Bioerodible crosslinked hydrogels based on multiarm polyoxazolines with cage-like silicon-oxygen cores

Abstract

A bioerodible crosslinked hydrogel based on a multi-arm polyoxazoline having a cage-like silicon-oxygen core is provided. In some aspects, the disclosure relates to reactive multi-arm polymers having a silicon-oxygen cage core and a plurality of polyoxazoline-containing arms extending from the core, the polyoxazoline-containing arms comprising a first end covalently bonded to the silicon-oxygen cage core and a second end comprising a moiety comprising a reactive end group. In other aspects, the disclosure relates to systems comprising such reactive multi-arm polymers and multifunctional compounds comprising functional groups reactive with the reactive end groups of the reactive multi-arm polymers. Other aspects relate to medical hydrogels formed by crosslinking such reactive multi-arm polymers with such multifunctional compounds, and to methods of treatment comprising administering to a subject a mixture comprising such reactive multi-arm polymers together with such multifunctional compounds.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 399,122, filed August 18, 2022, the disclosure of which is incorporated herein by reference. The present disclosure relates, among other aspects, to multi-armed polyoxazolines having a cage silicon-oxygen core, bioerodible crosslinked compositions comprising such multi-armed polymers, methods for making such multi-armed polymers, and methods of using such multi-armed polymers. The disclosed multi-armed polyoxazolines having a cage silicon-oxygen core are useful, for example, in a variety of biomedical applications. [Background technology]

[0002] Bioerodible injectable hydrogels are a class of newly emerging materials with a variety of medical uses. As one example, SpaceOAR®, a long-term bioerodible injectable hydrogel based on a multi-arm PEG base, is used to create or maintain space between tissues to reduce the side effects of untargeted radiation therapy. See “Augmenix Announces Positive Three-Year SpaceOAR Clinical Trial Results,” Imaging Technology News, October 27, 2016. As another example, Augmenix has developed TraceIT® Hydrogel, a bioerodible injectable hydrogel, which is a synthetic hydrogel composed primarily of water and iodinated cross-linked polyethylene glycol (PEG), that is visible under CT, cone beam, ultrasound, and MR imaging and is useful as a tissue marker (e.g., for targeted radiation therapy). “Augmenix Receives FDA Clearance to Market its TraceIT® TMSee "Tissue Marker," BusinessWire, January 28, 2013. TraceIT® hydrogel remains stable and visible in tissue for three months, sufficient time for radiation therapy, after which it is absorbed and eliminated from the body. Id.

[0003] Among other needs, there is a continuing need in the biomedical arts for additional hydrogels, including bioerodible injectable hydrogels, precursors to such hydrogels, methods of making such hydrogels and precursors, methods of using such hydrogels and precursors, and systems for forming such hydrogels. Summary of the Invention

[0004] In some aspects, the present disclosure relates to reactive multi-arm polymers having a silicon-oxygen cage core and a plurality of polyoxazoline-containing arms extending from the core, the polyoxazoline-containing arms comprising a first end covalently bonded to the silicon-oxygen cage core and a second end comprising a moiety comprising a reactive end group. In some embodiments, the silicon-oxygen cage core is a T6 silicon-oxygen cage core, a T8 silicon-oxygen cage core, a T 10 Cage-like silicon-oxygen core and T 12 The cage silicon-oxygen core and / or the polyoxazoline-containing arms are selected from oxazoline, 2-(C-C 10 -alkyl)-2-oxazoline, and combinations thereof. In some embodiments that can be used in combination with any of the above aspects and embodiments, the reactive end group is an electrophilic group. Examples of electrophilic groups can be selected from, for example, N-hydroxysuccinimidyl esters, imidazole esters, imidazole carboxylates, and benzotriazole esters, among others.

[0005] In some embodiments, which can be used in combination with any of the above aspects and embodiments, the moiety comprising a reactive end group may further comprise a hydrolyzable ester group. In some embodiments that can be used in combination with any of the above aspects and embodiments, the moiety comprising a reactive end group comprises a diester selected from a malonic acid-based diester, a succinic acid-based diester, a glutaric acid-based diester, and an adipic acid-based diester. In some aspects, the present disclosure relates to a system comprising: (a) a reactive multi-arm polymer according to any of the above aspects and embodiments; and (b) a multifunctional compound comprising a functional group that is reactive with the reactive end group of the reactive multi-arm polymer.

[0006] In some embodiments that can be used in combination with any of the above aspects, the reactive group of the reactive multi-arm polymer is an electrophilic group and the functional group of the multifunctional compound is a nucleophilic group. In some embodiments, which may be used in combination with any of the above aspects and embodiments, the polyfunctional compound may be a polyamine compound. In some embodiments that can be used in combination with any of the above aspects and embodiments, the polyfunctional compound can be a polyamine compound containing residues of 2 to 10 basic amino acids. In some embodiments that can be used in combination with any of the above aspects and embodiments, the polyfunctional compound comprises a plurality of —(CH) x It may also be a polyamine compound containing -NH2 groups (wherein x is 0, 1, 2, 3, 4, 5 or 6).

