Iodine-labeled hydrogels and precursors thereof with improved properties - Patents.com

Abstract

Iodine-labeled hydrogels and precursors thereof with improved properties are provided. 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 the amino groups of the iodinated polyamino compound. Another aspect of the disclosure relates to a medical hydrogel formed by crosslinking the iodinated polyamino compound and the reactive multi-arm polymer of such a system. A further aspect of the disclosure relates to a medical procedure that can be performed using such a system. Yet another aspect of the disclosure relates to a method for producing an iodinated polyamino compound.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 398,756, filed August 17, 2022, the disclosure of which is incorporated herein by reference. The present disclosure relates, among other aspects, to iodinated compounds, hydrogels formed from the iodinated compounds, and methods of making and using the iodinated compounds and hydrogels. The iodinated compounds of the present disclosure are useful, for example, in forming hydrogels for various biomedical applications. [Background technology]

[0002] In vivo cross-linked hydrogels based on star-poly(ethylene glycol) (star-PEG) polymers functionalized with reactive ester end groups that react with lysine trimer (Lys-Lys-Lys) as a cross-linker to rapidly form cross-linked hydrogels, such as SpaceOAR®, have become clinically important materials as adjuvants in radiation therapy. "Augmenix Announces Positive Three-Year SpaceOAR (R) See “Clinical Trial Results,” Imaging Technology News, October 27, 2016. Hydrogels have also been developed in which some of the star-PEG branches are functionalized with 2,3,5-triiodobenzamide (TIB) groups and some of the ester end groups are substituted, such as SpaceOAR® Vue, which enhances radiation contrast. Augmenix Receives FDA Clearance to Market with its TraceIT (R) See "Tissue Marker," BusinessWire Jan. 28, 2013. TraceIT® hydrogel remains stable and visible in tissue for three months, sufficient time for radiation therapy, after which it is absorbed and eliminated from the body. Id.

[0003] While the above approach is effective, functionalizing hydrogels with iodine using star polymer arms means fewer arms are available for crosslinking. This can be resolved by adding more polymer, but this increases the solids content and can adversely affect viscosity. Lowering the molecular weight can reduce the solids content, but it lowers the melting point and creates processability issues. A further consequence of lowering the crosslink density per star polymer is a slower setting rate for the resulting gel. This means the gel will remain liquid and mobile in vivo for longer periods, creating opportunities for unintended side reactions and material substitution. Furthermore, TIB's poor water solubility means there is an upper limit to the amount of iodine that can be added before affecting the gel's solubility. If the concentration of TIB groups is so high that the star PEG precipitates from solution, the TIB groups may physically crosslink the system before reacting, requiring significant force to dispense. Finally, star PEGs labeled with 2,3,5-triiodobenzamide end groups often exhibit discoloration due to thermal degradation. While this does not affect functionality, it is a cosmetic defect that is preferably avoided. Thus, there is a continuing need in the biomedical arts for, among other needs, additional hydrogels, precursors to such hydrogels, methods of making such hydrogels and precursors, methods of using such hydrogels and precursors, and systems for forming such hydrogels. Summary of the Invention

[0004] The present disclosure provides an alternative approach: rather than using the arms of a star polymer to functionalize the hydrogel with iodine, the crosslinker of the star polymer is functionalized with iodine.

[0005] 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 that are reactive with the amino groups of the iodinated polyamino compound. In some embodiments, the iodinated polyamino compound comprises a polyamino moiety linked to a carboxy-substituted iodinated moiety by an amide group. In some of these embodiments, the carboxy-substituted iodinated moiety comprises an iodinated group and a carboxylic acid or carboxylate group. In some of these embodiments, the carboxy-substituted iodinated moiety is an iodinated amino acid residue, for example, an iodinated amino acid residue that includes, among other things, an iodinated aromatic group. For example, the iodinated aromatic group may be, among other things, a monocyclic or polycyclic aromatic moiety substituted with one or more iodine groups and one or more hydroxyl groups.

[0006] In some embodiments that can be used in combination with the above aspects and embodiments, the polyamino moiety comprises multiple -(CH) x -NH groups, where x is 0, 1, 2, 3, 4, 5, or 6. In some of these embodiments, multiple -(CH) x The -NH2 groups may be positioned along the polymer segment. In some embodiments that can be used in combination with the above aspects and embodiments, the polyamino moiety comprises a residue of a carboxyl-substituted polyamino compound. In some embodiments that can be used in combination with the above aspects and embodiments, the polyamino moiety comprises two or more amino acid residues selected from residues of lysine, ornithine, and combinations thereof. In some embodiments that can be used in combination with the above aspects and embodiments, the hydrophilic polymer arms of the reactive multi-arm polymer comprise one or more hydrophilic monomers selected from ethylene oxide, N-vinylpyrrolidone, oxazoline, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate or PEG methyl ether methacrylate, or PNIPAAM.

[0007] 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 attached to the hydrophilic polymer arms by hydrolyzable esters. In some embodiments that can be used in combination with the above aspects and embodiments, the reactive end group of the reactive multi-arm polymer is an electrophilic group. In some of these embodiments, the electrophilic group is selected from an imidazole ester, an imidazole carboxylate, a benzotriazole ester, or an imide ester. In some embodiments that can be used in combination with the above aspects and embodiments, a system includes a first precursor composition that includes an iodinated polyamino compound and a second precursor composition that includes a reactive multi-arm polymer. In some embodiments that can be used in combination with the above aspects and embodiments, the system further comprises an accelerator composition. In some embodiments that can be used in combination 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 the syringe barrel.

