Iodinated compounds and hydrogels formed therefrom

Abstract

Iodinated compounds, hydrogels formed from iodinated compounds, and methods of making and using iodinated compounds and hydrogels are provided.SOLUTION: In some aspects, the present disclosure relates to a system for forming a hydrogel comprising (a) a first composition comprising a polyiodinated polyamino compound comprising a polyamino moiety linked to a polyiodinated aromatic moiety by an amide group or an ester group, and (b) a second composition comprising a reactive multi-arm polymer comprising a plurality of hydrophilic polymer arms having reactive terminal groups that are reactive with amino groups of the polyiodinated polyamino compound. Other aspects of the present disclosure relate to medical hydrogels and methods of making medical hydrogels based on such compositions. A further aspect of the present disclosure relates to a method of making a polyiodinated polyamino compound.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 305,792, filed February 2, 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] Injectable, biodegradable hydrogels are an emerging class of materials with a variety of medical uses. One specific example is SpaceOAR®, a long-term, injectable, biodegradable hydrogel based on star-shaped polyethylene glycol (PEG) polymers end-capped with reactive ester end groups that react with lysine oligomers to form crosslinked hydrogels. Such products are used to create or maintain space between tissues to reduce the side effects of non-targeted radiation therapy. See "Augmenix Announces Positive Three-Year SpaceOAR Clinical Trial Results," Imaging Technology News, October 27, 2016.

[0003] More recently, hydrogels in which some of the star-shaped PEG branches in the hydrogel have been functionalized with 2,3,5-triiodobenzamide (TIB) groups have demonstrated enhanced radiopacity. As a specific example, Augmenix has developed TraceIT® Hydrogel, an injectable, biodegradable synthetic hydrogel composed primarily of water and iodinated cross-linked star-shaped PEG, which is visible under CT, cone beam, ultrasound, and MR imaging and is useful as a tissue marker (e.g., for targeted radiation therapy). See "Augmenix Receives FDA Clearance to Market its TraceIT® Tissue Marker," BusinessWire, Jan. 28, 2013. TraceIT® Hydrogel remains stable and visible in tissues for three months, long enough for radiation therapy, after which it is absorbed and cleared from the body. Id.

[0004] TraceIT® hydrogels, although iodinated because they contain 2,3,5 triiodobenzoate groups, are not visible on flat panel X-ray imaging because the concentration of 2,3,5 triiodobenzoate groups in the hydrogel is limited by the hydrophobicity of such groups. More generally, for hydrogels in which some of the star-shaped PEG branches are functionalized with 2,3,5-triiodobenzamide groups, there is an upper limit to how many of these groups can be added before they affect the ability to form a stable hydrogel. This solubility limit effectively limits the amount of radiocontrast agent achievable using this strategy. The 2,3,5-triiodobenzamide groups must be added to the PEG prior to reactive functionalization, adding complexity to the manufacturing process of star-shaped PEGs and increasing product cost and the difficulty of maintaining product quality control. Furthermore, each added 2,3,5-triiodobenzamide group occupies one of the arms of the star polymer, reducing its ability to crosslink. To overcome this, lower molecular weight star PEGs can be used, but this comes at the expense of a lower melting point, which can make storage and transportation more difficult. Finally, star PEGs tagged with 2,3,5-triiodobenzamide end groups often exhibit discoloration due to thermal degradation. This does not affect the functional groups, but is a cosmetic defect that would preferably be avoided. 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

[0005] In some aspects, the present disclosure relates to a system for forming a hydrogel, the system comprising: (a) a first composition comprising a polyiodinated polyamino compound comprising a polyamino moiety linked to a polyiodinated aromatic moiety by an amide or ester group, and (b) a second composition comprising a reactive multi-arm polymer comprising a plurality of hydrophilic polymer arms having reactive end groups reactive with the amino groups of the polyiodinated polyamino compound. In some embodiments that may be used in connection with the above aspects, the polyiodinated aromatic moiety comprises a residue of an amino-substituted polyiodinated aromatic compound. In some of these embodiments, the residue of the amino-substituted polyiodinated aromatic compound comprises a monocyclic or polycyclic aromatic moiety substituted with (a) an amino group, (b) a plurality of iodine groups, and (c) one or more hydrophilic functional groups.