[0007] In some embodiments that can be used in combination with any of the above aspects and embodiments, the polyfunctional compound can be a polyamine compound that includes two or more amino acid residues selected from residues of lysine, ornithine, and combinations thereof. In some embodiments that can be used in combination with any of the above aspects and embodiments, a system can include a first precursor composition that includes a multifunctional compound and a second precursor composition that includes a reactive multi-arm polymer. In some embodiments that can be used in combination with any of the above aspects and embodiments, the system may further include an enhancer composition. For example, the enhancer composition may include a buffer having a pH in the range of about 9 to about 11. In some embodiments that can be used in combination with any of the above aspects and embodiments, the first precursor composition can be provided in a syringe barrel, the second precursor composition can be provided in a vial, and the accelerator composition can be provided in a syringe barrel.

[0008] In some embodiments, which may be used in combination with any of the above aspects and embodiments, the system may further include a delivery device. In some aspects, the present disclosure relates to medical hydrogels formed by crosslinking a reactive multi-arm polymer according to any of the above aspects and embodiments with a multifunctional compound that includes a functional group that is reactive with the reactive end group of the reactive multi-arm polymer according to any of the above aspects and embodiments. In some aspects, the present disclosure relates to methods of treatment comprising administering to a subject a mixture comprising a reactive multi-arm polymer according to any of the above aspects and embodiments and a multifunctional compound comprising a functional group reactive with the reactive end group of the reactive multi-arm polymer according to any of the above aspects and embodiments. In addition to the above, further aspects and embodiments of the present disclosure will become readily apparent upon review of the following detailed description. [Brief explanation of the drawings]

[0009] [Figure 1A] FIG. 1 shows a schematic diagram of a method in which a hydrogen silsesquioxane is used to form a hydroxyalkyl silsesquioxane, according to one embodiment of the present disclosure. [Figure 1B] FIG. 1B is a schematic diagram illustrating a method in which the hydroxyalkylsilsesquioxane of FIG. 1A is used to form a haloalkylsilsesquioxane, according to one embodiment of the present disclosure. [Figure 1C] FIG. 1C is a schematic diagram illustrating a method in which the haloalkylsilsesquioxane of FIG. 1B is used as an initiator for ring-opening polymerization to form a multi-arm polyoxazoline having terminal hydroxyl groups, according to one embodiment of the present disclosure. [Figure 1D] FIG. 1D is a schematic diagram illustrating a method for subsequently converting the multi-arm polyoxazoline of FIG. 1C into a multi-arm polyoxazoline terminated with a reactive succinimidyl glutarate group, according to one embodiment of the present disclosure. [Figure 2] FIG. 1 is a schematic diagram of a method for making a reactive multi-arm polyoxazoline according to one embodiment of the present disclosure. [Figure 3] FIG. 1 is a schematic diagram of a method for crosslinking a reactive multi-arm polyoxazoline with a multifunctional crosslinker, according to one embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0010] In some aspects, the present disclosure relates to multi-arm polymers having a cage-like silicon-oxygen core and having multiple polyoxazoline-containing arms. In various embodiments, the multi-arm polymer is a silsesquioxane compound having multiple polyoxazoline-containing arms. Silsesquioxanes are compounds having a cage-like silicon-oxygen core consisting of Si-O-Si bonds and tetrahedral Si vertices. -H groups or external organic groups may be covalently bonded to the cage-like silicon-oxygen core. In the present disclosure, the organic groups constitute the polyoxazoline-containing arms. Silsesquioxanes for use in the present disclosure include silsesquioxanes with 6 Si vertices, silsesquioxanes with 8 Si vertices, silsesquioxanes with 10 Si vertices, and silsesquioxanes with 12 Si vertices. The silicon-oxygen cores are designated T6, T8, and T9, respectively. 10 , and T12 (where T = number of Si vertices in the tetrahedron). In all cases, each Si atom is bonded to three O atoms, which in turn are bonded to other Si atoms.

[0011] Silsesquioxanes have the chemical formula [RSiO 3 / 2 ] n where n is an integer of at least 6, typically 6, 8, 10, or 12 (thereby defining T6, T8, and T 10 or T 12 T8 has a silicon-oxygen cage core of [RSiO 3 / 2 ]8, or equivalently R8Si8O 12 Such a structure has the formula: [ka] It is shown as follows. In the present disclosure, at least one R group is a polyoxazoline-containing arm, and typically all R groups are polyoxazoline-containing arms.

[0012] In various embodiments, the polyoxazoline-containing arms (e.g., the R groups in the silsesquioxane formulas and structures above, among many other possibilities) are 2-(C-C alkyl) oxazolines, including oxazolines and 2-alkyl-2-oxazolines, such as 2-methyl-2-oxazoline, 2-ethyl-2-oxazoline, 2-propyl-2-oxazoline, 2-butyl-2-oxazoline (including isomers of 2-n-butyl-2-oxazoline and 2-sec-butyl-2-oxazoline), 2-pentyl-2-oxazoline (including various isomers), 2-hexyl-2-oxazoline (including various isomers), and the like. 10 The polymerized monomers include one or more polymerized monomers selected from the group consisting of alkyl-2-oxazolines.