[0008] In some embodiments that can be used in combination with the above aspects and embodiments, the system further comprises a delivery device. Another aspect of the present disclosure relates to a medical hydrogel formed by crosslinking the first and second precursor compositions of the system according to any of the above aspects and embodiments. Another aspect of the present disclosure relates to a method of treatment comprising administering a mixture of the first and second precursor compositions of the system according to any of the above aspects and embodiments. In some embodiments that can be used in combination with the above aspects and embodiments, the system further 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, and during operation, the first and second precursor compositions are dispensed from the first and second reservoirs, after which the first and second precursor compositions interact with each other and crosslink 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 an accelerator composition, and during operation, the contents of the first and second reservoirs are dispensed, after which the first and second precursor compositions crosslink with each other to form a hydrogel. The first and second reservoirs may include, for example, syringe barrels.

[0009] Another aspect of the present disclosure relates to a medical hydrogel formed by crosslinking the first and second precursor compositions of the system according to any of the above aspects and embodiments. Yet another aspect of the present disclosure relates to a method for preparing an iodinated polyamino compound, the method comprising the steps of: (a) protecting an amino group of a carboxyl-substituted polyamino compound to form a protected carboxyl-substituted polyamino compound; (b) forming an amide bond between a carboxyl group of the protected carboxyl-substituted polyamino compound and an amino group of an iodinated amino acid compound; and (c) deprotecting the amino group of the product of step (b).

[0010] Potential advantages associated with the present disclosure include one or more of the following: maintaining radiation contrast; reducing the complexity and cost of the manufacturing process; maintaining the melting point of the solid components of the hydrogel above 40°C (improving storage and handling); improving the homogeneity of the final hydrogel; providing biopersistence; and maintaining the cure rate. These and other aspects, embodiments, features, and advantages of the present disclosure will become readily apparent from the following detailed description. [Brief explanation of the drawings]

[0011] [Figure 1A] FIG. 1 is a schematic diagram illustrating a method for adding a protecting group to a trilysine according to one embodiment of the present disclosure. [Figure 1B] FIG. 1B is a schematic diagram illustrating a method by which an iodinated amino acid compound is coupled to the protected trilysine of FIG. 1A, according to one embodiment of the present disclosure. [Figure 1C] FIG. 1C is a schematic diagram illustrating a method for deprotecting the protected compound of FIG. 1B to form an iodinated polyamino compound, according to one embodiment of the present disclosure. [Figure 2A] 1 is a chemical diagram of an iodinated polyamino compound according to three embodiments of the present disclosure. [Figure 2B] 1 is a chemical diagram of an iodinated polyamino compound according to three embodiments of the present disclosure. [Figure 2C] 1 is a chemical diagram of an iodinated polyamino compound according to three embodiments of the present disclosure. [Figure 3A] 1 is a chemical diagram of an iodinated polyamino compound according to three further embodiments of the present disclosure. [Figure 3B] 1 is a chemical diagram of an iodinated polyamino compound according to three further embodiments of the present disclosure. [Figure 3C] 1 is a chemical diagram of an iodinated polyamino compound according to three further embodiments of the present disclosure. [Figure 4]FIG. 1D is a schematic diagram illustrating a method for crosslinking a reactive multi-arm polymer comprising a core region and multiple hydrophilic polymer arms having reactive succinimidyl end groups with the iodinated polyamino product of FIG. 1C, according to one embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0012] In some aspects of the present disclosure, there is provided a radiopaque crosslinked hydrogel comprising the crosslinked reaction product of (a) an iodinated polyamino compound and (b) a reactive multi-arm polymer comprising a plurality of reactive end groups reactive with the amino groups of the iodinated polyamino compound. Unless otherwise indicated, as used herein, the prefix "poly" means two or more. In some aspects of the present disclosure, systems are provided that are configured to dispense 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 crosslink with each other. In certain embodiments, these conditions include an environment having a basic pH, e.g., a pH in the range of about 9 to about 11, typically about 9.5 to about 10.5, and advantageously about 9.8 to about 10.2.

[0013] In some aspects of the present disclosure, a system is provided that includes (a) a first composition comprising an iodinated polyamino compound and (b) a second composition comprising a reactive multi-arm polymer that includes a plurality of reactive end groups that are reactive with the amino groups of the iodinated polyamino compound. In some embodiments, a third composition in the form of an accelerator composition is provided. Such systems are advantageous in that the iodine functionality, and therefore radiopacity, is provided by, for example, an iodinated polyamino compound that acts as a crosslinker for the multi-arm polymer, thereby providing reactive end groups on each of the polymer arms, thereby maximizing the crosslinking capacity of the multi-arm polymer without sacrificing radiopacity.

[0014] In various embodiments, the iodinated polyamino compounds of the present disclosure comprise a polyamino moiety attached to a carboxy-substituted iodinated moiety. In certain embodiments, the polyamino moiety is attached to the carboxy-substituted iodinated moiety via an amide group. In certain embodiments, detailed below, the iodinated polyamino compound may comprise a peptide oligomer comprising 2-10 lysine and / or ornithine amino acid residues and one or more iodinated amino acid residues. Carboxy-substituted iodinated moieties of the present disclosure include those comprising an iodinated group and a carboxylic acid or carboxylate group, including anionic carboxylate groups, carboxylic acid amide groups, and carboxylic acid ester groups. In some embodiments, the carboxy-substituted iodinated moieties of the present disclosure include an iodinated aromatic group (also called an iodoaromatic group) and a carboxylic acid or carboxylate group. Examples of iodinated aromatic groups include iodine-substituted monocyclic aromatic groups and iodine-substituted polycyclic aromatic groups, such as iodophenyl and iodonaphthyl groups. The aromatic group may be substituted with one, two, three, four, five, six, or more iodine atoms. In certain embodiments, the carboxy-substituted iodinated moieties of the present disclosure comprise at least one hydroxy-iodo-aromatic group and a carboxylic acid or carboxylate group. Examples of hydroxy-iodo-aromatic groups include hydroxy-iodo-phenyl and hydroxy-iodo-naphthyl groups. More specific examples of hydroxy-iodo-aromatic groups include hydroxy-iodo-phenyl groups selected from mono-hydroxy-mono-iodo-phenyl, mono-hydroxy-di-iodo-phenyl, mono-hydroxy-tri-iodo-phenyl, mono-hydroxy-tetra-iodo-phenyl, di-hydroxy-mono-iodo-phenyl, di-hydroxy-di-iodo-phenyl, di-hydroxy-tri-iodo-phenyl, tri-hydroxy-mono-iodo-phenyl, and tri-hydroxy-di-iodo-phenyl groups.

