81 mol%).

[0179] In another embodiment, the polymer comprises: Approximately 5 mol% of OEGMA; Approximately 7 mol% of HEMA-PLA; Approximately 7 mol% of NAS; and Approximately 81 mol% of NIPAAm.

[0180] The preferred form of the polymer PNPHO used in this application is the polymer of formula (I) shown above.

[0181] Based on the previously defined equation I: A is oligo(ethylene glycol) monomethyl ether methacrylate OEGMA; B is hydroxyethyl methacrylate poly(lactic acid) (HEMA-PLA); C is N-acryloyloxysuccinimide (NAS); and D stands for N-isopropylacrylamide (NIPAAm).

[0182] The preferred form of the polymer PNPHO used in this application is the polymer of formula (I) as shown above. Furthermore, x is 1-1000, y is 1-1000, and m, n, p, and q are 1-20.

[0183] Those skilled in the art will recognize that monomers A, B, C, and D can exist in the polymer in any order, as long as the desired water binding, reinforcement, and / or crosslinking capabilities are achieved.

[0184] PPHO, for example, formula (II) Another preferred polymer of the present invention is poly(NIPAAm-co-(PLA / HEMA)-co-OEGMA), i.e., "PPHO". The polymer PPHO preferably comprises: about 1 mol% to about 15 mol% of OEGMA, about 5 mol% to about 50 mol% of PLA / HEMA, and the balance to make up 100% of the polymer composition, for example, about 50 to about 85 mol% of NIPAAm. In a preferred embodiment, PPHO comprises: OEGMA in an amount of about 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, or about 15 mol%; and / or PLA / HEMA in an amount of about 15 mol%, 16 mol%, 17 mol%, 18 mol%, 19 mol%, 20 mol%, 21 mol%, 22 mol%, 23 mol%, 24 mol%, 25 mol%, 26 mol%, 27 mol%, 28 mol%, 29 mol%, 30 mol%, 31 mol%, 32 mol%, 33 mol%, 34 mol%, 35 mol%, 36 mol%, 37 mol%, 38 mol%, 39 mol%, 40 mol%, 41 mol%, 42 mol%, 43 mol%, 44 mol%. 45 mol%, 46 mol%, 47 mol%, 48 mol%, 49 mol%, or about 50 mol%; and / or NIPAAm, in amounts of about 50 mol%, 51 mol%, 52 mol%, 53 mol%, 54 mol%, 55 mol%, 56 mol%, 57 mol%, 58 mol%, 59 mol%, 60 mol%, 61 mol%, 62 mol%, 63 mol%, 64 mol%, 65 mol%, 66 mol%, 67 mol%, 68 mol%, 69 mol%, 70 mol%, 71 mol%, 72 mol%, 73 mol%, 74 mol%, 75 mol%, 76 mol%, 77 mol%, 78 mol%, 79 mol%, 80 mol%, 81 mol%, 82 mol%, 83 mol%, 84 mol%, or about 85 mol%.

[0185] The percentages mentioned in this article refer to the composition of the final polymer, not the amount of feed used to form the polymer.

[0186] The preferred form of the polymer PPHO used in this application is the polymer of formula (II) shown below. Furthermore, x is 1-1000, y is 1-1000, and m, n, and q are 1-20.

[0187] Those skilled in the art will recognize that monomers A, B, and D can be present in the polymer in any order, as long as the desired water binding, reinforcement, and / or crosslinking capabilities are achieved.

[0188] (II) Polymer Synthesis Those skilled in the art will recognize suitable methods for synthesizing the preferred polymers used in this invention. These methods include methods such as ring-opening polymerization, addition polymerization (including free radical polymerization), and condensation polymerization.

[0189] The formation of preferred polymers PNPHO and PPHO is described in the following examples.

[0190] Excipients and bioactive agents Pharmaceutically acceptable excipients may be included in the compositions and / or polymers of the present invention, and pharmaceutically acceptable excipients include any and all solvents, dispersion media, inert diluents or other liquid solvents, dispersing or suspending agents, granulators, surfactants, disintegrants, isotonic agents, thickeners or emulsifiers, preservatives, binders, lubricants, buffers, oils, etc., suitable for the desired particular dosage form. Remington (Gennaro, AR, Remington: The Science and Practice of Pharmacy, 21st edition (2006) Lippincott Williams & Wilkins) discloses various excipients for formulating pharmaceutical compositions and known techniques for their preparation. Unless any conventional excipient is incompatible with a substance or its derivatives, for example, by producing any undesirable biological effects or interacting in a harmful manner with any other component of the pharmaceutical composition, the use of such excipient is contemplated within the scope of the present invention.

