Iodine-labeled hydrogels and precursors thereof with improved performance

Abstract

In various aspects, the present disclosure relates to systems for forming hydrogels comprising an iodinated polyamino compound and a reactive multi-arm polymer comprising a plurality of hydrophilic polymer arms having reactive 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. Other aspects of the present disclosure relate to methods of making iodinated polyamino compounds.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 398,756, filed on August 17, 2022, the disclosure of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to iodinated compounds, hydrogels formed from iodinated compounds, and methods of making and using iodinated compounds and hydrogels, among other things. The iodinated compounds of the present disclosure can be used, for example, to form hydrogels for 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-linking agents 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. 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] While the above methods are effective, 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 polymer, 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 and processability issues. An additional impact of the reduced crosslink density per star polymer is that the resulting gel has a slower solidification rate, which means that the gel is liquid and mobile in the body for a longer time, which provides opportunities for unintended side reactions and material displacement. In addition, TIB is slightly soluble in water, which means that there is an upper limit to how much iodine can be added before the solubility of the gel is affected. In cases where the concentration of TIB groups is so high that the star PEG precipitates out of solution, the TIB groups can even physically crosslink the system before reaction, requiring greater forces to disperse. Finally, star PEGs labeled with 2,3,5-triiodobenzamide end groups often discolor due to thermal degradation. While this does not affect its function, it is a cosmetic defect that is preferably avoided.

[0007] Thus, there is a continuing need in the biomedical arts for additional hydrogels, precursors to such hydrogels, methods of making such hydrogels and precursors, methods of using such hydrogels and precursors, systems for forming such hydrogels, and the like. Summary of the invention

[0008] The present disclosure provides an alternative 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.

[0009] In various aspects, the present disclosure relates to a system for forming a hydrogel comprising an iodinated polyamino compound and a reactive multi-arm polymer comprising a plurality of hydrophilic polymer arms having reactive end groups reactive with amino groups of the iodinated polyamino compound.

[0010] In some embodiments, the iodinated polyamino compound comprises a polyamino portion of an iodinated portion substituted by a carboxyl group. In some of these embodiments, the iodinated portion substituted by a carboxyl group comprises an iodinated group and a carboxyl or carboxylic acid group. In some of these embodiments, the iodinated portion substituted by a carboxyl group is an iodinated amino acid residue, for example, an iodinated amino acid residue comprising an iodinated aromatic group, etc. For example, the iodinated aromatic group can be a monocyclic or polycyclic aromatic portion substituted by one or more iodo groups and one or more hydroxyl groups, as well as other possibilities.

[0011] In some embodiments that may be used in combination with the above aspects and embodiments, the polyamino moiety comprises a plurality of -(CH 2 )x -NH 2 wherein x is 0, 1, 2, 3, 4, 5 or 6. In some of these embodiments, multiple -(CH 2 ) x -NH 2 The groups may be disposed along the polymer portion.

[0012] In some embodiments that may be used in conjunction with the above aspects and embodiments, the polyamino moiety comprises the residue of a carboxy-substituted polyamino compound.

[0013] In some embodiments that may be used in combination with the above aspects and embodiments, the polyamino moiety comprises two or more amino acid residues selected from the group consisting of lysine residues, ornithine residues, and combinations thereof.

[0014] In some embodiments that may be used in conjunction with the above aspects and embodiments, the hydrophilic polymer arms of the reactive multi-arm polymer 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.

[0015] In some embodiments that may be used in conjunction with the above aspects and embodiments, the reactive end groups of the reactive multi-arm polymer are linked to the hydrophilic polymer arms via hydrolyzable esters.

[0016] In some embodiments that can be used in combination with the above aspects and embodiments, the reactive end groups of the reactive multi-arm polymer are electrophilic groups. In some of these embodiments, the electrophilic groups are selected from imidazole esters, imidazole carboxylates, benzotriazole esters or imide esters.

[0017] In some embodiments that may be used in conjunction with the above aspects and embodiments, the system includes a first precursor composition comprising an iodinated polyamino compound and a second precursor composition comprising a reactive multi-arm polymer.

[0018] In some embodiments that may be used in combination with the above aspects and embodiments, the system further comprises an accelerator composition.

[0019] In some embodiments that may be used in conjunction with the above aspects and 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.

[0020] In some embodiments that may be used in conjunction with the above aspects and embodiments, the system further comprises a delivery device.

[0021] Other aspects of the present disclosure relate to medical hydrogels formed by cross-linking a first precursor composition and a second precursor composition of the system in any of the aspects and embodiments described above.

