Iodinated cross-linked hydrogels and methods of forming same

Abstract

In some aspects, the present disclosure relates to systems for forming hydrogels comprising (a) an iodinated polyamino compound and (b) a reactive multi-arm polymer comprising a plurality of hydrophilic polymer arms having unsaturated end groups that react with amino groups of the iodinated polyamino compound. Other aspects of the present disclosure relate to medical hydrogels formed by crosslinking iodinated polyamino compounds and reactive multi-arm polymers of such systems. Other aspects of the present disclosure relate to medical procedures that may be performed using such systems.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 398,765, filed on August 17, 2022, the disclosure of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to iodinated cross-linked hydrogels and methods of making and using iodinated compounds and hydrogels, etc. The iodinated cross-linked hydrogels of the present disclosure can be used, for example, in various biomedical applications. Background Art

[0004] In vivo cross-linked hydrogels based on star-shaped polyethylene glycol (star-PEG) polymers functionalized with reactive ester end groups that react with lysine trimers (Lys-Lys-Lys) as cross-linkers to rapidly form cross-linked hydrogels have become clinically important materials as adjuvants in radiotherapy. See “Augmenix Announces Positive Three-year Clinical Trial Results,” Imaging Technology News, October 27, 2016.

[0005] Hydrogels in which some of the star-shaped PEG branches were functionalized by replacing some of the ester end groups with 2,3,5-triiodobenzamide (TIB) groups have also been developed, such as Vue, which provides enhanced radiocontrast agents. See "Augmenix Receives FDA Clearance to Market Its Tissue Marker,” BusinessWire, January 28, 2013. The hydrogel remained stable and visible in tissue for three months, long enough for radiation therapy, after which it was absorbed and cleared from the body. Id.

[0006] Although the above methods are effective, some problems arise due to the introduction of the functional group TIB. First, TIB exhibits poor water solubility, a property that affects how many TIB groups can be added to the PEG arms before it affects the ability to form smooth, uniform hydrogels. In addition, the entire functionalization process from the commercially available hydroxyl-terminated 8-arm PEG to its functionalized form with two different end groups (i.e., TIB and succinimidyl glutarate (SG) groups) requires multiple steps. This increases the complexity of the star PEG manufacturing process, resulting in a sharp increase in product cost and difficulty in product quality control. Finally, using the arms of the star polymer to functionalize the hydrogel with iodine means that there are fewer arms available for crosslinking. This can be overcome by adding more polymers, but the solid loading increases, which can have an adverse effect on viscosity. Reducing the molecular weight can reduce the solid loading, but this also leads to a lower melting point, which has a great impact on storage and transportation conditions and brings processability issues. An additional impact of the reduced crosslink density per star polymer is that the resulting gel has a slower solidification rate, meaning that the gel is liquid and mobile in vivo for a longer period of time, which provides opportunities for unintended side reactions and material displacement. Finally, star PEGs labeled with TIB end groups often discolor due to thermal degradation. While this does not affect its functionality, it is a cosmetic defect that is preferably avoided. For these reasons, an innovative strategy for iodine-labeled crosslinkable hydrogels is needed.

[0007] The present disclosure relates to an alternative method to the above method. In the present disclosure, the crosslinker of the star polymer is functionalized with iodine, rather than using the arms of the star polymer to functionalize the hydrogel with iodine. In addition, the use of reactive succinimidyl glutarate groups on the star polymer can be avoided. Summary of the invention

[0008] In some aspects, the present disclosure relates to a system for forming a hydrogel, comprising (a) an iodinated polyamino compound and (b) a reactive multi-arm polymer comprising a plurality of hydrophilic polymer arms having unsaturated end groups that react with amino groups of the iodinated polyamino compound.

[0009] In some of these embodiments, the iodinated polyamino compound comprises a polyamino moiety connected to a carboxyl-substituted iodinated moiety via an amide group. In some of these embodiments, the carboxyl-substituted iodinated moiety comprises an iodinated group (such as an iodinated aromatic group) and a carboxyl or carboxylate group. In some of these embodiments, the carboxyl-substituted iodinated moiety is an iodinated amino acid residue. In some of these embodiments, the polyamino moiety comprises a plurality of -(CH2) x-NH2 group, wherein x is 0, 1, 2, 3, 4, 5 or 6. In some of these embodiments, the polyamino moiety comprises two or more amino acid residues selected from lysine residues, ornithine residues, and combinations thereof.

[0010] In some embodiments that may be used in combination with the above aspects and embodiments, the unsaturated end groups are selected from acrylate groups and propiolate groups.

[0011] In some embodiments that may be used in conjunction with the above aspects and embodiments, the hydrophilic polymer arms comprise one or more hydrophilic monomers selected from the group consisting of ethylene oxide, N-vinyl pyrrolidone, oxazoline, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate or PEG methyl ether methacrylate, or PNIPAAM.

[0012] In some embodiments that can be used in combination with the above aspects and embodiments, the unsaturated end groups are connected to the hydrophilic polymer arms via hydrolyzable ester groups. For example, the hydrolyzable ester groups can be selected from glutarate groups, succinate groups, carbonate groups, adipate groups, and the like.

[0013] In some embodiments that can be used in conjunction with the above aspects and embodiments, the system includes a first precursor composition comprising an iodinated polyamino compound, a second precursor composition comprising a reactive multi-arm polymer, and an optional accelerator composition. In some of these embodiments, 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.

[0014] In some embodiments that may be used in conjunction with the above aspects and embodiments, the system further comprises a delivery device.

[0015] In other aspects, the present disclosure relates to a medical hydrogel formed by crosslinking the iodinated polyamino compound and the reactive multi-arm polymer of the system of any of the above aspects and embodiments under conditions that form the medical hydrogel. For example, the medical hydrogel can be a medical implant or a medical device coating, among other possibilities.

[0016] In other aspects, the present disclosure relates to treatment methods, which include, for example, according to any of the above aspects and embodiments, administering to a subject a mixture comprising an iodinated polyamino compound and a reactive multi-arm polymer under conditions such that the iodinated polyamino compound and the reactive multi-arm polymer cross-link after administration, wherein the reactive multi-arm polymer comprises multiple hydrophilic polymer arms having unsaturated end groups that react with amino groups of the iodinated polyamino compound.