[0191] Depending on the formulator's judgment, the composition may contain excipients such as colorants, coating agents, sweeteners, flavoring agents, and fragrances.

[0192] Bioactive agents or pharmaceutical compounds that can be added to the compositions and / or polymers of the present invention include: proteins, glycosaminoglycans, carbohydrates, nucleic acids, and inorganic and organic bioactive compounds such as enzymes, antibiotics, antitumor agents, local anesthetics, hormones, angiogenic agents, anti-angiogenic agents, growth factors (e.g., insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming growth factor-b (TGFb)), antibodies, neurotransmitters, psychotropic drugs, anticancer drugs, chemotherapeutic agents, drugs affecting reproductive organs, genes, and oligonucleotides.

[0193] By combining the polymer of the present invention with NSPP, combining this combination with one or more other components, and then freeze-drying the resulting composition, compositions containing components such as excipients and / or bioactive agents can be prepared. This produces ready-to-use polymers.

[0194] The amounts of polymers, NSPP, and bioactive agents present in the composition will necessarily depend on the specific drug and the condition to be treated. Those skilled in the art will recognize the appropriate dosage and amount for treating the condition.

[0195] Composition for forming hydrogels The present invention also relates to preferred compositions for forming hydrogels used in the present invention.

[0196] The compositions of the present invention comprise a polymer and optionally NSPP, the polymer comprising: First water-bound monomer; and The second monomer that imparts mechanical properties; Optionally, the third monomer, as an NSPP-binding monomer, contains functional groups capable of binding with NSPP. A fourth monomer capable of imparting phase transition properties to hydrogels; The natural or synthetic peptides or proteins (NSPPs) may be thymosin β-4 or its functional homologs; and The combination of NSPP and the second monomer crosslinks the polymer, thereby enabling the formation of a hydrogel when the composition comes into contact with water.

[0197] As used herein, the term "composition" refers to a solid or liquid composition containing the components described above. In some embodiments, other components, such as pharmaceutically acceptable excipients and bioactive agents (e.g., drugs, vitamins, and minerals), may also be included in the preferred compositions used in this invention to aid in the repair and / or regeneration of target bone tissue and / or to provide a method for the targeted delivery of bioactive compounds.

[0198] Typically, the amount of polymer in the composition used in this invention is the amount that allows for the formation of a hydrogel.

[0199] In some embodiments, the amount of polymer in the composition is: about 1% w / w to about 90% w / w, about 2% w / w to about 80% w / w, about 4% w / w to about 70% w / w, about 5% w / w to about 60% w / w, about 5% w / w to about 50% w / w, about 6% w / w to about 40% w / w, about 7% w / w to about 30% w / w, or about 8% w / w to about 20% w / w.

[0200] In some embodiments, the amount of polymer is: about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, about 70% w / w, about 75% w / w, about 80% w / w, or more. In some embodiments, the amount of polymer is about 85% w / w.

[0201] Generally, the robustness of hydrogels increases with increasing polymer concentration in the composition.

[0202] Typically, the amount of NSPP in the compositions of this invention is the amount that allows for the formation of a hydrogel.

[0203] In some embodiments, the amount of NSPP in the composition is in the following ranges: about 0.01% w / w to about 60% w / w, about 1% w / w to about 50% w / w, about 1% w / w to about 40% w / w, about 5% w / w to about 30% w / w, about 5% w / w to about 20% w / w, or about 5% w / w to about 10% w / w.

[0204] In some implementations, the percentage of NSPP is: approximately 1% w / w, approximately 2% w / w, approximately 3% w / w, approximately 4% w / w, approximately 5% w / w, approximately 6% w / w, approximately 7% w / w, approximately 8% w / w, approximately 9% w / w, approximately 10% w / w, approximately 20% w / w, approximately 30% w / w, approximately 40% w / w, approximately 50% w / w, or more.