[0013] In various embodiments, the polyoxazoline-containing arms are comprised of a cage-like silicon-oxygen core (e.g., T6, T8, T 10 or T 12 and a second end comprising a moiety comprising a reactive end group. (Such molecules are also referred to herein as reactive multi-arm polyoxazolines.) In some of these embodiments, the reactive end group may be an electrophilic group selected from, for example, N-hydroxysuccinimide ester, imidazole ester, imidazole carboxylate, and benzotriazole ester, among other possibilities. In some of these embodiments, the reactive end group may be a nucleophilic group selected from, for example, an amine group or a thiol group, among other possibilities.

[0014] In some embodiments, the moiety comprising a reactive end group can further comprise a hydrolyzable ester group. For example, the moiety comprising a reactive end group can comprise a diester. In particular examples, the diester may be selected from malonic acid-based diesters, succinic acid-based diesters, glutaric acid-based diesters, and adipic acid-based diesters. The formation of these and other multi-arm polyoxazolines is generally shown in Figure 2, in which a molecule having a cage-like silicon-oxygen core 110 (e.g., a silsesquioxane core) is used to form a multifunctional initiator molecule 120, specifically a molecule having a cage-like silicon-oxygen core 110 and multiple moieties including a polymerization initiator group 120, from which oxazoline polymerization can proceed. Polymerization of oxazoline monomer 125 then proceeds from the multifunctional initiator molecule 120 to form a multi-arm polyoxazoline comprising a cage-like silicon-oxygen core 110 and multiple polyoxazoline-containing arms 130 extending from the core, each arm having a first end and a second end, with the first end attached to the core 110. A reactive group 140 can then be provided at the second end of each polyoxazoline-containing arm 130. In certain embodiments, the reactive group 140 is attached to the polyoxazoline-containing arm 130 by a hydrolyzable ester group.

[0015] In certain embodiments, cage-like silicon-oxygen cores (e.g., T6, T8, T9, among other possibilities) are used. 10 or T 12 Silsesquioxane precursor molecules having a cage-like silicon-oxygen core, such as those having the formula [RSiO 3 / 2 ] n wherein n is an integer of at least 6 and R=H, and a vinyl-substituted C3-C 10 Reaction with an alcohol, such as 2-propen-1-ol (also known as allyl alcohol), 3-buten-1-ol, 4-penten-1-ol, or 5-hexen-1-ol, to give C3-C 10 Hydroxyalkyl-substituted silsesquioxanes, such as omega-hydroxyalkyl-substituted silsesquioxanes, such as those having the formula [RSiO 3 / 2 ] n wherein n is an integer of at least 6 and R is —(CH) m OH, and m ranges from 3 to 10), such as 3-hydroxypropyl-substituted silsesquioxanes (e.g., where R = -CHCHCHCHOH), 4-hydroxybutyl-substituted silsesquioxanes (e.g., where R = -CHCHCHCHCHOH), 5-hydroxypentyl-substituted silsesquioxanes (e.g., where R = -CHCHCHCHCHCHOH), 6-hydroxyhexyl-substituted silsesquioxanes (e.g., where R = -CHCHCHCHCHCHCHOH), and the like. A specific example of such a reaction step is shown in Figure 1A, which shows a compound of the formula [RSiO 3 / 2 ]8, where R is H, is converted into a hydrogenated T8 silsesquioxane of the formula [RSiO 3 / 2 ]8 (where R is —CH 2 CH 2 CH 2 OH)

[0016] Next, C3-C 10 The hydroxyl groups of hydroxyalkyl-substituted silsesquioxanes can be converted to halogen groups by reaction with halogens (e.g., Cl2, Br2, I2), resulting in C3-C 10Haloalkyl-substituted silsesquioxanes, such as those represented by the formula [RSiO 3 / 2 ] n wherein n is an integer of at least 6 and R is —(CH) m X, m is in the range of 3-10, and X=Cl, Br, or I) to form omega-haloalkyl-substituted silsesquioxanes, such as 3-halopropyl-substituted silsesquioxanes (e.g., where R=-CH2CH2CH2X), 4-halobutyl-substituted silsesquioxanes (e.g., where R=-CH2CH2CH2CH2X), 5-halopentyl-substituted silsesquioxanes (e.g., where R=-CH2CH2CH2CH2X), 6-halohexyl-substituted silsesquioxanes (e.g., where R=-CH2CH2CH2CH2CH2X), and the like. A specific example of such a reaction step is shown in FIG. 1B, which illustrates the reaction of the hydroxyalkyl silsesquioxane of FIG. 1A with a compound of the formula [RSiO 3 / 2 ]8 (where R is —CH 2 CH 2 CH 2 I)

[0017] Next, C3-C 10 Haloalkyl-substituted silsesquioxanes are used as initiators for the ring-opening polymerization of oxazoline monomers, such as oxazolines or 2-alkyl-2-oxazolines as described above, followed by termination / quenching of the ring-opening polymerization, such that polyoxazoline arms are formed at each halide atom, e.g., a cage-like silicon-oxygen core (e.g., T6, T8, T 10 or T 12The reaction step results in a polyoxazoline containing a cage-like silicon-oxygen core, such as a silicon-oxygen core, and a silsesquioxane having a plurality of hydroxyl-terminated polyoxyazoline arms, such as a plurality of polyoxazoline-containing arms, each arm having a first end and a second end, formed from at least one oxazoline monomer, where the first end is attached to the core and the second end contains a hydroxyl group. A specific example of such a reaction step is shown in Figure 1C, in which the haloalkylsilsesquioxane of Figure 1B is used as an initiator for the ring-opening polymerization of 2-methyl-2-oxazoline, through which a silsesquioxane of the formula [RSiO 3 / 2 ]8 (wherein R is [ka] Figure 1C shows a schematic diagram of how multi-arm polyoxazolines having a core in the form of a T8 cage silicon-oxygen core (represented by POSS in Figure 1C) are formed, where n ranges from 10 to 25. Note that while halogen-based groups are exemplified in the above reaction steps, other leaving groups, including methylsulfonate / mesylate and tosylate groups, can be used as well.