[0017] Potential benefits associated with the present disclosure include one or more of the following: maintaining radiocontrast agents, reducing the complexity and cost of the manufacturing process, the melting point of the solid components of the hydrogel can be maintained above 40°C (improving storage and handling), improving the homogeneity of the final hydrogel, achieving in vivo persistence, and maintaining solidification kinetics.

[0018] The above and other aspects, embodiments, features and advantages of the present disclosure will become apparent from the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Schematically illustrated is a method for cross-linking a reactive multi-arm polymer comprising a core region and a plurality of hydrophilic polymer arms having acrylate end groups with an iodinated polyamino compound according to one aspect of the present disclosure.

[0020] Figure 2A , 2B 2C and 2C are chemical diagrams of iodinated polyamino compounds according to three embodiments of the present disclosure, which can be used as cross-linking agents.

[0021] Figure 3A , 3B and 3C are chemical diagrams of iodinated polyamino compounds according to three additional embodiments of the present disclosure, which can be used as cross-linking agents.

[0022] Figure 4 Schematically illustrated is a method for generating a reactive multi-arm polymer by reacting acryloyl chloride with a multi-arm polymer having a core region containing a polyol residue and eight hydroxyl-terminated polyethylene oxide arms, wherein the reactive multi-arm polymer comprises a core region and multiple polyethylene oxide (PEO) arms having acrylate end groups, according to one aspect of the present disclosure.

[0023] Figure 5 Schematically illustrated is a method for coupling an iodinated amino acid compound to trilysine to form an iodinated peptide sequence according to one embodiment of the present disclosure. DETAILED DESCRIPTION

[0024] In some aspects of the present disclosure, a radiopaque cross-linked hydrogel is provided, comprising a cross-linked reaction product of (a) an iodinated polyamino compound and (b) a reactive multi-arm polymer, the reactive multi-arm polymer comprising a plurality of unsaturated end groups reactive with the amino groups of the iodinated polyamino compound. Unless otherwise indicated, the prefix "poly" used herein means two or more.

[0025] In some aspects of the present disclosure, a system is provided, which is configured to distribute iodinated polyamino compounds and reactive multi-arm polymers comprising multiple unsaturated end groups under conditions such that the iodinated polyamino compounds and reactive multi-arm polymers are cross-linked with each other. In certain embodiments, those conditions include an environment with alkaline pH, for example, a pH range of about 9 to about 11, typically ranging from about 9.5 to about 10.5, and beneficially ranging from about 9.8 to about 10.2.

[0026] In some aspects of the present disclosure, a system is provided, comprising: (a) a first composition comprising an iodinated polyamino compound, and (b) a second composition comprising a reactive multi-arm polymer comprising a plurality of unsaturated end groups reactive with the amino groups of the iodinated polyamino compound. In some embodiments, a third composition in the form of a promoter composition is provided.

[0027] Such a system is advantageous, for example, because the iodinated polyamino compound as a crosslinker for the multi-arm polymer provides iodine functionality, thereby providing radiopacity. This allows for providing reactive end groups on each polymer arm, thereby maximizing the crosslinking ability of the multi-arm polymer without sacrificing radiopacity.

[0028] In various embodiments, the unsaturated end groups of the reactive multi-arm polymer and the amino groups of the iodinated polyamino compound react with each other via Michael addition. In certain embodiments, the reaction between the unsaturated end groups and the amino groups is carried out at a weakly alkaline pH (e.g., a pH range of 7.4 to 11), wherein the amino groups of the iodinated polyamino compound are deprotonated / neutral, and the Michael addition can occur spontaneously at body temperature.

[0029] Reactive multi-arm polymers used herein include those containing multiple polymer arms (e.g., having two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or more arms), wherein two or more polymer arms of the multi-arm polymer each contain one or more unsaturated end groups. Examples of unsaturated end groups include unsaturated end groups with carbon-carbon double bonds, such as acrylate groups, and an unsaturated terminal group having a carbon-carbon triple bond, such as a propiolate group,

[0030] In some embodiments, a composition containing a reactive multi-arm polymer can be provided, wherein the percentage of polymer arms comprising one or more unsaturated end groups can correspond to between 50% and 100% of the total number of polymer arms in the composition (e.g., any range of 50% to 70% to 80% to 90% to 95% to 99% to 100% of the total number of polymer arms). The typical average molecular weight range of the reactive multi-arm polymer used herein is 10 to 50 kDa or the like. In various embodiments, the reactive multi-arm polymer used herein has a melting point of 40° C. or greater, preferably 45° C. or greater.

[0031] In various embodiments, the polymer arm is a hydrophilic polymer arm. Such a hydrophilic polymer arm can be composed of any of a variety of synthetic, natural or synthetic-natural hybrid polymers, including, for example, poly(alkylene oxides), such as poly(ethylene oxide) (PEO) (also known as polyethylene glycol or PEG), poly(propylene oxide) or poly(ethylene oxide-co-propylene oxide), poly(N-vinyl pyrrolidone), polyoxazolines (including poly(2-alkyl-2-oxazolines) such as poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline) and poly(2-propyl-2-oxazoline)), poly(vinyl alcohol), poly(propylene alcohol), polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, PEG methyl ether acrylate or PEG methyl ether methacrylate or PNIPAAM, polysaccharides and combinations thereof.