[0205] % w / w is based on the total weight of the composition before it comes into contact with water.

[0206] Detailed description of the preferred implementation scheme Use of PNPHO / PPHO as a tumor spacer As previously described, the present invention relates to applying a polymer to a target tissue (e.g., the human prostate) or a treatment site adjacent to the target tissue, whereby the polymer forms a hydrogel at body temperature to provide a physical separation between the tissue and nearby cells / tissues / organs (e.g., the human rectum). This physical separation / isolation between the prostate and rectum allows radiotherapy to be focused on the separated target tissue without substantially affecting the cells / tissues / organs separated from it by the polymer hydrogel.

[0207] The preferred polymer is poly(N-isopropylacrylamide-co-(N-acryloyloxysuccinimide)-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric (ethylene glycol) / poly(NIPAAm-co-NAS-co-(PLA / HEMA)-co-OEGMA), i.e., PNPHO.

[0208] Alternatively, the polymer is poly(N-isopropylacrylamide-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric (ethylene glycol) / poly(NIPAAm-co-(PLA / HEMA)-co-OEGMA), i.e., “PPHO”.

[0209] The inventors unexpectedly discovered that, at concentrations higher than about 100 mg / mL in aqueous solutions, PNPHO and / or PPHO can be applied (preferably by injection) at or near cancerous organs (e.g., the prostate) to form a hydrogel that provides a physical separation between the tissue and nearby cells / tissues / organs (e.g., the rectum). This physical separation / isolation of the prostate from the rectum allows radiotherapy to be focused on the isolated target tissue without substantially affecting the cells / tissues / organs separated from it by the polymer hydrogel.

[0210] Injected aqueous solutions of PNPHO and / or PPHO form hydrogels at body temperature with 10 to 60 CT Henle units (HU), which is similar to the equivalent values ​​of water and soft tissue, thus making it suitable for ensuring accurate radiation oncology by obtaining the relationship between HU and the electron density of structures exposed to radiation beams.

[0211] Injected PHPHO and / or PPHO aqueous solutions form a hydrogel at body temperature at the application site, thereby generating (i) a reduction in the effects of therapeutic radiation on surrounding tissues; (ii) a filling of gaps to reduce or restore airbags to normal, and thus improve the accuracy of dose calculations; and (iii) a space to protect tissues (e.g., dermis) from direct radiation exposure.

[0212] In one form, when radiotherapy is targeted at the prostate, an aqueous solution of PHPHO and / or PPHO can be injected between the human rectum and the prostate to provide temporary space between these organs, thereby reducing the radiation dose delivered to the rectum.

[0213] In another form, injected PHPHO and / or PPHO aqueous solutions can be used to fill defects after cancer surgery (e.g., tumor resection) to reduce air pockets at the site, thereby improving the accuracy of electron density maps.

[0214] In another form, PHPHO and / or PPHO aqueous solutions can be applied to the skin surface layer (in injectable and / or malleable form) to cover the skin / dermis, thereby preventing direct exposure and thus reducing pigmentation during radiation.

[0215] In the experiment, “TP280” (280 mg / mL of PNPHO aqueous solution) was tested in a radiation oncology CT simulation to obtain its Henle (or CT) value. The Henle value is a fundamental input for radiotherapy planning systems that take into account tissue heterogeneity. The results showed that TP280 has a Henle value of less than 50, which is comparable to the Henle value for soft tissue, and is therefore suitable for creating space between different organs and / or filling a site to reduce air pockets.

[0216] Furthermore, the uniformity of the TP280 hydrogel product under the simulation confirms its potential application in filling voids to facilitate more accurate drawing.

[0217] Aqueous solutions of PHPHO and / or PPHO can be administered by direct injection into the site. Following temperature-triggered gelation, the resulting hydrogel provides sufficient mechanical / structural stability to create space under simulated radiographic CT and to provide a homogeneous structure for relatively precise radiography.

[0218] Applications of PNPHO / PPHO as a water separation tool As described above, the present invention relates to a polymer that can be applied as a non-irritating solution, which is ultrasound-visible (imaging) and facilitates precise hydrolysis (e.g., for perirectal fat). Such hydrolysis solutions allow for precise injection of the solution to prevent side effects such as rectal wall infiltration during the application of the spacer. Alternatively, one or more polymers of the present invention can be used as space fillers to reduce the presence of balloons / cavities in targeted radiotherapy (e.g., after breast mass resection and MammoSite treatment). Such hydrogel fillers for removing balloons / cavities can reduce balloon / cavity inhomogeneities in targeted radiotherapy (e.g., MammoSite) and thereby reduce dose errors to tissues located near the air / tissue interface due to the lack of attenuation effects and inverse square correction.