[0018] The terminal hydroxyl groups of the resulting polyoxyazoline arms of the silsesquioxane are available for subsequent reactions, for example, which may provide reactive end groups such as reactive electrophilic groups (e.g., N-hydroxysuccinimide ester groups such as succinimidyl glutarate, succinimidyl succinate, succinimidyl carbonate, or succinimidyl adipate, imidazole ester, imidazole carboxylate, and / or benzotriazole ester groups, among others) or reactive nucleophilic groups (e.g., amine and / or thiol groups, among others).

[0019] In certain embodiments, the terminal hydroxyl groups of the polyoxyazoline arms of the resulting silsesquioxane are reacted with a cyclic anhydride (e.g., glutaric anhydride, succinic anhydride, malonic anhydride, etc.) to form a reaction product in the form of a silsesquioxane having a cage-like silicon-oxygen core comprising a plurality of polyoxazoline-containing arms having a first end attached to the core and a second end comprising a moiety containing a carboxylic acid group, which is attached to the polyoxazoline-containing arm through a hydrolyzable ester group, which is then coupled to a coupling agent (e.g., N,N'-dicyclohexylcarbodiimide). The polyoxazoline may be treated with a carbodiimide coupling agent, such as carbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxybenzotriazole (HOBt), BOP reagent, and / or another coupling agent, and N-hydroxysuccinimide (NHS) to yield a reactive multi-arm polyoxazoline containing succinimidyl end groups, particularly hydrolyzable ester groups, and reactive succinimidyl ester end groups, such as succinimidyl glutarate, succinimidyl succinate, succinimidyl carbonate, or succinimidyl adipate. A specific example of such a reaction step is shown in Figure 1D, which schematically illustrates a method for producing a multi-arm polyoxazoline terminated with a reactive succinimidyl glutarate group by reacting the hydroxyl groups of the multi-arm polyoxazoline of Figure 1C with glutaric anhydride, followed by carbodiimide coupling with N-hydroxysuccinimide (NHS).

[0020] Using these and other techniques, reactive multi-arm polyoxazolines can be formed, which contain a cage-like silicon-oxygen core (e.g., T6, T8, T 10 or T 12 and a plurality of polyoxazoline-containing arms, each arm having a first end and a second end, each arm formed from the polymerization of at least one oxazoline monomer, wherein the first end is bonded to the silicon-oxygen cage core and the second end comprises a reactive group.

[0021] In some embodiments, at least a portion of the polyoxazoline arms may include one or more covalently attached radiopaque moieties, such as, for example, bromine or iodine groups. For example, the iodine-containing moieties may be attached to at least a portion of the polyoxazoline arms by a suitable covalent bond, such as an ester or amide bond, among others. Examples of such iodine-containing moieties include aromatic moieties containing monocyclic or polycyclic aromatic structures, such as benzene or naphthalene groups, substituted with one or more radiopaque functional groups, e.g., one or more iodine groups, and, optionally, multiple hydrophilic functional groups, such as hydrophilic functional groups selected from the following: one or more hydroxyl groups, C1-C4-hydroxyalkyl groups, C1-C4-aminoalkyl groups, or C1-C4-carboxyalkyl groups.

[0022] The reactive multi-arm polyoxazolines described herein can be crosslinked with a suitable crosslinker, either in vivo or in vitro, to form a crosslinked product, which, when hydrated, can be in the form of a hydrogel. In some embodiments, the reactive multi-arm polyoxazoline can be crosslinked with a polyfunctional compound having functional groups reactive with the reactive groups of the multi-arm polyoxazoline. As shown schematically in Figure 3, the reactive multi-arm polyoxazoline 210 described above is crosslinked with a polyfunctional compound 220 containing functional groups reactive with the reactive groups of the multi-arm polyoxazoline 210 to form a crosslinked product 230. In some embodiments, the reactive group of the reactive multi-arm polyoxazoline is a nucleophilic group and the functional group of the multifunctional compound is an electrophilic group, hi some embodiments, the reactive group of the reactive multi-arm polyoxazoline is an electrophilic group and the functional group of the multifunctional compound is a nucleophilic group.