[0032] In some embodiments, the polymer arms extend from the core region. In some of these embodiments, the core region includes the residues of the polyols for forming the polymer arms. Exemplary polyols can be selected from, for example, straight chain, branched and cyclic aliphatic polyols (including straight chain, branched and cyclic polyhydroxyalkanes), straight chain, branched and cyclic polyhydroxy ethers (including polyhydroxy polyethers), straight chain, branched and cyclic polyhydroxy alkyl ethers (including polyhydroxy alkyl polyethers), straight chain, branched and cyclic sugars and sugar alcohols (such as glycerol, mannitol, sorbitol, inositol, xylitol, quebracho, threitol, arabitol, erythritol, adonitol, galactitol, fucose, ribose, arabinose (arabinose), xylose, lyxose, rhamnose, galactose, glucose, sucrose ... The present invention relates to a polyol comprising a sucrose, fructose, sorbose, mannose, pyranose, altrose, talose, tagatose, pyranoside, sucrose, lactose and maltose), polymers of linear, branched and cyclic sugars and sugar alcohols (defined herein as two or more units) (including oligomers of linear, branched and cyclic sugars and sugar alcohols (defined herein as two to ten units, including dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, nonamers and decamers), sugars and sugar alcohols include the aforementioned sugars and sugar alcohols, starch, amylose, dextrin, cyclodextrin and polyhydroxy crown ethers and polyhydroxy alkyl crown ethers). Exemplary polyols also include aromatic polyols, including 1,1,1-tris(4'-hydroxyphenyl)alkanes, such as 1,1,1-tris(4-hydroxyphenyl)ethane and 2,6-bis(hydroxyalkyl)cresol and the like.

[0033] In certain beneficial embodiments, the core region comprises the residue of a polyol containing two, three, four, five, six, seven, eight, nine, ten or more hydroxyl groups. In certain beneficial embodiments, the core region comprises the residue of a polyol that is an oligomer of a sugar alcohol such as glycerol, mannitol, sorbitol, inositol, xylitol or erythritol.

[0034] In certain embodiments, the unsaturated end groups are linked to the polymer arms via hydrolyzable ester groups. The hydrolyzable ester groups may be selected from, for example, glutarate groups, succinate groups, carbonate groups, or adipate groups.

[0035] A multi-arm polymer having arms containing one or more unsaturated terminal groups (e.g., acrylate groups, propiolate groups, etc.) can be formed from a multi-arm polymer having arms containing one or more hydroxyl terminal groups. Figure 4In a specific embodiment shown, a reactive multi-arm polymer comprising a core region and a plurality of polyethylene oxide (PEO) arms having reactive acrylate end groups is formed by reacting acryloyl chloride with the hydroxyl end groups of a multi-arm polymer having a core region comprising a polyol residue R and n hydroxyl-terminated polyethylene oxide arms, wherein n ranges from 30 to 140. Specifically, a commercially available eight-arm hydroxyl-terminated polymer (wherein R is a tripentaerythritol polyol residue) is reacted with acryloyl chloride to produce an acrylate-terminated eight-arm PEO. Acrylate-terminated eight-arm PEO (also referred to as acrylate-terminated eight-arm PEG) having a tripentaerythritol residue core and acrylate-terminated four-arm PEO (also referred to as acrylate-terminated four-arm PEG) having a pentaerythritol residue core are also available from JenKem Technology USA (Plano, Texas, USA).

[0036] As previously described, in various embodiments of the present disclosure, the unsaturated end groups (eg, acrylate groups, propiolate groups, etc.) of reactive multi-arm polymers such as those described above can react with the amino groups of iodinated polyamino compounds via Michael addition to form a crosslinked composition.

[0037] In various embodiments, the iodinated polyamino compounds used in the present disclosure include polyamino moieties connected to the iodinated moieties substituted with carboxyl groups. In certain embodiments, the polyamino moieties are connected to the iodinated moieties substituted with carboxyl groups via amide groups. In the specific embodiments described in detail below, the iodinated polyamino compounds may include peptide oligomers containing 2 to 10 lysine and / or ornithine amino acid residues and one or more iodinated amino acid residues.

[0038] The carboxyl substituted iodinated moieties of the present disclosure include carboxyl substituted iodinated moieties comprising an iodinated group and a carboxyl or carboxylic acid group. The carboxylic acid groups include anionic carboxylate groups, carboxylate amide groups, and carboxylate ester groups.

[0039] In some embodiments, the iodinated moiety substituted with a carboxyl group of the present disclosure comprises an iodinated aromatic group (also referred to herein as an iodinated aromatic group) and a carboxyl or carboxylic acid group. Examples of iodinated aromatic groups include iodine-substituted monocyclic aromatic groups and iodine-substituted polycyclic aromatic groups, such as iodophenyl and iodonaphthyl. Aromatic groups can be substituted with one, two, three, four, five, six or more iodine atoms.

[0040] In a specific embodiment, the carboxyl-substituted iodinated moiety of the present disclosure comprises at least one hydroxyiodoaromatic group and a carboxyl or carboxylic acid group. Examples of hydroxyiodoaromatic groups include hydroxyiodophenyl and hydroxyiodonaphthyl. More specific examples of hydroxyiodoaromatic groups include hydroxyiodophenyl selected from the group consisting of monohydroxymonoiodophenyl, monohydroxydiiodophenyl, monohydroxytriiodophenyl, monohydroxytetraiodophenyl, dihydroxymonoiodophenyl, dihydroxydiiodophenyl, dihydroxytriiodophenyl, trihydroxymonoiodophenyl, trihydroxydiiodophenyl.

[0041] In some embodiments, the carboxyl-substituted iodinated moieties of the present disclosure comprise iodinated amino acid residues. As used herein, an "amino acid" is an organic compound that contains an amino group (-NH2), a carboxyl group (-COOH), and side groups specific to each amino acid. Depending on the pH of the environment, the amino group may be positively charged (-NH3 + ) and / or the carboxyl group may be negatively charged (-COO - ). Iodinated amino acids are amino acids that have one or more iodine atoms in their side groups.

[0042] Examples of the iodinated amino acid residue include an iodinated α-amino acid residue, an iodinated β-amino acid residue, an iodinated γ-amino acid residue and an iodinated δ-amino acid residue.

[0043] The example of iodinated amino acid residues includes amino acid residues containing iodinated aromatic groups. As previously described, examples of iodinated aromatic groups include iodophenyl and iodonaphthyl. In a specific embodiment, the iodinated amino acid residues include amino acid residues containing hydroxyl-iodoaromatic groups (such as hydroxyl-iodophenyl or hydroxyl-iodonaphthyl). More specific examples of hydroxyl-iodoaromatic groups include hydroxyl-iodophenyl selected from the group consisting of monohydroxyl-monoiodophenyl, monohydroxyl-diiodophenyl, monohydroxyl-triiodophenyl, monohydroxyl-tetraiodophenyl, dihydroxyl-monoiodophenyl, dihydroxyl-diiodophenyl, dihydroxyl-triiodophenyl, trihydroxyl-monoiodophenyl, trihydroxyl-diiodophenyl, as previously described.