[0022] Other aspects of the present disclosure relate to methods of treatment comprising administering a mixture of a first precursor composition and a second precursor composition of the system of any of the aspects and embodiments described above.

[0023] In some embodiments that can be used in combination with the above aspects and embodiments, the system also includes a delivery device. In some of these embodiments, the delivery device includes a first reservoir containing a first precursor composition and a second reservoir containing a second precursor composition, wherein during operation, the first precursor composition and the second precursor composition are distributed from the first reservoir and the second reservoir, whereby the first precursor composition and the second precursor composition interact and cross-link to form a hydrogel. In some of these embodiments, the delivery device includes a first reservoir containing a first precursor composition and a second precursor composition and a second reservoir containing a accelerator composition, wherein during operation, the contents of the first reservoir and the second reservoir are distributed, whereby the first precursor composition and the second precursor composition are cross-linked to form a hydrogel. For example, the first reservoir and the second reservoir can include a syringe tube.

[0024] Other aspects of the present disclosure relate to medical hydrogels formed by cross-linking the first precursor composition and the second precursor composition of the system of any of the aspects and embodiments described above.

[0025] Other aspects of the present disclosure relate to a method for preparing an iodinated polyamino compound, which comprises (a) forming a protected carboxyl-substituted polyamino compound by protecting the amino group of the carboxyl-substituted polyamino compound, (b) forming an amide bond between the carboxyl group of the protected carboxyl-substituted polyamino compound and the amino group of the iodinated amino acid compound, and (c) deprotecting the amino group of the product of step (b).

[0026] 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.

[0027] 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

[0028] Figure 1A A method for adding a protecting group to trilysine according to one embodiment of the present disclosure is schematically shown.

[0029] Figure 1B Schematically showing the coupling of an iodinated amino acid compound to Figure 1A A method for protecting trilysine.

[0030] Figure 1C Schematically shows that according to one embodiment of the present disclosure Figure 1B A method for deprotecting a protected compound to form an iodinated polyamino compound.

[0031] Figure 2A , 2B 2C and 2C are chemical diagrams of iodinated polyamino compounds according to three embodiments of the present disclosure.

[0032] Figure 3A , 3B 3C and 3C are chemical diagrams of iodinated polyamino compounds according to three additional embodiments of the present disclosure.

[0033] FIG. 4 schematically shows a method for making a reactive multi-arm polymer and Figure 1C The invention discloses a method for cross-linking an iodinated multi-amino product, wherein the reactive multi-arm polymer comprises a core region and a plurality of hydrophilic polymer arms having reactive succinimidyl end groups. DETAILED DESCRIPTION

[0034] 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 reactive end groups reactive with the amino groups of the iodinated polyamino compound. Unless otherwise indicated, the prefix "poly" used herein means two or more.

[0035] 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 reactive end groups that react with the amino groups of the iodinated polyamino compounds under conditions such that the iodinated polyamino compounds and the reactive multi-arm polymers are cross-linked with each other. In certain embodiments, those conditions include an environment with an 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.

[0036] 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 reactive 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.

[0037] 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.

[0038] In various embodiments, the iodinated polyamino compounds of 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.

[0039] 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.

[0040] In some embodiments, the iodinated moiety substituted with a carboxyl group of the present disclosure comprises an iodinated aromatic group (also referred to 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.

[0041] In a specific embodiment, the carboxyl-substituted iodinated moiety of the present disclosure includes 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.

[0042] In some embodiments, the carboxyl-substituted iodinated moieties of the present disclosure comprise iodinated amino acid residues. As used herein, "amino acid" is an organic compound containing an amino group (NH 2 ), 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 (-NH 3 +) 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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 selected, for example, from those described below (after protecting the amino group) and an iodinated amino acid derivative, for example, the C 1 -C 5-alkyl esters, preferably methyl esters of iodinated amino acids, which effectively serve as protecting groups for the carboxyl groups of the final iodinated polyamino compounds. Examples of such iodinated amino acid derivatives include C 1 -C 5 -alkyl ester. After coupling, the protecting group of the carboxyl-substituted polyamino compound residue is removed, and C 1 -C 5 The -alkyl esters can be converted to the corresponding carboxyl or anionic carboxylic acid groups to provide the final iodinated polyamino compounds.

[0047] 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.

[0048] In various embodiments, the iodinated polyamino compounds of the present disclosure comprise polyamino moieties having multiple (di, tri, tetra, penta, hexa, hepta, octa, nona, ten or more) amino groups. For example, the polyamino moiety may comprise multiple (di, tri, tetra, penta, hexa, hepta, octa, nona, ten or more)—(CH 2 ) x -NH 2 A group wherein x is 0, 1, 2, 3, 4, 5, or 6. In some of these embodiments, the polyamino moiety may include a plurality of -(CH 2 ) x -NH 2 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.