[0015] In some embodiments, the carboxy-substituted iodinated moieties of the present disclosure comprise iodinated amino acid residues. As used herein, an "amino acid" is an organic compound containing an amino group (-NH), a carboxylic acid group (-COOH), and a side chain specific to each amino acid. Depending on the ambient pH, the amino group may be positively charged (-NH + ) and / or the carboxylic acid group may be negatively charged (-COO - Iodinated amino acids are amino acids whose side chains contain one or more iodine atoms. Examples of iodinated amino acid residues include iodinated α-amino acid residues, iodinated β-amino acid residues, iodinated γ-amino acid residues and iodinated δ-amino acid residues.

[0016] Examples of iodinated amino acid residues include amino acid residues containing an iodinated aromatic group. As described above, examples of iodinated aromatic groups include an iodo-phenyl group and an iodo-naphthyl group. In certain embodiments, the iodinated amino acid residue comprises an amino acid residue containing a hydroxy-iodo-aromatic group, such as a hydroxy-iodo-phenyl group or a hydroxy-iodo-naphthyl group. More specific examples of hydroxy-iodo-aromatic groups include, as described above, hydroxy-iodo-phenyl groups selected from mono-hydroxy-mono-iodo-phenyl, mono-hydroxy-di-iodo-phenyl, mono-hydroxy-tri-iodo-phenyl, mono-hydroxy-tetra-iodo-phenyl, di-hydroxy-mono-iodo-phenyl, di-hydroxy-di-iodo-phenyl, di-hydroxy-tri-iodo-phenyl, tri-hydroxy-mono-iodo-phenyl, and tri-hydroxy-di-iodo-phenyl groups.

[0017] Specific examples of iodinated amino acid residues include the following iodinated amino acid residues: iodophenylalanine, which contains a mono-iodo-phenyl group; [ka] monoiodotyrosine, which contains a mono-iodo-phenyl group, specifically a mono-hydroxy-mono-iodo-phenyl group; [ka] diiodotyrosine, which contains a mono-hydroxy-di-iodo-phenyl group; [ka] Diiodothyronine, which contains a di-iodo-phenyl group and a hydroxy-phenyl group; [ka] Triiodothyronine, also known as T3, which contains a di-iodo-phenyl group and a mono-hydroxy-mono-iodo-phenyl group; [ka] Tetraiodothyronine, also known as thyroxine or T4, which contains a di-iodo-phenyl group and a mono-hydroxy-di-iodo-phenyl group; [ka] iodophenylalanine and 6-iodo-L-DOPA, which contains a di-hydroxy-mono-iodo-phenyl group. Many of these iodinated amino acids are relatively water-soluble, and some, such as 3,5-diiodotyrosine and L-thyroxine, have been well studied as monomers for bioerodible polymers.

[0018] As further described below, iodinated polyamino compounds of the present disclosure can be formed by an amide coupling reaction between a carboxyl-substituted polyamino compound (after protection of the amino groups), for example, selected from those described below, and an iodinated amino acid derivative, e.g., a C1-C5 alkyl ester of an iodinated amino acid, preferably a methyl ester of an iodinated amino acid, which effectively serves as a protecting group for the carboxylic acid groups of the final iodinated polyamino compound. Examples of such iodinated amino acid derivatives include C1-C5 alkyl esters of any of the aforementioned iodinated amino acids. After coupling, the protecting group on the residue of the carboxyl-substituted polyamino compound is removed, and the C1-C5 alkyl ester may be converted to the corresponding carboxylic acid or anionic carboxylate group, thereby providing the final iodinated polyamino compound.

[0019] In addition to a carboxy-substituted iodinated moiety such as one of those described above, the iodinated polyamino compounds of the present disclosure also include a polyamino moiety attached to the carboxy-substituted iodinated moiety. In various embodiments, the iodinated polyamino compounds of the present disclosure include a polyamino moiety having a plurality (2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of amino groups. For example, the polyamino moiety may include a plurality (2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of —(CH) x and x is 0, 1, 2, 3, 4, 5, or 6. In some of these embodiments, the polyamino moiety may comprise multiple -(CH) groups disposed along the polymeric portion (defined herein as a portion containing 2, 3, 4, 5, 6, 7, 8, 9, 10, or more monomer residues). x It may contain -NH2 groups. In some embodiments, the polymer moiety may be selected from a polyamide moiety, such as a peptide moiety, a polyalkylene moiety, or a polysaccharide moiety, among others.

[0020] In some embodiments, the polyamino moiety of the iodinated polyamino compound can correspond to the residue of a carboxyl-substituted polyamino compound (a compound containing a carboxyl group and multiple amino groups). Examples of carboxyl-substituted polyamino compounds include peptides containing 2-10 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.