[0023] For example, the functional group of the multifunctional compound may be a nucleophilic group selected from an amine group and / or a thiol group. As another example, the functional group of the multifunctional compound may be an electrophilic group selected from an imidazole ester, an imidazole carboxylate, a benzotriazole ester, and an imido ester, including an N-hydroxysuccinimidyl ester. In various aspects, the present disclosure relates to crosslinkable systems comprising reactive multi-arm polyoxazolines as described herein and multifunctional compounds as described herein. In various aspects, the present disclosure relates to crosslinked products of reactive multi-arm polyoxazolines as described herein and multifunctional compounds as described herein. Such crosslinked products can be formed in vivo, or they can be formed ex vivo and then administered to a subject. Such crosslinked products can be used in a wide variety of biomedical applications, including implants, lubricious coatings, and pharmaceutical compositions. In various embodiments, the reaction of a functional group of the multifunctional compound with a reactive end group of the reactive multi-arm polyoxazoline results in an amide bond.

[0024] In certain advantageous embodiments, the polyfunctional compound for use in the present disclosure may be a polyamine compound. Generally, polyamine compounds suitable for use in the present disclosure include, for example, small molecule polyamines (e.g., containing at least two amine groups, e.g., 3 to 20 or more amine groups in certain embodiments), polymers with amine side chains, and branched polymers with amine end groups, including dendritic polymers with amine end groups. Polyamine compounds suitable for use in the present disclosure include those containing multiple -(CH2) xThese include compounds containing an -NH group, where x is 0, 1, 2, 3, 4, 5, or 6. Suitable polyamine compounds for use in the present disclosure include polyamine compounds containing basic amino acid residues, including residues of amino acids having two or more primary amine groups, such as lysine and ornithine, for example, polyamines containing 2 to 10 lysine and / or ornithine amino acid residues (e.g., dilysine, trilysine, tetralysine, pentalysine, diornithine, triornithine, tetraornithine, pentornithine, etc.).

[0025] Specific examples of polyamine compounds that can be used as the polyfunctional compound include, among others, ethylenetriamine, diethylenetriamine, hexamethylenetriamine, di(heptamethylene)triamine, di(trimethylene)triamine, bis(hexamethylene)triamine, triethylenetetraamine, tripropylenetetraamine, tetraethylenepentamine, hexamethyleneheptamine, pentaethylenehexamine, dimethyloctylamine, dimethyldecylamine, and JEFFAMINE polyetheramines available from Huntsman Corporation, chitosan and its derivatives, and poly(allylamine).

[0026] In certain advantageous embodiments, the polyfunctional compound contains one or more covalently bound radiopaque moieties, such as bromine or iodine groups. For example, polyamine compounds such as those described above, among others, can be bound to iodine-containing moieties by suitable covalent bonds, such as ester or amide bonds, among others. Examples of such iodine-containing moieties include aromatic moieties containing monocyclic or polycyclic aromatic structures, such as benzene or naphthalene groups, substituted with one or more radiopaque functional groups, e.g., one or more iodine groups, and, optionally, multiple hydrophilic functional groups, such as hydrophilic functional groups selected from the following: one or more hydroxyl groups, C1-C4-hydroxyalkyl groups, C1-C4-aminoalkyl groups, or C1-C4-carboxyalkyl groups. In embodiments in which the reactive multi-arm polyoxazoline and / or polyfunctional compound comprises one or more covalently attached radiopaque moieties, the crosslinked product of such reactive multi-arm polyoxazoline and / or polyfunctional compound is visible under fluoroscopy. In various embodiments, such crosslinked products have a radiopacity of greater than 250 Hounsfield Units (HU), advantageously ranging from 250 HU to 500 HU to 750 HU to 1000 HU or more (in other words, a range between any two of the foregoing values).

[0027] As previously mentioned, in various aspects, the present disclosure relates to crosslinkable systems comprising a reactive multi-arm polyoxazoline as described herein and a multifunctional compound as described herein. In certain embodiments, systems are provided that are configured to deliver a polyamine compound and a reactive multi-arm polyoxazoline comprising multiple reactive end groups reactive with the amino groups of the polyamine compound under conditions such that the polyamine compound and the reactive multi-arm polyoxazoline crosslink with each other. Such conditions include basic conditions, such as having a pH in the range of about 9 to about 11, typically in the range of about 9.5 to about 10.5, and more typically in the range of about 9.8 to about 10.2. In some embodiments, a system can be provided that includes a first composition that includes a polyamine compound as described herein and a second composition that includes a reactive multi-arm polyoxazoline as described herein.

[0028] The first composition may be a first fluid composition containing a polyamine compound, or may be a first dry composition containing a polyamine compound, to which an appropriate fluid, such as water for injection or saline, can be added to form the first fluid composition. In addition to the polyamine compound, the first composition may further include additional agents, including those described below. The second composition may be a second fluid composition comprising the reactive multi-arm polyoxazoline, or may be a second dry composition comprising the reactive multi-arm polyoxazoline to which a suitable fluid, such as water for injection, saline, or the like, can be added to form the second fluid composition. In addition to the reactive multi-arm polyoxazoline, the second composition may further comprise additional agents, including those described below.

[0029] In some embodiments, the polyamine compound is first combined with the reactive multi-arm polyoxazoline at an acidic pH (e.g., about 3 to about 5, typically about 3.5 to about 4.5, more typically about 3.8 to about 4.2) that inhibits crosslinking between the reactive groups of the reactive multi-arm polyoxazoline and the amino groups of the polyamine compound. Then, if crosslinking is desired, the pH of the mixture of the polyamine compound and the reactive multi-arm polyoxazoline is changed from an acidic pH to a basic pH (e.g., about 9 to about 11, typically about 9.5 to about 10.5, more typically about 9.8 to about 10.2) to allow crosslinking between the polyamine compound and the reactive multi-arm polyoxazoline to occur.