[0219] The preferred polymer is poly(N-isopropylacrylamide-co-(N-acryloyloxysuccinimide)-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric (ethylene glycol) / poly(NIPAAm-co-NAS-co-(PLA / HEMA)-co-OEGMA), i.e., PNPHO.

[0220] Alternatively, the polymer is poly(N-isopropylacrylamide-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric (ethylene glycol) / poly(NIPAAm-co-(PLA / HEMA)-co-OEGMA), i.e., “PPHO”.

[0221] The inventors unexpectedly discovered that PNPHO and / or PPHO can be administered (preferably by injection) at or near the tissue originally intended for water separation at concentrations of about 25 mg / mL to about 100 mg / mL in aqueous solution. Such observations have two main applications: (1) injection into tissue to separate target tissue; and (2) visibility under ultrasound and / or CT scans to facilitate more precise needle placement / water separation.

[0222] Injected aqueous solutions of PNPHO and / or PPHO form hydrogels at body temperature with 10 to 60 CT-Henness units (HU), which is similar to the equivalent values ​​of water and soft tissue.

[0223] In one form, an aqueous solution of PHPHO and / or PPHO can be injected into the perirectal fat as an alternative to conventional water separation.

[0224] In the experiment, “TP50” (50 mg / mL of PNPHO aqueous solution) was tested in the aqueous separation of perirectal fat.

[0225] Aqueous solutions of PHPHO and / or PPHO can be administered by direct injection into the site. Following temperature-triggered gelation, the resulting hydrogel provides sufficient mechanical / structural stability to create space under simulated radiographic CT and to provide a homogeneous structure for relatively precise radiography.

[0226] Product Heinz units Four formulations were prepared, and their Heinz units were measured. The results are shown in Table 1.

[0227] The results confirmed that the formulation containing iohexol was radiopaque and returned Heinz values ​​from approximately 100 to approximately 1000, demonstrating the product's modularity. The product was coded as "IOPXX," where XX represents the concentration of iohexol in the final formulation. For example, IOP20 indicates a formulation containing 20 mg / mL iohexol in the final product.

[0228] Table 1. Heinz Units of Different TL150 Formulations with Different Iohexol Content

[0229] * TL150 = 150 mg / mL PPHO solution Space generation and volume formation This study confirmed that TL150-IOP50 can be programmed for injection via an 18G needle in 5 mL, 10 mL, and γ-irradiated variants.

[0230] Secondly, TRUS (transrectal ultrasound) visibility after TL150-IOP40 gelation was confirmed at t=0 and t=10 minutes after initial implantation. The extended time was confirmed during follow-up injections (see [link to relevant documentation]). Figure 5 ).

[0231] Volume formation after gelation is shown in Figure 6 It is visible on CT scans.

[0232] Water separation In this study, a gap (water separation) was created by injecting 5 mL of saline at the site prior to the injection of TL150-IOP40.

[0233] After the initial injection (6 mL), another 6 mL of TL150-IOP40 was injected to confirm the product’s selectability (compatible with water separation and multi-stage injection).

[0234] Figure 7 The results confirmed product formation and spatial generation following water separation and two injections (two separate time sequences).

[0235] Subtle differences in TRUS-guided implantation and anatomy between pig and human models The anatomy of the porcine prostate / rectum model is more complex than that of humans, especially when considering its relationship to the space surrounding the rectum. Standard operating procedures have been effectively adapted from human models. This provides the intended end-users with confidence that the results and outcomes obtained in this study can be further improved in human research models.

[0236] Preferred formulation of TL150-IOP40 in a 10 mL syringe This study provides an excellent opportunity to test the functional parameters and design inputs of injectable products. Finding the "sweet spot" involves the following considerations: Determine the highest TP or TL concentration that can be continuously injected via a non-pressurized 18G × 150 mm needle.