[0021] Commercially available examples of carboxyl-substituted polyamino compounds 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-ornityl-L-ornithine, N 2 -[1-[N 2 -[N 2 -(NL-valyl-L-alanyl)-L-lysyl]-L-lysyl]-L-prolyl]-L-lysine, L-lysyl-L-tryptophyl-L-lysyl-L-lysine, N 2 ,N 5 ,N 5 -Tris(3-aminopropyl)-L-ornithine, L-lysyl-L-ornityl-L-lysine, D-lysyl-D-lysyl-D-lysine, glycylglycyl-L-lysylglycylglycyl-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-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-lysine, L-lysyl-L-lysyl-L-lysine, L-lysyl-L-lysyl-L-arginyl-L-glutamine, L-seryl-L-isoleucyl-L-lysyl-L-lysyl-L-lysine, N 2 -(N 2 Also included are (L-ornityl-L-lysyl)-L-lysine, lysyl-lysyl-lysine, and L-lysyl-L-lysyl-L-lysyl-L-alanine.

[0022] As mentioned above, in certain embodiments, the iodinated polyamino compounds of the present disclosure comprise a polyamino moiety linked to a carboxy-substituted iodinated moiety via an amide group. The amide group may be the result of a coupling reaction between the amino group of an iodinated amino acid, such as any of those described above, and the carboxyl group of a carboxyl-substituted polyamino compound, such as any of those described above. The resulting iodinated polyamino compound thus comprises a residue of the carboxyl-substituted polyamino compound and a residue of the iodinated amino acid. In other words, the iodinated polyamino compounds of the present disclosure may be formed by an amidation reaction in which the carboxyl group of a carboxyl-substituted polyamino compound reacts with the amino group of an iodinated amino acid to form an amide bond between the two residues.

[0023] In some aspects, the present disclosure relates to a process for producing such iodinated polyamino compounds.

[0024] In the first process, the amino group of a 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 a carboxyl-substituted polyamino compound can be protected by reaction with di-tert-butyl dicarbonate. In a specific example, referring to FIG. 1A, the amino group of trilysine (110) is protected using di-tert-butyl dicarbonate (CAS No. 24424-99-5) (112), thereby forming tBoc-protected trilysine (114). This makes the carboxyl group of the protected compound (tBoc-protected trilysine) available for amide coupling.

[0025] In the second process, an iodinated amino acid derivative, specifically an iodinated amino acid C1-C5 alkyl ester, is coupled to the protected carboxyl-substituted polyamino compound formed in the first process via an amide coupling reaction (e.g., via a carbodiimide coupling reagent) to form a protected iodinated polyamino compound. In a specific example, referring to Figure 1B, t-Boc-protected trilysine (114) in Figure 1A is coupled with iodinated amino acid derivative (116), specifically diiodotyrosine methyl ester (CAS No. 76318-50-8), in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) in dimethylformamide (DMF) to give 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 Publication No. 2019 / 0142863 and U.S. Patent No. 8,288,505).

[0026] In the third process, the product of the second process is deprotected and hydrolyzed (e.g., under acidic conditions) to form the final carboxyl-substituted iodinated polyamino compound. For example, as shown in Figure 1C, the t-Boc-protected iodinated peptide segment (t-Boc-Lys-Lys-Lys-Tyr-I2) (118) is deprotected and hydrolyzed under acidic conditions using an acid such as trifluoroacetic acid to form the activated iodinated polyamino compound (Lys-Lys-Lys-Tyr-I2) (120). The above process can be carried out with a variety of carboxyl-substituted polyamino compounds and a variety of iodinated amino acid derivatives. With regard to the latter, when diiodotyrosine methyl ester is coupled to trilysine as described above, the resulting compound is shown in Figure 2A, while when thyroxine methyl ester is coupled to trilysine, the resulting compound is shown in Figure 3A.

[0027] Further, by repeating the first, second, and third processes, more iodinated amino acid groups can be successively added to the chain ends; however, the iodinated polyamino compound formed in the third process displaces the trilysine from the first step to form a protected compound, which is then coupled with another iodinated amino acid C1-C5 alkyl ester in an amide coupling reaction along the lines of the second process, followed by deprotection and hydrolysis along the lines of the third process. When the iodinated amino acid C1-C5 alkyl ester is diiodotyrosine methyl ester, the result of performing these additional steps once is shown in Figure 2B, which contains two diiodotyrosine residues. When the iodinated amino acid C1-C5 alkyl ester is thyroxine methyl ester, the result of performing these additional steps once is shown in Figure 3B, which contains two thyroxine residues.

[0028] Repeating the first, second, and third processes again using the product of Figure 2B in place of trilysine and diiodotyrosine methyl ester as the iodinated amino acid C1-C5 alkyl ester yields a product containing three diiodotyrosine residues as shown in Figure 2C. Repeating the first, second, and third processes again using the product of Figure 3B in place of trilysine and thyroxine methyl ester as the iodinated amino acid C1-C5 alkyl ester yields a product containing three thyroxine residues as shown in Figure 3C. Additional iodinated amino acid residues can be added, if desired. As noted above, some aspects of the present disclosure provide radiopaque crosslinked hydrogels comprising the crosslinked reaction product of (a) an iodinated polyamino compound as described above and (b) a reactive multi-arm polymer comprising a plurality of polymer arms having reactive end groups reactive with the amino groups of the iodinated polyamino compound.

[0029] In various embodiments, the crosslinked products of the present disclosure are visible under fluoroscopy. In various embodiments, such crosslinked products have a radiopacity of greater than 250 Hounsfield Units (HU), and advantageously have a radiopacity ranging from 250 HU to 500 HU to 750 HU to 1000 HU or more (in other words, a range between any two of the aforementioned values). Such crosslinked products can be formed in vivo (e.g., using a delivery device such as those described below), or they can be formed ex vivo and then administered to a subject. Such crosslinked products can be used in a wide variety of biomedical applications, including medical devices, implants, and pharmaceutical compositions. 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 crosslinked product. The reactive multi-arm polymer may be water-soluble.