[0049] 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.

[0050] 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-[N2 -[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, N 2 -(N 2 -L-ornithine-L-lysyl)-L-lysine, lysyllysyl-lysine and L-lysyl-L-lysyl-L-lysyl-L-alanine.

[0051] 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.

[0052] In some aspects, the present disclosure relates to methods of preparing iodinated polyamino compounds, such as the iodinated polyamino compounds described above.

[0053] In the first 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. In a specific example, reference Figure 1A , the amino group of trilysine (110) was protected with di-tert-butyl dicarbonate (CAS#24424-99-5) (112) to form tBoc-protected trilysine (114). This makes the carboxyl group of the protected compound (tBoc-protected trilysine) available for amide coupling.

[0054] In the second step, the iodinated amino acid derivative, specifically, the iodinated amino acid C 1 -C 5 The -alkyl ester is coupled with the protected carboxyl-substituted polyamino compound formed in the first 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 1B In the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) in dimethylformamide (DMF), Figure 1A The tBoc-protected trilysine (114) was coupled to an iodinated amino acid derivative (116) (specifically, diiodotyrosine methyl ester (CAS#76318-50-8)) to produce a t-Boc-protected iodinated peptide oligomer (t-Boc-Lys-Lys-Lys-Tyr-I2) (118). 3,5-Diiodo-L-tyrosine has been used to improve radiopacity in in vivo biological applications (see, e.g., U.S. Patent Application No. US2019 / 0142863A1 and U.S. Patent No. 8,288,505).

[0055] In the third step, the product of the second step is deprotected and hydrolyzed (e.g., under acidic conditions) to form the final carboxyl-substituted iodinated polyamino compound. Figure 1C 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) (118) is deprotected and hydrolyzed to form an activated iodinated polyamino compound (Lys-Lys-Lys-Tyr-I2) (120).

[0056] 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 2AAs shown, when thyroxine methyl ester is coupled to trilysine, the resulting compound is as shown Figure 3A shown.

[0057] In addition, 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 C in the amide coupling reaction according to the route of the second step. 1 -C 5 -alkyl ester, followed by deprotection and hydrolysis according to the third step. 1 -C 5 In the case where the -alkyl ester is diiodotyrosine methyl ester, the results of performing these additional steps once are shown in Figure 2B It contains two diiodotyrosine residues. 1 -C 5 In the case where the -alkyl ester is thyroxine methyl ester, performing these additional steps once results in Figure 3B It contains two thyroxine residues.

[0058] If the first, second and third steps are repeated again, Figure 2B The product replaces trilysine and uses diiodotyrosine methyl ester as the iodinated amino acid C 1 -C 5 Alkyl esters, the result is Figure 2C The product shown contains three diiodotyrosine residues. If the first, second and third steps are repeated, Figure 3B The product replaces trilysine and uses thyroxine methyl ester as the iodinated amino acid C 1 -C 5 -alkyl esters, resulting in Figure 3C The product shown contains three thyroxine residues. Additional iodinated amino acid residues can be added as desired.

[0059] 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 above-mentioned iodinated polyamino compound) and (b) a reactive multi-arm polymer, the reactive multi-arm polymer comprising a plurality of polymer arms having reactive end groups reactive with the amino groups of the iodinated polyamino compound.

[0060] In various embodiments, the cross-linked product 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 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.

[0061] In various embodiments, the reactive 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. The reactive multi-arm polymer may be water-soluble.

[0062] 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 include one or more reactive end groups. In some embodiments, a composition containing a reactive multi-arm polymer can be provided, wherein the percentage of the polymer arm containing one or more reactive end groups can correspond to between 50% and 100% of the total number of polymer arms in the composition (e.g., 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 of the reactive multi-arm polymer used herein is at least 10kDa, and in some cases ranges from 10kDa to 50kDa or higher. In various embodiments, the reactive multi-arm polymer used herein has a melting point of 40°C or greater, preferably 45°C or greater.

[0063] 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 mixed 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.

[0064] 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.

[0065] 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.