[0006] In some embodiments that may be used in connection with the above aspects, the polyiodinated aromatic moiety comprises a monocyclic or polycyclic aromatic moiety substituted with (a) a plurality of iodine groups and (b) one or more hydrophilic functional groups. In some embodiments that may be used in connection with any of the above embodiments, the monocyclic or polycyclic aromatic moiety is selected from benzene and naphthalene, and the hydrophilic functional group comprises a hydroxyalkyl group. In some embodiments that may be used in connection with the above aspects and embodiments, the polyiodinated aromatic moiety is a 1,3-substituted-2,4,6-triiodobenzene moiety, wherein the substituents at each of the 1- and 3-positions comprise dihydroxyalkyl groups.

[0007] In some embodiments that may be used in connection with the above aspects and embodiments, the polyamino moiety comprises a residue of a carboxy-substituted polyamino compound comprising a carboxy group and a polyamino moiety. In some of these embodiments, the carboxy-substituted polyamino compound is selected from a polylysine compound, a carboxy-substituted carboxy-terminated poly(allylamine) compound, a carboxy-terminated polyvinylamine compound, and a carboxy-terminated chitosan compound. In some embodiments that may be used in connection with the above aspects and embodiments, the polyamino moiety comprises a plurality of —(CH) x -NH groups, and x is 0, 1, 2, 3, 4, 5, or 6. In some of these embodiments, multiple -(CH) x The -NH2 groups are located along polymer segments selected from, for example, polyamide segments, polyalkylene segments, and polysaccharide segments, among others. In some embodiments that may be used in connection with the above aspects and embodiments, 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, PEG methyl ether methacrylate, or PNIPAAM. In some embodiments that may be used in connection with the above aspects and embodiments, the reactive end group is linked to the hydrophilic polymer arm by a hydrolyzable ester.

[0008] In some embodiments that may be used in connection with the above aspects and embodiments, the reactive end group is an electrophilic group. For example, the electrophilic group may be selected from imidazole esters, imidazole carboxylates, benzotriazole esters, or imide esters, among others. In some embodiments that may be used in connection with the above aspects and embodiments, the hydrophilic polymer arms extend from a polyol residue. In some embodiments that can be used in connection with the above aspects and embodiments, the system further comprises a delivery device. In some of these embodiments, the delivery device can comprise a first reservoir containing the first composition and a second reservoir containing the second composition, and upon operation of the delivery device, the first composition and the second composition can be dispensed from the first and second reservoirs, whereupon the first and second compositions interact and crosslink with each other to form a hydrogel. In some embodiments, the first and second reservoirs comprise syringe barrels.

[0009] In some aspects, the present disclosure relates to a medical hydrogel formed by reaction of the first composition and the second composition of the system according to any of the above aspects and embodiments. In some aspects, the present disclosure relates to a method of making a medical hydrogel, comprising reacting a first composition and a second composition of a system according to any of the above aspects and embodiments. In some of these aspects, the reaction occurs spontaneously at room or body temperature. In some aspects, the present disclosure relates to a method for making a polyiodinated polyamino compound, the method comprising: (a) forming an amide bond between an amino group of an amino-substituted polyiodinated aromatic compound and a carboxy group of a protected carboxy-substituted polyamino compound (wherein the amino group is protected); and (b) deprotecting the protected amino group. For example, the amino-substituted polyiodinated aromatic compound may be a protected amino-substituted polyiodinated aromatic compound comprising a monocyclic or polycyclic aromatic moiety substituted with one or more hydrophilic functional groups, including (a) an amino group, (b) multiple iodine groups, and (c) an acetal-protected dihydroxyalkyl group.