[0030] Reactive multi-arm polymers for use herein include those containing multiple polymer arms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more arms), where two or more polymer arms of the multi-arm polymer contain one or more reactive end groups. In some embodiments, compositions are provided that contain reactive multi-arm polymers, where the percentage of polymer arms containing one or more reactive end groups can represent 50% to 100% of the total number of polymer arms in the composition (e.g., any range of 50%, 70%, 80%, 90%, 95%, 99%, to 100% of the total number of polymer arms). Typical average molecular weights of reactive multi-arm polymers for use herein are at least 10 kDa, and in some cases range from 10 kDa to 50 kDa or more. In various embodiments, reactive multi-arm polymers for use herein have a melting point of 40°C or higher, preferably 45°C or higher.

[0031] In various embodiments, the polymer arms are hydrophilic polymer arms. Such hydrophilic polymer arms can be comprised of any of a variety of synthetic, natural, or synthetic-natural hybrid polymers, including, for example, poly(ethylene oxide) (PEO, also known as polyethylene glycol or PEG), poly(alkylene oxide) such as poly(propylene oxide) or poly(ethylene oxide-co-propylene oxide), poly(N-vinylpyrrolidone), 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(allyl 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 a core region. In certain of these embodiments, the core region comprises the residue of a polyol used to form the polymer arms. Exemplary polyols include, for example, linear, branched, and cyclic aliphatic polyols, including linear, branched, and cyclic polyhydroxyalkanes; linear, branched, and cyclic polyhydroxyethers, including polyhydroxypolyethers; linear, branched, and cyclic polyhydroxyalkylethers, including polyhydroxyalkylpolyethers; linear, branched, and cyclic sugars and sugar alcohols, such as glycerol, mannitol, sorbitol, inositol, xylitol, quebrachitol, threitol, arabitol, erythritol, adonitol, dulcitol, fucose, ribose, arabinose, xylose, lyxose, rhamnose, galactose, glucose, fructose, sorbose, mannolol, and the like. The polyols may be selected from linear, branched, and cyclic sugar and sugar alcohol polymers (defined herein as two or more units), including oligomers (defined herein as ranging from 2 to 10 units, including dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, enneamers, and decamers) of linear, branched, and cyclic sugar and sugar alcohols, including sugars, pyranses, altroses, taloses, tagatoses, pyranosides, sucrose, lactose, and maltose, the aforementioned sugars and sugar alcohols, starches, amyloses, dextrins, cyclodextrins, and polyhydroxy crown ethers and polyhydroxyalkyl crown ethers. Exemplary polyols also include aromatic polyols, including 1,1,1-tris(4'-hydroxyphenyl)alkanes, e.g., 1,1,1-tris(4-hydroxyphenyl)ethane, and 2,6-bis(hydroxyalkyl)cresols.

[0033] In certain advantageous embodiments, the core region comprises residues of a polyol that contains 2, 3, 4, 5, 6, 7, 8, 9, 10 or more hydroxyl groups, hi certain advantageous embodiments, the core region comprises residues of a polyol that is an oligomer of a sugar alcohol such as glycerol, mannitol, sorbitol, inositol, xylitol, or erythritol, among others.

[0034] In certain embodiments, the reactive end group may be an electrophilic group selected from imidazole ester, imidazole carboxylate, benzotriazole ester, or imidoester, including N-hydroxysuccinimidyl ester. A particularly useful reactive end group is an N-hydroxysuccinimidyl ester group. In certain embodiments, the reactive end group is attached to the polymer arm via a hydrolyzable ester group. The hydrolyzable ester group may be selected from, for example, a glutarate group, a succinate group, a carbonate group, or an adipate group. In certain embodiments, the polymer arm may be terminated with a reactive hydrolyzable group, such as, inter alia, succinimidyl glutarate, succinimidyl succinate, succinimidyl carbonate, or succinimidyl adipate.

[0035] Further examples of reactive multi-arm polymers are described, for example, in U.S. Patent Application Nos. 2011 / 0142936, 2021 / 0061950, 2021 / 0061954, and 2021 / 0061957. In some aspects of the present disclosure, systems are provided that are configured to deliver an iodinated polyamino compound and a reactive multi-arm polymer that includes multiple 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 crosslink with each other. Such systems can be used to form crosslinked hydrogels either in vivo or in vitro.

[0036] For example, as shown schematically in FIG. 4, a reactive multi-arm polymer (410) such as described above, comprising a core region and multiple hydrophilic polyethylene oxide arms having reactive end groups (i.e., succinimidyl glutarate groups) (where R is a core region such as a polyol residue, and n is, for example, in the range of 25 to 140), can be crosslinked with an iodinated polyamino compound (120) such as described above, comprising amino groups reactive with the reactive groups (i.e., succinimidyl glutarate groups) of the reactive multi-arm polymer (410), by reacting the iodinated polyamino compound (120) with the reactive multi-arm polymer (410) under basic conditions to form a crosslinked product (412), which may be in the form of a hydrogel when hydrated. The advantage of this approach is that the iodination is independent of the parent polymer, allowing the multi-arm polymer to be exchanged for hydrophilic polymer arms other than polyethylene oxide arms, for example, N-hydroxysuccinimidyl-ester functionalized systems with synthetic, natural, or hybrid synthetic-natural hydrophilic polymer arms as described above.

[0037] As mentioned above, some aspects of the present disclosure provide a system comprising: (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). The first composition may be a first fluid composition comprising an iodinated polyamino compound, or may be a first dry composition comprising an iodinated polyamino compound to which an appropriate fluid, such as water for injection or saline, can be added to form the first fluid composition. In addition to the iodinated polyamino compound, the first composition may further comprise additional agents, including those described below. The second composition can be a second fluid composition comprising the reactive multi-arm polymer, or a second dry composition comprising the reactive multi-arm polymer to which a suitable fluid, such as water for injection, saline, or the like, can be added to form the second fluid composition. In addition to the reactive multi-arm polymer, the second composition can further comprise additional agents, including those described below.