[0237] The TL concentrations of TL100 and TL200 were previously tested in mouse models for safety, efficacy, and absorption. Results from that study were obtained at 6 and 10 weeks, respectively, after which the measured absorption reduced the implant size to below 100%. TL150 was chosen as it offered good potential to produce absorption results at 8 weeks.

[0238] The results obtained ensured that 10 mL of TL150 should be sufficient to create space comparable to that required in a human model. The additional cost of a larger syringe (e.g., 20 mL), plastic waste, and internal pressure were considered before deciding on the standard 10 mL device design. Furthermore, it was observed that patients requiring more than 10 mL of prostate spacer are not common. However, this study has confirmed that TL150 implants can be "added" if needed.

[0239] Transrectal ultrasound (TRUS) visibility TRUS visibility is excellent for every sample used. This is important for the safety and effectiveness of the perrectal septum. Visibility is also important for the operator to reduce the risk of human error related to needle insertion and placement during the procedure. Ultrasonic visibility also ensures that the operator can check the placement and contour of the septum in real time, reducing the risk of poor implantation results due to the inability to “add” or trim the septum implant to correct the initial placement. Two points are noteworthy because they relate to the pre-implantation device: SpaceOar Vue (Boston Scientific) has poor (or even no) visibility on TRUS once the hydrogel has formed; and its visibility is comparable to that of Barrigel (Teleflex), which similarly allows for greater procedural flexibility.

[0240] Ambient temperature management Previous bench testing of the product led to the hypothesis that the TL150-IOP40 could be managed at temperatures closer to ambient, which prompted this study. The completed tests and observed results suggest that the addition of a temperature strip to commercial packaging should be recommended immediately, along with formal storage and shelf testing to validate this temperature.

[0241] Industrial applicability It should be understood that the present invention has immediate applicability in the fields of biomedicine, surgery, and treatment. Aqueous solutions of biocompatible PNPHO or PPHO polymers allow for application at the treatment site (preferably by injection) to form a hydrogel, thereby physically separating / isolating the target tissue for radiotherapy. For cancers such as prostate cancer, where several unaffected organs / tissues (e.g., bladder, rectum) may be very close together, it is obviously desirable to minimize their exposure to radiation.

[0242] Regarding the first aspect of the invention, the key finding of this study is: At concentrations above approximately 100 mg / mL, aqueous solutions of PNPHO and PPHO can be used to create space between different organs to facilitate more targeted therapeutic radiation.

[0243] The injection solution forms a hydrogel at body temperature at the application site, thereby creating space to reduce the impact of therapeutic radiation on surrounding tissues; filling gaps to reduce or restore airbags to normal, and thus improving the accuracy of dose calculation; and protecting tissues (e.g., dermis) from direct radiation exposure.

[0244] When radiotherapy targets the prostate, the solution of the present invention can be injected between the human rectum and the prostate to provide temporary space between these organs, thereby reducing the radiation dose delivered to the rectum.

[0245] The solution of the present invention can be used to fill defects after cancer surgery (e.g., tumor removal) to reduce air pockets at the site, thereby improving the accuracy of electron density maps.

[0246] The solution of the present invention can cover the skin surface layer (in an injectable and / or malleable form) to cover the skin / dermis, thereby preventing direct exposure and thus reducing pigmentation during radiation.

[0247] In the experiment, “TP280” (280 mg / mL of PNPHO aqueous solution) was tested in a radiation oncology CT simulation to obtain its Henle (or CT) value. The Henle value is a fundamental input for radiation therapy planning systems that take into account tissue heterogeneity.

[0248] The results showed that TP280 has a Henle value of less than 50, which is comparable to the Henle value of soft tissue, making it suitable for creating space and / or filling sites between different organs to reduce air pockets.

[0249] Furthermore, the uniformity of the TP280 hydrogel product in this simulation confirms its potential application in filling gaps for more accurate drawing.

[0250] The solution of this invention can be applied by direct injection to the site. After temperature-triggered gelation, the resulting hydrogel provides sufficient mechanical / structural stability to create space under simulated radiographic CT and to provide a homogeneous structure for relatively accurate radiography.

[0251] Pig cadaver studies confirmed the design of TL150-IOP40, locked in a 10 mL gamma-sterilized syringe, for use in a first-in-human feasibility study sponsored by the institute. The relevant conclusions are summarized below: TL150 is the highest polymer concentration that can be flowed through a non-pressurized 18G × 150 mm needle when managed at the manufacturer’s recommended 2–8°C.