[0044] Specific examples of iodinated amino acid residues include residues of the following iodinated amino acids: iodophenylalanine, It contains monoiodophenyl; monoiodotyrosine, It contains monoiodophenyl, specifically, monohydroxymonoiodophenyl; diiodotyrosine, It contains monohydroxydiiodophenyl; diiodothyronine, It contains diiodophenyl and hydroxyphenyl; triiodothyronine, also known as T3, It contains diiodophenyl and monohydroxymonoiodophenyl; tetraiodothyronine, also known as thyroxine or T4, It includes diiodophenyl and monohydroxydiiodophenyl; iodophenylalanine and 6-iodo-L-DOPA, which includes dihydroxymonoiodophenyl, etc. Many of these iodinated amino acids are relatively water-soluble, and some, including 3,5-diiodotyrosine and L-thyroxine, have been well studied as monomers for bioerodible polymers.

[0045] As further described below, the iodinated polyamino compounds of the present disclosure can be formed by an amide coupling reaction between a carboxyl-substituted polyamino compound and an iodinated amino acid derivative, wherein the carboxyl-substituted polyamino compound is selected from, for example, those described below (after protecting the amino group), and the iodinated amino acid derivative is such as a C1-C5-alkyl ester of an iodinated amino acid, preferably a methyl ester of an iodinated amino acid, which effectively acts as a protecting group for the carboxyl group of the final iodinated polyamino compound. Examples of such iodinated amino acid derivatives include any of the aforementioned C1-C5-alkyl esters of iodinated amino acids. After coupling, the protecting group on the carboxyl-substituted polyamino compound residue is removed, and the C1-C5-alkyl ester can be converted into the corresponding carboxyl or anionic carboxylic acid group, thereby providing the final iodinated polyamino compound.

[0046] In addition to a carboxy-substituted iodinated moiety, such as one of those described above, the iodinated polyamino compounds of the present disclosure also comprise a polyamino moiety attached to the carboxy-substituted iodinated moiety.

[0047] In various embodiments, the iodinated polyamino compounds of the present disclosure comprise polyamino moieties having multiple (two, three, four, five, six, seven, eight, nine, ten or more) amino groups. For example, the polyamino moiety may comprise multiple (two, three, four, five, six, seven, eight, nine, ten or more)—(CH2) x -NH2 group, wherein x is 0, 1, 2, 3, 4, 5 or 6. In some of these embodiments, the polyamino moiety may include multiple -(CH2) arranged along the polymer moiety (defined herein as a moiety comprising 2, 3, 4, 5, 6, 7, 8, 9, 10 or more monomer residues). x -NH2 group. In some embodiments, the polymer moiety can be selected from a polyamide moiety (such as a peptide moiety), a polyalkylene moiety, or a polysaccharide moiety, etc.

[0048] In some embodiments, the polyamino portion of the iodinated polyamino compound can correspond to the residue of a carboxyl-substituted polyamino compound (a compound comprising a carboxyl group and multiple amino groups). Examples of carboxyl-substituted polyamino compounds include peptides containing 2 to 10 lysine and / or ornithine amino acid residues, including polylysine (e.g., dilysine, trilysine, tetralysine, pentalysine, etc.) and carboxyl-terminated polyamines, such as carboxyl-terminated poly(allylamine), carboxyl-terminated poly(vinylamine), or carboxyl-terminated chitosan.

[0049] Examples of commercially available carboxyl-substituted polyamino compounds also include 16-amino-3-[2-[(4-aminobutyl)(3-aminopropyl)amino]-2-oxoethyl]-12-(3-aminopropyl)-6,9-bis(carboxymethyl)-11-oxo-3,6,9,12-tetraazahexadecanoic acid, L-ornithine-L-ornithine-L-ornithine, N 2 -[1-[N 2 -[N 2 -(NL-valyl-L-alanyl)-L-lysyl]-L-lysyl]-L-prolyl]-L-lysine, L-lysyl-L-tryptophanyl-L-lysyl-L-lysine, N 2 ,N 5 ,N 5 -Tris(3-aminopropyl)-L-ornithine, L-lysyl-L-ornithine-L-lysine, D-lysyl-D-lysyl-D-lysine, glycylglycyl-L-lysylglycyl-L-lysine, N 2 -[N 4 -[N-[N-(N-glycylglycyl)glycyl]glycyl]-L-lysyl]-L-lysine, L-lysyl-L-threonyl-L-lysyl-L-lysine, glycylglycyl-L-lysyl-L-lysyl-L-lysylglycyl-L-cysteine, L-lysyl-L-arginyl-L-lysyl-L-lysine, L-arginyl-L-lysyl-L-lysyl-L-lysine, L-leucyl-L-lysyl-L-seryl-L-lysyl-L- Lysine, L-alanyl-L-methionylglycyl-L-lysyl-L-lysyl-L-lysine, L-lysyl-L-lysyl-L-lysyl-L-arginyl-L-glutamine, L-seryl-L-isoleucyl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysine, N2-(N2-L-ornithine-L-lysyl)-L-lysine, lysyllysyl-lysine and L-lysyl-L-lysyl-L-lysyl-L-alanine.

[0050] As previously mentioned, in certain embodiments, the iodinated polyamino compounds of the present disclosure comprise polyamino moieties connected to the iodinated moieties substituted by carboxyl groups via amide groups. The amide groups can be the result of a coupling reaction between the amino group of an iodinated amino acid (such as one of those described above) and the carboxyl group of a carboxyl-substituted polyamino compound (such as one of those described above). Therefore, the resulting iodinated polyamino compounds comprise the residue of the carboxyl-substituted polyamino compound and the iodinated amino acid residue. In other words, the iodinated polyamino compounds of the present disclosure can be formed by an amidation reaction, wherein the carboxyl group of the carboxyl-substituted polyamino compound reacts with the amino group of the iodinated amino acid to form an amide bond between the two residues.