[0038] In some embodiments, iodinated polyamino compound (120) is first combined with reactive multi-arm polymer (410) at an acidic pH that inhibits crosslinking between the reactive groups of reactive multi-arm polymer (410) and the amino groups of iodinated polyamino compound (120). Then, if crosslinking is desired, the pH of the mixture of iodinated polyamino compound (120) and reactive multi-arm polymer (410) is changed from an acidic pH to a basic pH to allow crosslinking to occur between the two. In certain embodiments, the system includes (a) a first precursor composition comprising the iodinated polyamino compound described above, (b) a second precursor composition comprising the reactive multi-arm polymer described above, and (c) a third composition, specifically an accelerator composition, comprising an accelerator configured to accelerate the crosslinking reaction between the iodinated polyamino compound and the reactive multi-arm polymer.

[0039] The first precursor composition may be a first fluid composition comprising an iodinated polyamino compound buffered at an acidic pH, or a first dry composition comprising an iodinated polyamino compound and an acidic buffer composition, to which an appropriate fluid, such as water for injection or saline, may be added to form the first fluid composition comprising an iodinated polyamino compound buffered at an acidic pH. In some embodiments, for example, the acidic buffer composition may comprise monobasic sodium phosphate, among other possibilities. The first fluid composition comprising the iodinated polyamino compound may have a pH, for example, in the range of about 3 to about 5, typically in the range of about 3.5 to about 4.5, and more typically in the range of about 3.8 to about 4.2. In addition to the iodinated polyamino compound, the first precursor composition may further comprise additional agents, such as a therapeutic agent and / or an additional imaging agent (other than the iodine groups present in the iodinated polyamino compound). The second precursor composition may be a second fluid composition comprising the reactive multi-arm polymer, or may be a second dry composition comprising the reactive multi-arm polymer from which a fluid composition is formed by the addition of an appropriate fluid, such as, for example, water for injection, saline, or a first fluid composition comprising an iodinated polyamino compound buffered at an acidic pH. In addition to the reactive multi-arm polymer, the second precursor composition may further comprise additional agents, such as a therapeutic agent and / or an additional imaging agent (other than the iodine groups present in the iodinated polyamino compound).

[0040] In a particularly advantageous embodiment, the first precursor composition is a first fluid composition including an iodinated polyamino compound buffered at an acidic pH, and the second precursor composition includes a dry composition including a reactive multi-arm polymer. The first precursor composition can then be mixed with the second precursor composition to provide a prepared fluid composition including an iodinated polyamino compound and a reactive multi-arm polymer, buffered at an acidic pH. In a particular example, a syringe can be provided containing the first fluid composition including an iodinated polyamino compound buffered at an acidic pH, and a vial can be provided containing a dry composition (e.g., a powder) including the reactive multi-arm polymer. The syringe can then be used to inject the first fluid composition into the vial containing the reactive multi-arm polymer to form a prepared fluid composition including the iodinated polyamino compound and the reactive multi-arm polymer, which can be withdrawn into the syringe for administration.

[0041] The enhancer composition may be a fluid enhancer composition buffered at a basic pH, or may be a dry composition containing a basic buffered composition to which an appropriate fluid, such as water for injection or saline, can be added to form a fluid enhancer composition buffered at a basic pH. For example, the basic buffered composition may contain sodium borate and dibasic sodium phosphate, among other possibilities. The fluid enhancer composition may have, for example, a pH in the range of about 9 to about 11, typically about 9.5 to about 10.5, and more typically about 9.8 to about 10.2. In addition to the above, the fluid enhancer composition may further contain additional agents, such as a therapeutic agent and / or an additional imaging agent (other than the iodine groups present in the iodinated polyamino compound).

[0042] Examples of additional imaging agents include: (a) fluorescent dyes such as fluorescein, indocyanine green, and fluorescent proteins (e.g., green, blue, and cyan fluorescent proteins); (b) Gd (III) , Mn (II) , Fe (III)(c) contrast agents for use with ultrasound imaging, including organic and inorganic echogenic particles (i.e., particles that result in an increase in reflected ultrasound energy) or organic and inorganic echolucent particles (i.e., particles that result in a decrease in reflected ultrasound energy); (d) contrast agents for use with magnetic resonance imaging (MRI), including contrast agents that contain elements that form paramagnetic ions such as gadolinium ion chelated with diethylenetriaminepentaacetic acid, and compounds (including chelates) containing these, such as gadolinium ion chelated with diethylenetriaminepentaacetic acid; 99m Tc-based, and 123 I, 125 I, 131 I, 111 In, 57 Co, 153 Sm, 133 Xe, 51 Cr, 81m Kr, 201 Tl, 67 Ga, 75 (e) contrast agents, such as other gamma emitters such as Se; 18 F, 11 C. 13 N, 15 O. 68 (f) contrast agents for use in connection with near-infrared (NIR) imaging, which can be selected to impart near-infrared fluorescence to the coatings of the present disclosure, enabling deep tissue imaging and device marking, including NIR-sensitive nanoparticles such as gold nanoshells, carbon nanotubes (e.g., nanotubes derivatized with hydroxyl or carboxyl groups, e.g., partially oxidized carbon nanotubes), dye-containing nanoparticles such as dye-doped nanofibers and dye-encapsulated nanoparticles, and semiconductor quantum dots. NIR-sensitive dyes include cyanine dyes, squaraines, phthalocyanines, porphyrin derivatives, boron dipyrromethane (BODIPY) analogs, and the like.

[0043] A prepared fluid composition buffered at an acidic pH and comprising an iodinated polyamino compound and a reactive multi-arm polymer, as described above, can be combined with a fluid-enhancing composition buffered at a basic pH, as described above, to form a crosslinked hydrogel either in vivo or in vitro. In various embodiments, a system is provided that includes one or more delivery devices for delivering the first and second compositions to a subject.