[0066] In certain embodiments, the reactive end group can be an electrophilic group selected from imidazole esters, imidazole carboxylates, benzotriazole esters or imide esters (including N-hydroxysuccinimide esters). Particularly beneficial reactive end groups are N-hydroxysuccinimide ester groups. In certain embodiments, the reactive end group is connected to the polymer arm by a hydrolyzable ester group. The hydrolyzable ester group can be selected from, for example, glutaric acid ester group, succinic acid ester group, carbonate group or adipic acid ester group. In specific embodiments, the polymer arm can be end-capped with the following reactive, hydrolyzable groups: succinimide glutaric acid ester group, succinimide succinic acid ester group, succinimide carbonate group or succinimide adipic acid ester group.

[0067] For example, additional examples of reactive multi-arm polymers are described in U.S. Patent Application Nos. 2011 / 0142936, 2021 / 0061950, 2021 / 0061954, and 2021 / 0061957.

[0068] 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 reactive 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.

[0069] For example, as schematically shown in Figure 4, by reacting an iodinated polyamino compound (120) with a reactive multi-arm polymer (410) under alkaline conditions, the reactive multi-arm polymer (410) as described above can be cross-linked with the iodinated polyamino compound (120) as described above to form a cross-linked product (412) that can be in the form of a hydrogel when hydrated, wherein the reactive multi-arm polymer (410) comprises a core region and multiple hydrophilic polyethylene oxide arms having reactive end groups (i.e., succinimidyl glutarate groups) (wherein R is a core region, such as a polyol residue, and n ranges from, for example, 25 to 140), and the iodinated polyamino compound (120) comprises an amino group that reacts with the reactive group (i.e., succinimidyl glutarate group) of the reactive multi-arm polymer (410).

[0070] One advantage of this approach is that the iodination is separate from the parent polymer and the multi-arm polymer can be replaced with an N-hydroxysuccinimide ester functionalized system having hydrophilic polymer arms other than polyethylene oxide arms, such as synthetic, natural or synthetic-natural hybrid hydrophilic polymer arms, such as those described above.

[0071] 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 (120), and (b) a second composition comprising a reactive multi-arm polymer comprising a plurality of reactive end groups reactive with the amino groups of the iodinated polyamino compound (140).

[0072] 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 additives, including those described below.

[0073] 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, to which a suitable fluid such as water for injection, saline solution, etc. can be added to form a second fluid composition. In addition to the reactive multi-arm polymer, the second composition can also include additives, including those described below.

[0074] In some embodiments, the iodinated polyamino compound (120) is initially combined with the reactive multi-arm polymer (410) at an acidic pH, at which the cross-linking between the reactive groups of the reactive multi-arm polymer (410) and the amino groups of the iodinated polyamino compound (120) is inhibited. Then, when cross-linking is required, the pH of the mixture of the iodinated polyamino compound (120) and the reactive multi-arm polymer (410) is changed from an acidic pH to an alkaline pH, resulting in cross-linking between them.

[0075] 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)

[0076] 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.

[0077] 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, etc. 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, 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).

[0078] 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).

[0079] 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 an iodinated polyamino compound and a reactive multi-arm polymer. 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 a powder) can be provided, the dry composition comprising a reactive multi-arm polymer. 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 an iodinated polyamino compound and a reactive multi-arm polymer, which can be withdrawn in a syringe for use.

[0080] 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 a suitable fluid 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, from 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 additional imaging agents (except for the iodine groups present in the iodinated polyamino compounds).

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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 as described above, the reactive multi-arm polymer comprising a plurality of reactive end groups that react with the amino groups of the iodinated polyamino compound. 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.

[0085] Regardless of the first and second compositions selected, 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 the first composition, a first plunger movable in the first barrel), a second barrel having a second barrel outlet (the second barrel containing the second composition and a second plunger movable in the second barrel).

[0086] In some embodiments, device can also include a mixing part, and this mixing part has a first mixing part inlet that is communicated with the first pipe outlet fluid, a second mixing part inlet that is communicated with the second pipe outlet fluid, and a mixing part outlet. In some embodiments, device can also include sleeve pipe or conduit, which 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.

[0087] 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.

[0088] During operation, when the first and second plungers are depressed, the first fluid composition and the second fluid composition are distributed from the first pipe and the second pipe, whereby 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 subject or in the tissue. For example, the first fluid composition and the second fluid composition can enter the mixing part via the first mixing part inlet and the second mixing part inlet from the first pipe and the second pipe, whereby the first fluid composition and the second fluid composition mix to form a mixture, and the mixture leaves the mixing part via the mixing part outlet. In some embodiments, a sleeve tube or a conduit is attached to the mixing part outlet, thereby allowing the mixture to be applied to the subject after passing through a sleeve tube or a conduit.

[0089] 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, whereby the first fluid composition and the second fluid composition are mixed in the mixing part to form a mixture, which leaves the mixing part via the mixing part outlet.