[0030] In certain embodiments, the system includes (a) a first precursor composition comprising a polyamine compound described herein, (b) a second precursor composition comprising a reactive multi-arm polyoxazoline described herein, and (c) a third composition, specifically an accelerator composition, comprising an accelerator configured to accelerate the crosslinking reaction between the polyamine compound and the reactive multi-arm polyoxazoline. The first precursor composition can be a first fluid composition containing a polyamine compound buffered at an acidic pH, or a first dry composition containing a polyamine compound and an acidic buffer composition, to which an appropriate fluid, such as water for injection or saline, can be added to form a first fluid composition containing a polyamine compound buffered at an acidic pH. In some embodiments, for example, the acidic buffer composition can include monobasic sodium phosphate, among other possibilities. The first fluid composition containing a polyamine compound can have, for example, a pH in the range of about 3 to about 5, typically about 3.5 to about 4.5, and more typically about 3.8 to about 4.2. In addition to the polyamine compound, the first precursor composition can further include additional agents, such as a therapeutic agent and / or an imaging agent. The second precursor composition may be a second fluid composition comprising the reactive multi-arm polyoxazoline, or may be a second dry composition comprising the reactive multi-arm polyoxazoline from which a fluid composition is formed by the addition of a suitable fluid, such as, for example, water for injection, saline, or a first fluid composition comprising a polyamine compound buffered at an acidic pH. In addition to the reactive multi-arm polyoxazoline, the second precursor composition may further comprise additional agents, such as a therapeutic agent and / or an imaging agent.

[0031] In one embodiment, the first precursor composition is a first fluid composition including a polyamine compound buffered at an acidic pH, and the second precursor composition includes a dry composition including a reactive multi-arm polyoxazoline. The first precursor composition can then be mixed with the second precursor composition to provide a prepared fluid composition including a polyamine compound and a reactive multi-arm polyoxazoline buffered at an acidic pH. In a particular example, a syringe can be provided that includes the first fluid composition including a polyamine compound buffered at an acidic pH, and a vial can be provided that includes a dry composition (e.g., a powder) including the reactive multi-arm polyoxazoline. The syringe can then be used to inject the first fluid composition into the vial containing the reactive multi-arm polyoxazoline to form a prepared fluid composition including a polyamine compound and a reactive multi-arm polyoxazoline, which can be withdrawn into the syringe for administration.

[0032] The enhancer composition may be a fluid enhancer composition buffered at a basic pH, or may be a dry composition containing a basic buffered composition to which an appropriate fluid, such as water for injection or saline, can be added to form a fluid enhancer composition buffered at a basic pH. For example, the basic buffered composition may contain sodium borate and dibasic sodium phosphate, among other possibilities. The fluid enhancer composition may have, for example, a pH in the range of about 9 to about 11, typically about 9.5 to about 10.5, and more typically about 9.8 to about 10.2. In addition to the above, the fluid enhancer composition may further contain additional agents, such as a therapeutic agent and / or a contrast agent.

[0033] Examples of imaging agents include: (a) fluorescent dyes such as fluorescein, indocyanine green, or fluorescent proteins (e.g., green, blue, or cyan fluorescent proteins); (b) Gd (III) , Mn (II) , Fe (III)(c) contrast agents for use with ultrasound imaging, including organic and inorganic echogenic particles (i.e., particles that result in an increase in reflected ultrasound energy) or organic and inorganic echolucent particles (i.e., particles that result in a decrease in reflected ultrasound energy); (d) radiological contrast agents for use in connection with X-ray fluoroscopy, including metals and metal compounds (e.g., metal salts, metal oxides, etc.), such as barium compounds, bismuth compounds, and tungsten, among others, and iodinated compounds, and clinically significant isotopes, among others. 99m Tc-based radiocontrast agents, as well as, inter alia, 123 I, 125 I, 131 I, 111 In, 57 Co, 153 Sm, 133 Xe, 51 Cr, 81m Kr, 201 Tl, 67 Ga, and 75 Other gamma emitters such as Se, (e) among others 18 F, 11 C. 13 N, 15 O, and 68(f) contrast agents for use in connection with near-infrared (NIR) imaging, which can be selected to impart near-infrared fluorescence to the coatings of the present disclosure, enabling deep tissue imaging and device marking, including NIR-sensitive nanoparticles such as gold nanoshells, carbon nanotubes (e.g., nanotubes derivatized with hydroxyl or carboxyl groups, e.g., partially oxidized carbon nanotubes), dye-containing nanoparticles such as dye-doped nanofibers and dye-encapsulated nanoparticles, and semiconductor quantum dots. NIR-sensitive dyes include cyanine dyes, squaraines, phthalocyanines, porphyrin derivatives, boron dipyrromethane (BODIPY) analogs, and the like.