[0044] In some embodiments, a system may include a delivery device including a first reservoir containing a first composition comprising an iodinated polyamino compound, as described above, and a second reservoir containing 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, as described above. In some embodiments, a system may include a delivery device including a first reservoir containing a first composition, such as the prepared fluid composition described above, buffered at an acidic pH, comprising an iodinated polyamino compound and a reactive multi-arm polymer, and a second reservoir containing a second composition, such as the fluid enhancer composition described above. In either case, during operation, the first and second compositions are dispensed from the first and second reservoirs and combined, after which the iodinated polyamino compound and the reactive multi-arm polymer crosslink to each other to form a hydrogel.

[0045] Regardless of the first and second compositions selected, in certain embodiments, the system may include a delivery device comprising a dual-barrel syringe including a first barrel having a first barrel outlet (the first barrel containing the first composition), a first plunger movable within the first barrel, a second barrel having a second barrel outlet (the second barrel containing the second composition), and a second plunger movable within the second barrel. In some embodiments, the device may further include a mixing section having a first mixing section inlet in fluid communication with the first barrel outlet, a second mixing section inlet in fluid communication with the second barrel outlet, and a mixing section outlet. In some embodiments, the device may further include a cannula or catheter tube configured to receive the first and second fluid compositions from the first and second barrels. For example, the cannula or catheter tube can be configured to form a fluid connection with the mixing section outlet by attaching the cannula or catheter tube to the mixing section outlet via a suitable fluid connector, such as a Luer connector.

[0046] As another example, the catheter may be a multi-lumen catheter including a first lumen and a second lumen, a proximal end of the first lumen configured to form a fluid connection with the first barrel outlet, and a proximal end of the second lumen configured to form a fluid connection with the second barrel outlet. In some embodiments, the multi-lumen catheter may include a mixing section having a first mixing section inlet in fluid communication with the distal end of the first lumen, a second mixing section inlet in fluid communication with the distal end of the second lumen, and a mixing section outlet.

[0047] In operation, when the first and second plungers are depressed, the first and second fluid compositions are dispensed from the first and second barrels, after which the first and second fluid compositions interact and eventually crosslink to form a hydrogel, which is administered onto or into the tissue of a subject. For example, the first and second fluid compositions can enter the mixing section from the first and second barrels through the first and second mixing section inlets, after which the first and second fluid compositions mix to form a mixture, which exits the mixing section through the mixing section outlet. In some embodiments, a cannula or catheter tube can be attached to the mixing section outlet, and the mixture can be administered to a subject after passing through the cannula or catheter tube. As another example, a first fluid composition can enter a first lumen of a multi-lumen catheter through a first barrel outlet, and a second fluid composition can enter a second lumen of the multi-lumen catheter through a second barrel outlet. In some embodiments, the first and second fluid compositions can enter a mixing section at a distal end of the multi-lumen catheter from the first and second lumens through first and second mixing section inlets, respectively, and then the first and second fluid compositions mix in the mixing section to form an admixture, which exits the mixing section through a mixing section outlet.

[0048] Regardless of the type of device used to mix the first and second fluid compositions or the method by which the first and second fluid compositions are mixed, once the mixture of the first and second fluid compositions is formed, the mixture is initially in a fluid state and can be administered to a subject (e.g., a mammal, particularly a human) by a variety of techniques. Alternatively, the first and second fluid compositions can be administered separately to the subject, forming a fluid mixture of the first and second fluid compositions in or on the subject. In either approach, the fluid mixture of the first and second fluid compositions is formed and can be used in a variety of medical procedures.

[0049] For example, among other uses, the first and second fluid compositions or fluid admixtures thereof can be injected to create spacing between tissues, the first and second fluid compositions or fluid admixtures thereof can be injected to create fiducial markers (e.g., in the form of blebs), the first and second fluid compositions or fluid admixtures thereof can be injected for tissue augmentation or regeneration, the first and second fluid compositions or fluid admixtures thereof can be injected as a filler or replacement for soft tissue, the first and second fluid compositions or fluid admixtures thereof can be injected to provide mechanical support for damaged tissue, the first and second fluid compositions or fluid admixtures thereof can be injected as a scaffold, and / or the first and second fluid compositions or fluid admixtures thereof can be injected as a carrier for therapeutic agents in the treatment of disease and cancer and tissue repair and regeneration.

[0050] After administration of the compositions of the present disclosure (either separately as first and second fluid compositions that mix in vivo, or as a fluid admixture of the first and second fluid compositions), a crosslinked hydrogel is ultimately formed at the site of administration. After administration, the compositions of the present disclosure can be imaged using a suitable imaging technique, typically an X-ray-based imaging technique such as computed tomography or fluoroscopy. As can be seen from the above, the compositions of the present disclosure can be used in a variety of medical procedures, including, inter alia, the following: implanting a fiducial marker comprising the cross-linked product of the first and second fluid compositions; implanting a tissue regeneration scaffold comprising the cross-linked product of the first and second fluid compositions; implanting a tissue support comprising the cross-linked product of the first and second fluid compositions; implanting a tissue expander comprising the cross-linked product of the first and second fluid compositions; implanting a therapeutic agent-containing depot comprising the cross-linked product of the first and second fluid compositions; tissue augmentation procedures comprising implanting the cross-linked product of the first and second fluid compositions; and introducing the cross-linked product of the first and second fluid compositions between a first tissue and a second tissue to space the first tissue from the second tissue.