[0090] 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 the 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] As previously described, 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.).

[0097] Example 1. Formation of Boc-trilysine (Boc-TL)

[0098] Trilysine (H-Lys-Lys-Lys-OH) acetate (1 eq) was suspended in DMF:H 2O (1:1) mixture. Triethylamine (4.1eq) was slowly added and the mixture was stirred at room temperature for 10 minutes to obtain a clear solution. Di-tert-butyl dicarbonate (4.2eq) was added to the solution and stirred overnight. Then, the reaction solution was diluted in dichloromethane (DCM) and the solution was acidified to pH = 4-5 with 1N HCl (aq). The aqueous layer was saturated with NaCl and extracted twice with DCM. The combined organic layer was washed twice with water, twice with brine, and washed with anhydrous sodium sulfate (Na 2 SO 4 Then, after filtering the solution, the solvent was removed and dried in vacuo without further purification to obtain a white product (yield: 80%).

[0099] Example 2. Formation of Boc-trilysine-diiodotyrosine methyl ester (Boc-TL-DIT-OMe)

[0100] Diiodotyrosine methyl ester hydrochloride (1 eq) was dissolved in DMF, and a certain amount of triethylamine (1 eq) was added for neutralization. The mixture was stirred for one hour and used directly after further purification.

[0101] To a DMF solution of Boc-trilysine (Boc-TL) (1 eq) of Example 1, EDC-HCl (1 eq) and a catalytic amount of n-hydroxysuccinimide (NHS) were added in sequence at room temperature, and the mixture was stirred for 15 min. Diiodotyrosine methyl ester (1 eq) prepared in situ in DMF was then directly transferred to the reaction solution and stirred overnight at room temperature. Afterwards, the solvent was removed, and the obtained residue was redissolved in DCM and extracted with water to remove the ammonium salt and urea salt. Subsequently, the organic layer was washed three times with water to remove the DMF residue and washed with anhydrous Na 2 SO 4 Finally, the solution was filtered, the solvent was removed, and vacuum dried to obtain a light yellow product (yield: 80%).

[0102] Example 3. Formation of trilysine-diiodotyrosine

[0103] The Boc-trilysine-diiodotyrosine methyl ester (Boc-TL-DIT-OMe) of Example 2 was dissolved in a mixture of DCM. An equal amount of trifluoroacetic acid (TFA) was added as a solvent, and the solution was stirred at room temperature overnight. The reaction mixture was then evaporated in vacuo, and after adding DCM, it was evaporated several times to remove residual TFA to obtain a product in quantitative yield.

[0104] Example 4. Hydrogel formation

[0105] The iodinated trilysine of Example 3 is dissolved in an acidic buffer solution (pH between 3.8-4.2), and then further mixed with a reactive star PEG (e.g., a star PEG having a polyol residue core region and 8 hydrophilic polyethylene oxide arms having reactive succinimidyl glutarate end groups) as a prepared fluid composition in one syringe. Another buffer solution with 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 an iodinated polyamino compound and a reactive multi-arm polymer, wherein the reactive multi-arm polymer comprises a plurality of hydrophilic polymer arms, and the hydrophilic polymer arms have reactive 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.

5. The system of claim 4, wherein the iodinated amino acid residue comprises an iodinated aromatic group.

6. The system of claim 5, wherein the iodinated aromatic group is a monocyclic or polycyclic aromatic moiety substituted with one or more iodine groups and one or more hydroxyl groups.

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

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

9. The system according to any one of claims 2 to 6, wherein the polyamino moiety comprises two or more amino acid residues selected from the group consisting of lysine residues, ornithine residues, and combinations thereof.

10. The system of any one of claims 1-9, 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.

11. The system of any one of claims 1-10, wherein the reactive end group is linked to the hydrophilic polymer arm via a hydrolyzable ester and / or wherein the reactive end group is an electrophilic group.

12. The system of any one of claims 1-11, wherein the system comprises a first precursor composition comprising the iodinated polyamino compound, a second precursor composition comprising the reactive multi-arm polymer, and optionally an accelerator composition.

13. The system of any one of claims 1-12, further comprising a delivery device.

14. 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 13.

15. A method for preparing an iodinated polyamino compound, which comprises (a) forming a protected carboxyl-substituted polyamino compound by protecting the amino group of the carboxyl-substituted polyamino compound, (b) forming an amide bond between the carboxyl group of the protected carboxyl-substituted polyamino compound and the amino group of an iodinated amino acid compound, and (c) deprotecting the amino group of the product of step (b).

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