[0034] A prepared fluid composition buffered at an acidic pH and comprising a polyamine compound and a reactive multi-arm polyoxazoline, as described above, can be combined with a fluidity enhancing composition buffered at a basic pH, as described above, to form a crosslinked hydrogel either in vivo or in vitro. In various embodiments, a system is provided that includes one or more delivery devices for delivering the first and second compositions to a subject. In some embodiments, a system may include a delivery device comprising a first reservoir containing a first composition comprising a polyamine compound as described above and a second reservoir containing a second composition comprising a reactive multi-arm polyoxazoline as described above. In some embodiments, a system may include a delivery device comprising a first reservoir containing a first composition, such as the prepared fluid composition described above, comprising a polyamine compound and a reactive multi-arm polyoxazoline and buffered at an acidic pH, and a second reservoir containing a second composition, such as the fluid enhancer composition described above. In either case, during operation, the first and second compositions are dispensed from the first and second reservoirs and combined, after which the polyamine compound and the reactive multi-arm polyoxazoline crosslink to each other to form a hydrogel.

[0035] Regardless of the particular first and second compositions selected, in certain embodiments, the system can include a delivery device comprising a dual-barrel syringe including a first barrel having a first barrel outlet (the first barrel containing the first composition), a first plunger movable within the first barrel, a second barrel having a second barrel outlet (the second barrel containing the second composition), and a second plunger movable within the second barrel. In some embodiments, the device may further include a mixing section having a first mixing section inlet in fluid communication with the first barrel outlet, a second mixing section inlet in fluid communication with the second barrel outlet, and a mixing section outlet. In some embodiments, the device may further include a cannula or catheter tube configured to receive the first and second fluid compositions from the first and second barrels. For example, the cannula or catheter tube can be configured to form a fluid connection with the mixing section outlet by attaching the cannula or catheter tube to the mixing section outlet via a suitable fluid connector, such as a Luer connector.

[0036] As another example, the catheter may be a multi-lumen catheter including a first lumen and a second lumen, a proximal end of the first lumen configured to form a fluid connection with the first barrel outlet, and a proximal end of the second lumen configured to form a fluid connection with the second barrel outlet. In some embodiments, the multi-lumen catheter may include a mixing section having a first mixing section inlet in fluid communication with the distal end of the first lumen, a second mixing section inlet in fluid communication with the distal end of the second lumen, and a mixing section outlet. In operation, when the first and second plungers are depressed, the first and second fluid compositions are dispensed from the first and second barrels, after which the first and second fluid compositions interact and eventually crosslink to form a hydrogel, which is administered onto or into the tissue of a subject. For example, the first and second fluid compositions can enter the mixing section from the first and second barrels through the first and second mixing section inlets, after which the first and second fluid compositions mix to form a mixture, which exits the mixing section through the mixing section outlet. In some embodiments, a cannula or catheter tube can be attached to the mixing section outlet, and the mixture can be administered to a subject after passing through the cannula or catheter tube.

[0037] As another example, a first fluid composition can enter a first lumen of a multi-lumen catheter through a first barrel outlet, and a second fluid composition can enter a second lumen of the multi-lumen catheter through a second barrel outlet. In some embodiments, the first and second fluid compositions can enter a mixing section at a distal end of the multi-lumen catheter from the first and second lumens through first and second mixing section inlets, respectively, and then the first and second fluid compositions mix in the mixing section to form an admixture, which exits the mixing section through a mixing section outlet. Regardless of the type of device used to mix the first and second fluid compositions or the method by which the first and second fluid compositions are mixed, once the mixture of the first and second fluid compositions is formed, the mixture is initially in a fluid state and can be administered to a subject (e.g., a mammal, particularly a human) by a variety of techniques. Alternatively, the first and second fluid compositions can be administered separately to the subject, forming a fluid mixture of the first and second fluid compositions in or on the subject. In either approach, the fluid mixture of the first and second fluid compositions is formed and can be used in a variety of medical procedures.

[0038] For example, among other uses, the first and second fluid compositions or fluid admixtures thereof can be injected to create spacing between tissues, the first and second fluid compositions or fluid admixtures thereof can be injected to create fiducial markers (e.g., in the form of blebs), the first and second fluid compositions or fluid admixtures thereof can be injected for tissue augmentation or regeneration, the first and second fluid compositions or fluid admixtures thereof can be injected as a filler or replacement for soft tissue, the first and second fluid compositions or fluid admixtures thereof can be injected to provide mechanical support for damaged tissue, the first and second fluid compositions or fluid admixtures thereof can be injected as a scaffold, and / or the first and second fluid compositions or fluid admixtures thereof can be injected as a carrier for therapeutic agents in the treatment of disease and cancer and tissue repair and regeneration.

[0039] After administration of the compositions of the present disclosure (either separately as first and second fluid compositions that mix in vivo, or as a fluid admixture of the first and second fluid compositions), a crosslinked hydrogel is ultimately formed at the site of administration. As can be seen from the above, the compositions of the present disclosure can be used in a variety of medical procedures, including, inter alia: a procedure of implanting a tissue regeneration scaffold comprising the cross-linked product of the first and second fluid compositions; a procedure of implanting a tissue support comprising the cross-linked product of the first and second fluid compositions; a procedure of implanting a tissue expander comprising the cross-linked product of the first and second fluid compositions; a procedure of implanting a therapeutic agent-containing depot comprising the cross-linked product of the first and second fluid compositions; a tissue augmentation procedure comprising implanting the cross-linked product of the first and second fluid compositions; a procedure of introducing the cross-linked product of the first and second fluid compositions between a first tissue and a second tissue to space the first tissue from the second tissue; or a procedure of implanting a fiducial marker comprising the cross-linked product of the first and second fluid compositions.