[0010] In another aspect, the present disclosure relates to a method of making a polyiodinated polyamino compound, the method comprising the steps of: (a) forming an ester bond between a hydroxy group of a hydroxy-substituted polyiodinated aromatic compound and a carboxy group of a protected carboxy-substituted polyamino compound (wherein the amino group is protected); and (b) deprotecting the protected amino group. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a diagram illustrating a method for making a polyiodinated polyamino compound according to an embodiment of the present disclosure. [Figure 2] FIG. 1 is a diagram illustrating a method for making a polyiodinated polyamino compound according to an embodiment of the present disclosure. [Figure 3A]FIG. 1 is a diagram illustrating a method for making a polyiodinated polyamino compound according to an embodiment of the present disclosure. [Figure 3B] FIG. 1 is a diagram illustrating a method for making a polyiodinated polyamino compound according to an embodiment of the present disclosure. [Figure 4] FIG. 1 is a diagram illustrating a method of making a hydrogel composition according to an 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) a polyiodinated polyamino compound and (b) a reactive multi-arm polymer comprising a plurality of reactive end groups reactive with the amino groups of the polyiodinated polyamino compound. Unless otherwise indicated, as used herein, the prefix "poly" means two or more.

[0013] In some aspects of the present disclosure, a system is provided that includes: (a) a first composition comprising a polyiodinated polyamino compound; and (b) a second composition comprising a reactive multi-arm polymer that includes a plurality of reactive end groups reactive with the amino groups of the polyiodinated polyamino compound. Such systems are advantageous in that, for example, the iodine functionality, and therefore radiopacity, is provided by the polyiodinated polyamino compound, which acts as a crosslinker for the multi-arm polymer, thereby providing reactive end groups on each of the polymer arms, thereby maximizing the crosslinkability of the multi-arm polymer without sacrificing radiopacity. In some aspects, the present disclosure relates to polyiodinated polyamino compounds (compounds containing multiple iodine groups and multiple amino groups), useful, for example, as crosslinkers.

[0014] In various embodiments, the polyiodinated polyamino compounds of the present disclosure comprise a polyamino moiety and a polyiodinated aromatic moiety. In various embodiments, the polyiodinated polyamino compounds of the present disclosure comprise residues of a carboxy-substituted polyamino compound and residues of an amino-substituted polyiodinated aromatic compound. Such polyiodinated polyamino compounds may be formed by an amidation reaction in which a carboxy group of the carboxy-substituted polyamino compound reacts with an amino group of the amino-substituted polyiodinated aromatic compound to form an amide bond between the two residues. In various embodiments, the polyiodinated polyamino compounds of the present disclosure comprise residues of a carboxy-substituted polyamino compound and residues of a hydroxy-substituted polyiodinated aromatic compound. Such polyiodinated polyamino compounds may be formed by an esterification reaction in which a carboxy group of the carboxy-substituted polyamino compound reacts with a hydroxy group of the hydroxy-substituted polyiodinated aromatic compound to form an ester bond between the two residues.

[0015] In various embodiments, the polyiodinated polyamino compounds of the present disclosure include polyamino moieties having multiple (2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino groups. For example, the polyamino moiety may comprise multiple (two, three, four, five, six, seven, eight, nine, ten or more) -(CH) x and x is 0, 1, 2, 3, 4, 5, or 6. In some of these embodiments, the polyamino moiety comprises 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 polymeric moiety may be selected from a polyamide moiety, a polyalkylene moiety, or a polysaccharide moiety, among others. As noted above, in some embodiments, the polyamino portion of the polyiodinated polyamino compound may correspond to the residue of a carboxy-substituted polyamino compound (a compound containing a carboxy group and multiple amino groups). Examples of carboxy-substituted polyamino compounds include polylysines (e.g., dilysine, trilysine, tetralysine, pentalysine, etc.) and carboxy-terminated polyamines such as carboxy-terminated poly(allylamine), carboxy-terminated poly(vinylamine), or carboxy-terminated chitosan. In various embodiments, the polyiodinated polyamino compounds of the present disclosure comprise a polyiodinated aromatic moiety having a plurality (2, 3, 4, 5, 6, 7, 8, 9, 10 or more) iodine groups.

[0016] For example, the polyiodinated aromatic moiety can include a monocyclic or polycyclic aromatic structure substituted with (a) multiple iodine groups (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more iodine groups) and (b) one or more hydrophilic functional groups (e.g., 1, 2, 3, 4, 5, 6 or more hydrophilic functional groups).

[0017] The monocyclic or polycyclic aromatic structures may be selected, for example, from monocyclic aromatic structures such as those based on benzene, and polycyclic aromatic structures such as those based on naphthalene, among others.