[0051] In some aspects, the present disclosure relates to methods of preparing iodinated polyamino compounds, such as the iodinated polyamino compounds described above.

[0052] In the first process step, the amino group of the carboxyl-substituted polyamino compound can be protected with a suitable protecting agent. The amino group is protected for compatibility with other reactants in the subsequent amide coupling reaction (described below). For example, the amino group of the carboxyl-substituted polyamino compound can be protected by reacting with di-tert-butyl dicarbonate.

[0053] In the specific example, refer to Figure 4 , the amino group of trilysine (110) is protected with di-tert-butyl dicarbonate (CAS#24424-99-5) to form tBoc protected trilysine (112). This makes the carboxyl group of the protected compound (tBoc protected trilysine) available for amide coupling. In the second step, the iodinated amino acid derivative, specifically, the iodinated amino acid C1-C5-alkyl ester is coupled with the protected carboxyl substituted polyamino compound formed in the first process step in an amide coupling reaction (e.g., by a carbodiimide coupling reagent) to form a protected iodinated polyamino compound. In a specific example, reference is made to Figure 4 , tBoc-protected trilysine (112) is coupled to an iodinated amino acid derivative (specifically, 3,5-diiodo-L-tyrosine methyl ester (CAS#76318-50-8)) in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) in dimethylformamide (DMF) to produce a t-Boc-protected iodinated peptide oligomer (t-Boc-Lys-Lys-Lys-Tyr-I2) (114). 3,5-Diiodo-L-tyrosine has been used to improve radiopacity in in vivo biological applications (see, e.g., U.S. Patent Application No. US 2019 / 0142863A1 and U.S. Patent No. 8,288,505). In a third process step, deprotection and hydrolysis (e.g., under acidic conditions) of the product of the second process step are performed to form the final carboxyl-substituted iodinated polyamino compound. For example, as Figure 4 As shown, under acidic conditions using an acid such as trifluoroacetic acid, the t-Boc protected iodinated peptide fragment (t-Boc-Lys-Lys-Lys-Tyr-I2) (114) is deprotected and hydrolyzed to form an activated iodinated polyamino compound (Lys-Lys-Lys-Tyr-I2) (116).

[0054] The above method can be carried out using various carboxyl-substituted polyamino compounds and various iodinated amino acid derivatives. Regarding the latter, when diiodotyrosine methyl ester is coupled to trilysine as described above, the resulting compound is Figure 2A As shown, when thyroxine methyl ester is coupled to trilysine, the resulting compound is as shown Figure 3A shown.

[0055] Furthermore, more iodinated amino acid groups can be added to the chain ends in sequence by repeating the first, second and third steps, except that the iodinated polyamino compound formed in the third step replaces the trilysine in the first step to form a protected compound, which is then coupled to another iodinated amino acid C1-C5-alkyl ester in an amide coupling reaction according to the route of the second step, followed by deprotection and hydrolysis according to the route of the third step. In the case where the iodinated amino acid C1-C5-alkyl ester is diiodotyrosine methyl ester, the results of performing these additional steps once are shown in Figure 2B In the case where the iodinated amino acid C1-C5-alkyl ester is thyroxine methyl ester, the results of performing these additional steps once show that Figure 3B It contains two thyroxine residues.

[0056] If the first, second and third steps are repeated again, Figure 2B The product of replacing trilysine with diiodotyrosine methyl ester as the iodinated amino acid C1-C5-alkyl ester results in Figure 2C The product shown contains three diiodotyrosine residues. If the first, second and third steps are repeated, Figure 3B The product of replacing trilysine with thyroxine methyl ester as the iodinated amino acid C1-C5-alkyl ester results in Figure 3C The product shown contains three thyroxine residues. Additional iodinated amino acid residues can be added as desired.

[0057] As described above, in some aspects of the present disclosure, a radiopaque cross-linked hydrogel is provided, which comprises a cross-linked reaction product of (a) an iodinated polyamino compound (e.g., the iodinated polyamino compound described above) and (b) a reactive multi-arm polymer, the reactive multi-arm polymer comprising a plurality of polymer arms, the polymer arms having unsaturated end groups (e.g., the unsaturated end groups described above) that react with the amino groups of the iodinated polyamino compound by Michael addition. In one embodiment of the present disclosure, reference is made to Figure 1, an iodinated polyamino compound, specifically, an iodinated peptide oligomer (Lys-Lys-Lys-Tyr-I2) (116) and an acrylate-terminated 8-arm PEG (118) having a core of a pentaerythritol residue are mixed under certain conditions so that Michael addition occurs between the acrylate group of the acrylate-terminated 8-arm PEG 118 and the amino group of the iodinated peptide oligomer (116), thereby forming a cross-linked hydrogel 120. For example, the Michael addition can be performed in an aqueous solution under weakly alkaline conditions (for example, in the presence of a buffer solution such as phosphate buffered saline (PBS) or a borax-related buffer solution, etc., with a pH range of 7.4 to 11).

[0058] In various embodiments, the cross-linked hydrogel of the present disclosure is visible under fluoroscopy. In various embodiments, such a cross-linked product has a radiopacity greater than 250 Hounsfield units (HU), advantageously in any range of 250HU to 500HU to 750HU to 1000HU or higher (in other words, in the range between any two of the aforementioned numerical values). Such a cross-linked product can be formed in vivo (e.g., using a delivery device as described below), or such a cross-linked product can be formed in vitro and then applied to a subject. Such a cross-linked product can be applied to various biomedical applications, including medical devices, implants, and pharmaceutical compositions.

[0059] In various embodiments, the unsaturated end groups of the reactive multi-arm polymer and the amino groups of the iodinated polyamino compound react with each other to form a cross-linked product.

[0060] In some aspects of the present disclosure, a system is provided, which is configured to deliver an iodinated polyamino compound and a reactive multi-arm polymer comprising a plurality of unsaturated end groups reactive with the amino groups of the iodinated polyamino compound under conditions such that the iodinated polyamino compound and the reactive multi-arm polymer are cross-linked with each other. Such a system can be used to form a cross-linked hydrogel in vivo or in vitro.