[0051] The first and second fluid compositions, the fluid blend of the first and second fluid compositions, or the crosslinked product of the first and second fluid compositions can be injected in conjunction with a variety of medical procedures, including injections between the prostate or vagina and the rectum for spacing purposes in radiotherapy for rectal cancer, injections between the rectum and the prostate for spacing purposes in radiotherapy for prostate cancer, subcutaneous injections for palliative treatment of prostate cancer, transurethral or submucosal injections for female stress urinary incontinence, intravesical injections for urinary incontinence, intrauterine injections for Asherman's syndrome, submucosal injections for anal incontinence, percutaneous injections for heart failure, intramyocardial injections for heart failure and dilated cardiomyopathy, transendocardial injections for myocardial infarction, intra-articular injections for osteoarthritis, spinal injections for spinal fusion and spinal, oral maxillofacial, and orthopedic trauma surgery, spinal injections for posterolateral lumbar fusion, intradiscal injections for degenerative disc disease, and injections for pancreatic adenocarcinoma. injections between the pancreas and duodenum for diagnostic imaging, resection bed injections for diagnostic imaging of oropharyngeal cancer, injections around the tumor bed for diagnostic imaging of bladder cancer, submucosal injections for gastrointestinal tumors and polyps, visceral pleural injections for lung biopsy, renal injections for type 2 diabetes and chronic kidney disease, renal cortical injections for chronic kidney disease due to congenital anomalies of the kidney or urinary tract, intravitreal injections for neovascular age-related macular degeneration, intratympanic injections for sensorineural hearing loss, correction of wrinkles, creases, folds, signs of facial fat loss, volume loss, shallow to deep contour defects, correction of depressed skin scars, perioral wrinkles, lip augmentation, facial lip atrophy, intradermal injections for stimulation of natural collagen production.

[0052] As discussed above, crosslinked 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 crosslinked hydrogel), and implants (which may be formed in vitro or in vivo) (e.g., compositions for use as tissue markers, compositions acting as spacers to reduce the side effects of extra-targeted radiation therapy, cosmetic compositions, etc.).

[0053] Example 1 Formation of Boc-trilysine (Boc-TL) Trilysine (H-Lys-Lys-Lys-OH) acetate (1 equiv.) was suspended in a mixture of DMF:HO (1:1). Triethylamine (4.1 equiv.) was slowly added, and the mixture was stirred at room temperature for 10 minutes to obtain a clear solution. Di-tert-butyl dicarbonate (4.2 equiv.) was added to the solution and stirred overnight. Next, the reaction solution was diluted with 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 layers were washed twice with water, twice with brine, and dried over anhydrous sodium sulfate (NaSO). Next, the solution was filtered, the solvent was removed, and the mixture was dried under vacuum without further purification to obtain a white product (yield: 80%).

[0054] Example 2 Formation of Boc-trilysine diiodotyrosine methyl ester (Boc-TL-DIT-OMe) Diiodotyrosine methyl ester hydrochloride (1 equivalent) was dissolved in DMF and neutralized by adding a quantitative amount of triethylamine (1 equivalent), and the mixture was stirred for 1 hour before further purification and direct use.

[0055] To a DMF solution of Boc-trilysine (Boc-TL) (1 equivalent) from Example 1, EDC-HCl (1 equivalent) and a catalytic amount of n-hydroxysuccinimide (NHS) were added sequentially at room temperature, and the mixture was stirred for 15 minutes. Next, diiodotyrosine methyl ester (1 equivalent), prepared in situ in DMF, was directly transferred to the reaction solution and stirred overnight at room temperature. The solvent was then removed, and the resulting residue was redissolved in DCM and extracted with water to remove ammonium and urea salts. The organic layer was then washed three times with water to remove DMF residues and dried over anhydrous Na2SO4. Finally, the solution was filtered, the solvent was removed, and the mixture was dried under vacuum to obtain a pale yellow product (yield: 80%).

[0056] Example 3 Formation of trilysine diiodotyrosine Boc-trilysine diiodotyrosine methyl ester (Boc-TL-DIT-OMe) from Example 2 was dissolved in a mixture of DCM. Trifluoroacetic acid (TFA) was added in an amount equal to the solvent, and the solution was stirred at room temperature overnight. The reaction mixture was then evaporated in vacuo, and DCM was added and evaporated several times to remove residual TFA, affording the product in quantitative yield.

[0057] Example 4 Hydrogel formation The iodinated trilysine of Example 3 was dissolved in an acidic buffer solution (pH 3.8-4.2) and then mixed with a reactive star PEG, e.g., a star PEG having a polyol residue core region and eight hydrophilic polyethylene oxide arms with reactive succinimidyl glutaric acid end groups, and the resulting mixture was placed in one syringe as a prepared fluid composition. Another syringe contained a separate buffer solution with a pH controlled at approximately 9.8-10.4 as a fluid promoter composition. The prepared fluid composition and the fluid promoter composition were then combined to form a hydrogel, simultaneously forming a crosslinked hydrogel.

Claims

1. 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 the amino groups of the iodinated polyamino compound.

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

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

4. The system of claim 2 , wherein the carboxy-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. 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 polyamino moiety is a polyamino moiety having a plurality of —(CH 2 ) x -NH 2 7. The system of claim 2, comprising a group, wherein x is 0, 1, 2, 3, 4, 5, or 6.

8. The system of any one of claims 2 to 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 lysine, ornithine, and combinations thereof.

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

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

12. 12. The system of any one of claims 1 to 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 an optional accelerator composition.

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

14. A medical hydrogel formed by crosslinking the iodinated polyamino compound and the reactive multi-arm polymer of the system according to any one of claims 1 to 13.

15. 1. A method for preparing an iodinated polyamino compound, comprising the steps of: (a) protecting an amino group of a carboxyl-substituted polyamino compound to form a protected carboxyl-substituted polyamino compound; (b) forming an amide bond between the carboxyl group of the protected carboxyl-substituted polyamino compound and an amino group of an iodinated amino acid compound; and (c) deprotecting the amino group of the product of step (b).

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