[0252] IOP40 is the optimal iodine concentration, which has been observed not to negatively impact the intended performance of the biocompatible polymers of this invention, and has been measured to have Heinz units at a design threshold of 1000.

[0253] The TL150-IOP40 creates the necessary space, provides procedural options, and is visible on CT and TRUS – even during “additional” injections after implantation.

[0254] Transrectal ultrasound-guided insertion is suitable for first-time human use and has become a standard procedure.

[0255] The procedural effectiveness of the TL150-IOP40 product in pig models also demonstrates that commercial veterinary interval products are technically feasible.

[0256] Although the invention has been described with reference to specific embodiments, those skilled in the art will understand that the invention may be embodied in many other forms.

Claims

1. A polymer for application at a treatment site to form a hydrogel, thereby physically separating / isolating target tissue for radiotherapy, said polymer comprising: The first monomer used for binding water; The second monomer used to impart mechanical properties; Optionally, a third monomer for binding to natural or synthetic peptides or proteins (NSPPs); and The fourth monomer used to impart phase transition behavior.

2. A polymer for application to a treatment site to form a hydrogel, thereby physically hydrolyzing two or more adjacent tissues, said polymer comprising: The first monomer used for binding water; The second monomer used to impart mechanical properties; Optionally, a third monomer for binding to natural or synthetic peptides or proteins (NSPPs); and The fourth monomer used to impart phase transition behavior.

3. The polymer according to claim 1 or 2, wherein the first monomer is selected from: polyether, polyvinyl alcohol (PVA); poly(vinylpyrrolidone) (PVP); poly(amino acid) and dextran.

4. The polymer according to claim 3, wherein the polyether is selected from: polyethylene glycol (PEG), oligomeric (ethylene glycol) (OEG), polyethylene oxide (PEO), polyethylene oxide-co-propylene oxide (PPO), copolymerized ethylene oxide blocks or random copolymers thereof.

5. The polymer according to claim 4, wherein the first monomer is oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA).

6. The polymer according to any one of the preceding claims, wherein the second monomer is a methacrylate or a random copolymer containing a methacrylate.

7. The polymer according to claim 6, wherein the second monomer is selected from: hydroxyethyl methacrylate (HEMA), hydroxyethyl methacrylate poly(lactic acid) copolymer (PLA / HEMA), poly(lactic acid), poly(caprolactone), poly(glycolic acid), poly(glycolic acid), poly(glycolic acid-co-glycolic acid), or poly(glycolic acid-co-caprolactone).

8. The polymer according to claim 7, wherein the second monomer is hydroxyethyl methacrylate poly(lactic acid) (PLA / HEMA).

9. The polymer according to any one of the preceding claims, wherein the third monomer has an electrophilic functional group for binding with the NSPP.

10. The polymer of claim 9, wherein the third monomer is selected from: N-hydroxysulfosuccinimide (SNHS), N-hydroxyethoxysuccinimide (ENHS), and N-acryloyloxysuccinimide (NAS).

11. The polymer of claim 10, wherein the third monomer is N-acryloyloxysuccinimide (NAS).

12. The polymer according to any one of the preceding claims, wherein the fourth monomer has a low critical solution temperature (LCST) of less than about 37°C.

13. The polymer according to claim 12, wherein the fourth monomer is selected from homopolymers and copolymers of poly(ethylene oxide) / poly(propylene oxide) and poly(N-isopropylacrylamide) (PNIPAAm).

14. The polymer according to claim 13, wherein the fourth monomer is (N-isopropylacrylamide) (NIPAAm).

15. The polymer according to any one of the preceding claims, wherein the polymer comprises about 1 mol% to about 15 mol% of the first monomer.

16. The polymer according to any one of the preceding claims, wherein the polymer comprises about 5 mol% to about 50 mol% of the second monomer.

17. The polymer according to any one of the preceding claims, wherein the polymer comprises about 0 mol% to about 15 mol% of the third monomer.

18. The polymer according to any one of the preceding claims, wherein the polymer comprises about 50 mol% to about 85 mol% of the fourth monomer.