[0061] For example, refer again to Figure 1 A second composition comprising a reactive multi-arm polymer (118) as described above can be cross-linked with a first composition comprising an iodinated polyamino compound (116) as described above to form a cross-linked product (120) that can be in the form of a hydrogel when hydrated, wherein the reactive multi-arm polymer (118) comprises a core region and multiple hydrophilic polyethylene oxide arms having unsaturated end groups (i.e., acrylate end groups) (wherein R is the core region, such as a tripentaerythritol polyol residue, and n is eight), and the iodinated polyamino compound (116) comprises amino groups that can react with the unsaturated end groups of the reactive multi-arm polymer (118).

[0062] One advantage of this approach is that iodination is separated from the parent polymer and the reactive multi-arm polymer having unsaturated end groups can be replaced with a multi-arm polymer having hydrophilic polymer arms other than polyethylene oxide arms and having unsaturated end groups, such as synthetic, natural or synthetic-natural hybrid hydrophilic polymer arms, such as those described above.

[0063] As previously described, in some aspects of the present disclosure, a system is provided, which includes: (a) a first composition comprising an iodinated polyamino compound, and (b) a second composition comprising a reactive multi-arm polymer comprising a plurality of unsaturated end groups that react with the amino groups of the iodinated polyamino compound.

[0064] The first composition can be a first fluid composition comprising an iodinated polyamino compound, or a first dry composition comprising an iodinated polyamino compound, to which a suitable fluid such as water for injection, saline solution, etc. can be added to form a first fluid composition. In addition to the iodinated polyamino compound, the first composition can also include a pH regulator and / or additives, such as those described below.

[0065] The second composition can be a second fluid composition comprising a reactive multi-arm polymer, or a second dry composition comprising a reactive multi-arm polymer, and suitable fluids such as water for injection, saline solution, etc. can be added to the second dry composition to form a second fluid composition. In addition to the reactive multi-arm polymer, the second composition can also include a pH adjusting agent and / or additives, such as those described below.

[0066] In some embodiments, the iodinated polyamino compound is initially mixed with the unsaturated multi-arm polymer at an acidic pH, at which the crosslinking between the unsaturated groups of the reactive multi-arm polymer and the amino groups of the iodinated polyamino compound is inhibited. Then, when crosslinking is required, the pH of the mixture of the iodinated polyamino compound and the reactive multi-arm polymer is changed from an acidic pH to an alkaline pH, resulting in crosslinking between them.

[0067] In certain embodiments, the system comprises (a) a first precursor composition comprising an iodinated polyamino compound as described above, (b) a second precursor composition comprising a reactive multi-arm polymer as described above, and (c)

[0068] The third composition, specifically the accelerator composition, contains an accelerator configured to accelerate the cross-linking reaction between the iodinated polyamino compound and the reactive multi-arm polymer.

[0069] The first precursor composition can be a first fluid composition comprising an iodinated polyamino compound buffered to an acidic pH, or a first dry composition comprising an iodinated polyamino compound and an acidic buffer composition, suitable fluids such as water for injection, saline solution, etc. can be added to the first dry composition to form a first fluid composition comprising an iodinated polyamino compound buffered to an acidic pH. In some embodiments, for example, the acidic buffer composition can include sodium dihydrogen phosphate or the like. The pH range of the first fluid composition comprising an iodinated polyamino compound can be, for example, about 3 to about 5, typically ranging from about 3.5 to about 4.5, and more typically ranging from about 3.8 to about 4.2. In addition to the iodinated polyamino compound and the buffer substance, the first precursor composition can also include additives, such as therapeutic agents and / or other imaging agents (except the iodine groups present in the iodinated polyamino compound).

[0070] The second precursor composition can be the second fluid composition comprising reactive multi-arm polymer, or the second dry composition comprising reactive multi-arm polymer, for example, by adding suitable fluid such as water for injection, saline solution or the first fluid composition comprising the iodinated polyamino compound being buffered to acidic pH, fluid composition is formed by the second dry composition.Except reactive multi-arm polymer, the second precursor composition can also include additive, such as therapeutic agent and / or other imaging agent (except the iodine group present in the iodinated polyamino compound).

[0071] In a particularly beneficial embodiment, the first precursor composition is a first fluid composition comprising an iodinated polyamino compound buffered to an acidic pH, and the second precursor composition comprises a dry composition containing a reactive multi-arm polymer. The first precursor composition can then be mixed with the second precursor composition to provide a fluid composition prepared by being buffered to an acidic pH and comprising both iodinated polyamino compounds and reactive multi-arm polymers. In a specific example, a syringe containing the first fluid composition can be provided, the first fluid composition comprising an iodinated polyamino compound buffered to an acidic pH, and a vial comprising a dry composition (such as powder) can be provided, the dry composition comprising reactive multi-arm polymers. The first fluid composition can then be injected into the vial containing a reactive multi-arm polymer using a syringe, to form a fluid composition prepared by containing iodinated polyamino compounds and reactive multi-arm polymers, which can be withdrawn in the syringe for use.

[0072] The promoter composition can be a fluid promoter composition buffered to an alkaline pH, or a dry composition comprising an alkaline buffer composition, to which suitable fluids such as water for injection, saline solution, etc. can be added to form a fluid promoter composition buffered to an alkaline pH. For example, the alkaline buffer composition can include sodium borate and disodium hydrogen phosphate, etc. The pH range of the fluid promoter composition can be, for example, about 9 to about 11, typically ranging from about 9.5 to about 10.5, more typically ranging from about 9.8 to about 10.2. In addition to the above, the fluid promoter composition can also include additives, such as therapeutic agents and / or other imaging agents (except the iodine groups present in the iodinated polyamino compounds). In a specific example, a syringe containing the fluid promoter composition can be provided.

[0073] The prepared fluid composition buffered to an acidic pH as described above and comprising an iodinated polyamino compound and a reactive multi-arm polymer, and the fluidity enhancer composition buffered to an alkaline pH as described above, can be combined in vivo or in vitro to form a cross-linked hydrogel.