[0040] The first and second fluid compositions, the fluid blend of the first and second fluid compositions, or the crosslinked product of the first and second fluid compositions can be injected in conjunction with a variety of medical procedures, including injections between the prostate or vagina and the rectum for spacing purposes in radiotherapy for rectal cancer, injections between the rectum and the prostate for spacing purposes in radiotherapy for prostate cancer, subcutaneous injections for palliative treatment of prostate cancer, transurethral or submucosal injections for female stress urinary incontinence, intravesical injections for urinary incontinence, intrauterine injections for Asherman's syndrome, submucosal injections for anal incontinence, percutaneous injections for heart failure, intramyocardial injections for heart failure and dilated cardiomyopathy, transendocardial injections for myocardial infarction, intra-articular injections for osteoarthritis, spinal injections for spinal fusion and spinal, oral maxillofacial, and orthopedic trauma surgery, spinal injections for posterolateral lumbar fusion, intradiscal injections for degenerative disc disease, and injections for pancreatic adenocarcinoma. injections between the pancreas and duodenum for diagnostic imaging, resection bed injections for diagnostic imaging of oropharyngeal cancer, injections around the tumor bed for diagnostic imaging of bladder cancer, submucosal injections for gastrointestinal tumors and polyps, visceral pleural injections for lung biopsy, renal injections for type 2 diabetes and chronic kidney disease, renal cortical injections for chronic kidney disease due to congenital anomalies of the kidney or urinary tract, intravitreal injections for neovascular age-related macular degeneration, intratympanic injections for sensorineural hearing loss, correction of wrinkles, creases, folds, signs of facial fat loss, volume loss, shallow to deep contour defects, correction of depressed skin scars, perioral wrinkles, lip augmentation, facial lip atrophy, intradermal injections for stimulation of natural collagen production.

Claims

1. A reactive multi-arm polymer having a silicon-oxygen cage core and a plurality of polyoxazoline-containing arms extending from the core, the polyoxazoline-containing arms having a first end covalently bonded to the silicon-oxygen cage core and a second end comprising a moiety comprising a reactive end group.

2. The cage-like silicon-oxygen core is T 6 Cage-like silicon-oxygen core, T 8 Cage-like silicon-oxygen core, T 10 Cage-like silicon-oxygen core and T 12 2. The reactive multi-arm polymer of claim 1, wherein the core is selected from a cage-like silicon-oxygen core.

3. The polyoxazoline-containing arms may be oxazoline, 2-(C 1 -C 10 3. The reactive multi-arm polymer of claim 1, comprising polymerized monomers selected from the group consisting of (a)-(-alkyl)-2-oxazoline, (b)-(a ...

4. The reactive multi-arm polymer of any one of claims 1 to 3, wherein the reactive end group is an electrophilic group.

5. 5. The reactive multi-arm polymer of claim 1, wherein the portion comprising a reactive end group can further comprise a hydrolyzable ester group, or the portion comprising a reactive end group comprises a diester selected from malonic acid-based diesters, succinic acid-based diesters, glutaric acid-based diesters, and adipic acid-based diesters.

6. 10. A system comprising: (a) the reactive multi-arm polymer of any one of claims 1 to 5; and (b) a multifunctional compound comprising a functional group that is reactive with the reactive end group of the reactive multi-arm polymer.

7. The system of claim 6 , wherein the reactive group of the reactive multi-arm polymer is an electrophilic group and the functional group of the multifunctional compound is a nucleophilic group.

8. The system of claim 7 , wherein the polyfunctional compound is a polyamine compound.

9. The polyamine compound contains 2 to 10 residues of a basic amino acid, and the polyamine compound contains a plurality of —(CH 2 ) x -NH 2 9. The system of claim 8, wherein the polyamine compound comprises a group (wherein x is 0, 1, 2, 3, 4, 5, or 6), or wherein the polyamine compound comprises two or more amino acid residues selected from residues of lysine, ornithine, and combinations thereof.

10. 10. The system of any one of claims 6 to 9, comprising a first precursor composition comprising the multifunctional compound and a second precursor composition comprising the reactive multi-arm polymer.

11. The system of claim 10 further comprising an accelerator composition.

12. 12. The system of claim 11, wherein the enhancer composition comprises a buffer having a pH in the range of about 9 to about 11.

13. 13. The system of claim 11 or 12, wherein the first precursor composition is provided in a syringe barrel, the second precursor composition is provided in a vial, and the accelerator composition is provided in a syringe barrel.

14. The system of any one of claims 6 to 13, further comprising a delivery device.

15. 6. A medical hydrogel formed by crosslinking the reactive multi-arm polymer of any one of claims 1 to 5 with a multifunctional compound comprising a functional group reactive with the reactive end group of the reactive multi-arm polymer.

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