19. The polymer according to any one of the preceding claims, wherein the polymer comprises: a first monomer in an amount of about 1 mol% to about 15 mol%; a second monomer in an amount of about 5 mol% to about 50 mol%; a third monomer in an amount of 0 mol% to about 15 mol%; and a fourth monomer in an amount that makes up the balance of 100% of the polymer.

20. The polymer of any one of the preceding claims, wherein: The first monomer is OEGMA; the second monomer is PLA / HEMA; the third monomer is NAS; and the fourth monomer is NIPAAm. The polymer comprises: about 1 mol% to about 15 mol% of OEGMA; 5 mol% to about 50 mol% of PLA / HEMA; 0 mol% to about 15 mol% of NAS; and up to about 85 mol% of NIPAAm.

21. The polymer according to any one of claims 1 to 20, wherein, for application to a treatment site, the polymer is dissolved or dispersed in an aqueous solution at a polymer concentration greater than about 100 mg / mL.

22. The polymer of claim 21, wherein, for application to a treatment site, the polymer is dissolved or dispersed in an aqueous solution at a polymer concentration of about 280 mg / mL.

23. The polymer according to claim 21 or 22, wherein the target tissue for radiotherapy is a human prostate gland.

24. The polymer of claim 23, wherein the application of the polymer to the treatment site is performed by injection.

25. The polymer of claim 24, wherein the polymer is injected between the patient's rectum and prostate to provide temporary space between the organs, thereby reducing the radiation dose delivered to the rectum.

26. The polymer according to any one of claims 2 to 20, wherein, for application to a treatment site, the polymer is dissolved or dispersed in an aqueous solution at a polymer concentration of about 25 mg / mL to about 100 mg / mL.

27. The polymer of claim 26, wherein the application of the polymer to the treatment site is performed by injection.

28. The polymer according to any one of the preceding claims, wherein The first monomer is OEGMA; the second monomer is PLA / HEMA; the third monomer is NAS; and the fourth monomer is NIPAAm; The polymer comprises: about 1 mol% to about 15 mol% of OEGMA; 5 mol% to about 50 mol% of PLA / HEMA; 0 mol% to about 15 mol% of NAS; and up to about 85 mol% of NIPAAm; The target tissue used in radiotherapy is the human prostate gland; and The polymer is present at a concentration of approximately 280 mg / mL.

29. A method for physically separating / isolating target tissue for radiotherapy, the method comprising administering to a subject in need at or near the target tissue an effective concentration of a polymer as defined in any one of claims 1 to 25.

30. A method for physically separating two or more adjacent tissues at a treatment site, the method comprising administering to a subject in need an effective concentration of a polymer as defined in claims 2 to 20, 26 or 27 at or near the treatment site.

31. The method of claim 29 or 30, wherein the application is performed at body temperature.

32. The method according to any one of claims 29 to 31, wherein the application is performed by injection.

33. The method according to any one of claims 29 to 32, wherein the target tissue for radiotherapy is a human prostate gland.

34. The method according to any one of claims 29 to 33, wherein, in order to apply the polymer to the treatment site, it is dissolved or dispersed in an aqueous solution at a polymer concentration of about 280 mg / mL.

35. The method of claim 34, wherein the polymer is injected between the patient's rectum and prostate to provide temporary space between the organs, thereby reducing the radiation dose delivered to the rectum.

36. Use of the polymer as defined in any one of claims 1 to 28 for physically spaced / isolated target tissues for radiotherapy.

37. The use according to claim 36, wherein the application is performed at body temperature.

38. The use according to claim 36 or 37, wherein the application is performed by injection.

39. The use according to any one of claims 36 to 38, wherein the target tissue for radiotherapy is a human prostate gland.

40. The use according to any one of claims 36 to 39, wherein, for application to a treatment site, the polymer is dissolved or dispersed in an aqueous solution at a polymer concentration of about 280 mg / mL.

41. The use according to claim 40, wherein the polymer is injected between the patient's rectum and prostate to provide temporary space between the organs, thereby reducing the radiation dose delivered to the rectum.

42. A kit for physically spacing / isolating a target tissue for radiotherapy, the kit comprising: The polymer as defined in any one of claims 1 to 28; and an apparatus for applying the polymer. And instructions for applying the polymer to or near the target tissue.

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