[0074] Examples of additional imaging agents include (a) fluorescent dyes, such as fluorescein, indocyanine green, or fluorescent proteins (e.g., green, blue, cyan fluorescent protein), (b) contrast agents used in conjunction with magnetic resonance imaging (MRI), including contrast agents containing elements that form paramagnetic ions, such as Gd (III) , Mn (II) , Fe (III) and compounds containing them (including chelates), such as gadolinium ions chelated with diethylenetriaminepentaacetic acid, (c) contrast agents used in conjunction with ultrasound imaging, including organic and inorganic echogenic particles (i.e., particles that cause an increase in reflected ultrasound energy) or organic and inorganic echolucent particles (i.e., particles that cause a decrease in reflected ultrasound energy), (d) radiocontrast agents, such as those based on clinically important isotopes 99m Tc radiocontrast agents, as well as other gamma emitters, such as 123 I. 125 I. 131 I. 111 In, 57 Co. 153 Sm, 133 Xe, 51 Cr, 81m Kr, 201 Tl, 67 Ga and 75 Se, etc.; (e) positron emitters, such as 18 F. 11 C. 13 N.15 O and 68 Ga, etc., which can be used to produce functionalized radiotracer coatings; and (f) contrast agents used in conjunction with near-infrared (NIR) imaging, which can be selected to impart near-infrared fluorescence to the coating of the present disclosure, thereby allowing deep tissue imaging and device labeling, such as NIR-sensitive nanoparticles, such as gold nanoshells, carbon nanotubes (e.g., nanotubes derivatized with hydroxyl or carboxyl groups, such as partially oxidized carbon nanotubes), dye-containing nanoparticles, such as dye-doped nanofibers and dye-encapsulated nanoparticles, and semiconductor quantum dots, etc. NIR-sensitive dyes include cyanine dyes, squarylium cyanines, phthalocyanines, porphyrin derivatives, and boron bipyrrolmethane (BODIPY) analogs, etc.

[0075] In various embodiments, a system is provided that includes one or more delivery devices for delivering a first composition and a second composition to a subject.

[0076] In some embodiments, the system may include a delivery device, the delivery device comprising a first reservoir and a second reservoir, the first reservoir containing a first composition comprising an iodinated polyamino compound as described above, the second reservoir containing a second composition comprising a reactive multi-arm polymer comprising multiple unsaturated end groups as described above. In some embodiments, the system may include a delivery device, the delivery device comprising a first reservoir and a second reservoir, the first reservoir containing a first composition comprising an iodinated polyamino compound and a reactive multi-arm polymer and buffered to an acidic pH, such as the prepared fluid composition described above, the second reservoir containing a second composition, such as the fluid promoter composition described above. In either case, during operation, the first composition and the second composition are distributed and combined from the first reservoir and the second reservoir, whereby the iodinated polyamino compound and the reactive multi-arm polymer are cross-linked to form a hydrogel.

[0077] In certain embodiments, the system can include a delivery device comprising a double-barreled syringe comprising a first barrel having a first barrel outlet (the first barrel containing a first composition, a first plunger movable in the first barrel), a second barrel having a second barrel outlet (the second barrel containing a second composition and a second plunger movable in the second barrel).

[0078] No matter the selected first composition and the second composition, in some embodiments, device can also include a mixing part, and this mixing part has the first mixing part inlet that is communicated with the first tube outlet fluid, the second mixing part inlet that is communicated with the second tube outlet fluid and a mixing part outlet.In some embodiments, device can also include sleeve pipe or conduit, it is configured to receive the first fluid composition and the second fluid composition from the first pipe and the second pipe.For example, sleeve pipe or conduit can be configured to be connected with the outlet of mixing part by sleeve pipe or conduit being attached to the outlet (for example, via suitable fluid connector such as Luer connector) to form fluid with mixing part.

[0079] As another example, the catheter can be a multi-lumen catheter including a first lumen and a second lumen, the proximal end of the first lumen being configured to form a fluid connection with the first tube outlet, and the proximal end of the second lumen being configured to form a fluid connection with the second tube outlet. In some embodiments, the multi-lumen catheter can 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.

[0080] During operation, when depressing the first and second plungers, the first fluid composition and the second fluid composition are distributed from the first pipe and the second pipe, thus the first fluid composition and the second fluid composition interact and finally crosslink to form a hydrogel, which is applied to the tissue of the experimenter or in the tissue. For example, the first fluid composition and the second fluid composition can enter the mixed part via the first mixed part entrance and the second mixed part entrance from the first pipe and the second pipe, so the first fluid composition and the second fluid composition mix to form a mixture, and the mixture leaves the mixed part via the mixed part outlet. In some embodiments, a sleeve tube or a conduit is attached to the mixed part outlet, thus allowing the mixture to be applied to the experimenter after passing through a sleeve tube or a conduit.

[0081] As another example, the first fluid composition can enter the first lumen of the multi-lumen catheter from the first tube outlet, and the second fluid composition can enter the second lumen of the multi-lumen catheter from the second tube outlet. In some embodiments, the first fluid composition and the second fluid composition can enter the mixing part at the far end of the multi-lumen catheter from the first lumen and the second lumen via the first mixing part inlet and the second mixing part inlet, respectively, so that the first fluid composition and the second fluid composition are mixed in the mixing part to form a mixture, and the mixture leaves the mixing part via the mixing part outlet.

[0082] No matter how the type of the device for mixing the first fluid composition and the second fluid composition or the first fluid composition and the second fluid composition are mixed, after the mixture of the first fluid composition and the second fluid composition is formed, the mixture is initially a fluid state, and can be applied to a subject (for example, mammal, particularly people) by various technologies. Or, the first fluid composition and the second fluid composition can be applied to a subject independently, and the fluid mixture of the first fluid composition and the second fluid composition is formed in the subject or on the body surface. In either method, the fluid mixture of the first fluid composition and the second fluid composition is formed, and is used for various medical procedures.

[0083] For example, in the treatment of diseases and cancers, and in the repair and regeneration of tissues, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected to provide spacing between tissues, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected (for example, in the form of blisters) to provide reference markers, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected for tissue augmentation or regeneration, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected as a filler or replacement for soft tissue, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected to provide mechanical support for damaged tissue, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected as a scaffold, and / or the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected as a carrier for therapeutic agents.

[0084] Upon administration of the disclosed composition (either alone as a first fluid composition and a second fluid composition that are mixed in vivo, or as a fluid mixture of the first fluid composition and the second fluid composition), a cross-linked hydrogel is ultimately formed at the site of administration.

[0085] After administration, the compositions of the present disclosure can be imaged using a suitable imaging technique. Typically, the imaging technique is an X-ray based imaging technique, such as computed tomography or X-ray fluoroscopy.

[0086] As can be seen from the foregoing, the compositions of the present disclosure can be used in various medical procedures, including the following, among others: a procedure for implanting a fiducial marker comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for implanting a tissue regeneration scaffold comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for implanting a tissue support comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for implanting a tissue expander comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for implanting a therapeutic agent-containing depot comprising a cross-linked product of a first fluid composition and a second fluid composition, a tissue augmentation procedure comprising implanting a cross-linked product of a first fluid composition and a second fluid composition, and a procedure for introducing a cross-linked product of a first fluid composition and a second fluid composition between a first tissue and a second tissue to separate the first tissue from the second tissue.

[0087] The first fluid composition and the second fluid composition, the fluid mixture of the first fluid composition and the second fluid composition, or the cross-linked product of the first fluid composition and the second fluid composition can be injected in conjunction with various medical procedures including: injection for spacing between the prostate or vagina and rectum in radiation therapy for rectal cancer, injection for spacing between the rectum and prostate in radiation therapy for prostate cancer, subcutaneous injection for palliative treatment of prostate cancer, transurethral or submucosal injection for female stress urinary incontinence, intravesical injection for urinary incontinence, intrauterine cavity injection for Asherman's syndrome, submucosal injection for anal incontinence, percutaneous injection for heart failure, intramyocardial injection for heart failure and dilated cardiomyopathy, transendocardial injection for myocardial infarction, intra-articular injection for osteoarthritis, for spinal fusion and spinal, oral maxillofacial and orthopedic surgery. Spinal injections for invasive surgery, Spinal injections for posterolateral lumbar fusion, Intradiscal injections for degenerative disc disease, Injections between the pancreas and duodenum for imaging of pancreatic cancer, Injections in the resection bed for imaging of oropharyngeal cancer, Injections around the tumor bed for 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 from congenital anomalies of the kidney and urinary tract, Intravitreal injections for neovascular age-related macular degeneration, Intratympanic injections for sensorineural hearing loss, Dermal injections for correction of wrinkles, creases and folds, signs of facial fat loss, volume loss, contour defects from superficial to deep, correction of depressed skin scars, Perioral wrinkles, Lip augmentation, Facial lipoatrophy, Stimulation of natural collagen production.

[0088] Cross-linked hydrogel compositions according to the present disclosure include lubricious compositions for medical applications, compositions for therapeutic agent release (e.g., by including one or more therapeutic agents in the matrix of the cross-linked hydrogel), and implants (which can be formed in vitro or in vivo) (e.g., compositions used as tissue markers, compositions that act as spacers to reduce side effects of off-target radiation therapy, cosmetic compositions, etc.).

[0089] Example

[0090] An iodinated polyamino compound, such as one of those described above, is dissolved in an acidic buffer solution (pH between 3.8-4.2), and then further mixed with a reactive star PEG having unsaturated end groups (e.g., a star PEG having a core region of polyol residues and 8 hydrophilic polyethylene oxide arms having acrylate end groups) as a prepared fluid composition in one syringe. Another buffer solution having a pH controlled at about 9.8-10.4 is prepared as a fluid promoter composition in another syringe. Subsequently, a hydrogel is formed by combining the prepared fluid composition with the fluid promoter composition to simultaneously form a cross-linked hydrogel.

Claims

1. A system for forming a hydrogel, comprising (a) an iodinated polyamino compound and (b) a reactive multi-arm polymer, wherein the reactive multi-arm polymer comprises a plurality of hydrophilic polymer arms having unsaturated end groups that react with the amino groups of the iodinated polyamino compound.

2. The system of claim 1, wherein the iodinated polyamino compound comprises a polyamino moiety linked to a carboxyl-substituted iodinated moiety via an amide group.

3. The system of claim 2, wherein the carboxyl-substituted iodinated moiety comprises an iodinated group and a carboxyl or carboxylic acid group.

4. The system of claim 2, wherein the carboxyl-substituted iodinated moiety is an iodinated amino acid residue and / or wherein the carboxyl-substituted iodinated moiety comprises an iodinated aromatic group and a carboxyl or carboxylic acid group.

5. The system according to any one of claims 2 to 4, wherein the polyamino moiety comprises a plurality of -(CH2) x -NH2 group, wherein x is 0, 1, 2, 3, 4, 5 or 6.

6. The system of any one of claims 2-4, wherein the polyamino moiety comprises a residue of a carboxyl-substituted polyamino compound.

7. The system according to any one of claims 2 to 4, wherein the polyamino moiety comprises two or more amino acid residues selected from the group consisting of lysine residues, ornithine residues, and combinations thereof.

8. The system of any one of claims 1 to 7, wherein the unsaturated end groups are selected from acrylate groups and propiolate groups.

9. The system of any one of claims 1-8, wherein the hydrophilic polymer arms comprise one or more hydrophilic monomers selected from the group consisting of ethylene oxide, N-vinyl pyrrolidone, oxazoline, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate or PEG methyl ether methacrylate, or PNIPAAM.

10. The system of any one of claims 1-9, wherein the unsaturated end groups are linked to the hydrophilic polymer arms via hydrolyzable ester groups.

11. The system of claim 10, wherein the hydrolyzable ester group is selected from glutarate, succinate, carbonate, or adipate.

12. The system of any one of claims 1-9, wherein the system comprises a first precursor composition comprising the iodinated polyamino compound, a second precursor composition comprising the reactive multi-arm polymer, and an optional accelerator composition.

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

14. The system of any one of claims 1-13, further comprising a delivery device.

15. A medical hydrogel formed by cross-linking the iodinated polyamino compound and the reactive multi-arm polymer of the system according to any one of claims 1 to 14 under conditions that form the medical hydrogel.

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