[0018] The one or more hydrophilic functional groups may comprise, for example, a hydroxyalkyl group, such as, for example, a C1-C4-hydroxyalkyl group (e.g., a C1-C4-monohydroxyalkyl group, a C1-C4-dihydroxyalkyl group, a C1-C4-trihydroxyalkyl group, a C1-C4-tetrahydroxyalkyl group, etc.), among others. The hydroxyalkyl group may be linked to the monocyclic or polycyclic aromatic structure directly or via any suitable linking moiety, which may be selected from, for example, an amide group, an amine group, an ether group, an ester group, or a carbonate group, among others.

[0019] In certain embodiments, the polyiodinated aromatic moiety may comprise a 1,3-substituted-2,4,6-triiodobenzene group, wherein the substituents at each of the 1- and 3-positions comprise a hydrophilic functional group, e.g., a hydroxyalkyl group, which may be selected from those described above and may be linked to the benzene structure directly or via any suitable linking moiety. In a particular example, the 1,3-substituted-2,4,6-triiodobenzene group may be an N,N'-bis(hydroxyalkyl)-2,4,6-triiodobenzene-1,3-dicarboxamide group, e.g., an N,N'-bis(C-C-hydroxyalky)-2,4,6-triiodobenzene-1,3-dicarboxamide group. The 1,3-substituted-2,4,6-triiodobenzene group can then be linked to the remainder of the polyiodinated polyamino compound at the 5-position via any suitable linking moiety, including an amide bond, an amine linking group, an ester linking group, a carbonate linking group, or an ether linking group. In certain embodiments, the iodinated aromatic moiety can comprise a 1,3-(C1-C4-hydroxyalkyl-substituted)-2,4,6-triiodobenzene group, where the hydroxyalkyl group is linked to the benzene structure via an amide bond, and the iodinated aromatic moiety can be linked to the remainder of the polyiodinated polyamino compound at the 5-position via an amide group.

[0020] As indicated above, in some embodiments, the polyiodinated aromatic portion of the polyiodinated polyamino compound may correspond to the residue of an amino-substituted polyiodinated aromatic compound. For example, an amino-substituted polyiodinated aromatic compound may comprise a monocyclic or polycyclic aromatic structure substituted with multiple iodine groups, one or more hydrophilic functional groups, such as those described above, and an amino group. For example, in some embodiments, the polyiodinated polyamino compound comprises the residue of a 5-amino-1,3-substituted-2,4,6-triiodobenzene compound, wherein the substituents at each of the 1- and 3-positions comprise a hydrophilic functional group, such as a hydroxyalkyl group, which may be selected from those described above and may be linked to the benzene structure directly or via any suitable linking moiety, and the 5-amino group is used to form an amide bond to the remainder of the polyiodinated polyamino compound. In a particular example, the polyiodinated polyamino compound may include the residue of a 5-amino-N,N′-bis(hydroxyalkyl)-2,4,6-triiodo-1,3-benzenedicarboxamide compound, such as the residue of 5-amino-1,3-hydroxyalkyl-substituted-2,4,6-triiodo-1,3-benzenedicarboxamide compound, e.g., 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide, also known as 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (CAS No. 76801-93-9), where the 5-amino group is used to form an amide bond to the remainder of the polyiodinated polyamino compound.

[0021] As also indicated above, in some embodiments, the polyiodinated aromatic portion of the polyiodinated polyamino compound may correspond to the residue of a hydroxy-substituted polyiodinated aromatic compound.

[0022] For example, the hydroxy-substituted polyiodinated aromatic compound may contain a monocyclic or polycyclic aromatic structure, multiple iodine groups, and one or more hydroxy groups. For example, in some embodiments, the polyiodinated polyamino compound may contain, among others, residues of 2,3,5-triiodobenzenemethanol. [ka] Residue of 2,3,5-triiodobenzeneethanol [ka] Residue of 2,3,5-triiodobenzenepropanol [ka] or residues of iodixanol [ka] may include:

[0023] In some aspects, the present disclosure relates to methods of making polyiodinated polyamino compounds such as those described above.

[0024] For example, in an optional first method, an amino-substituted polyiodinated aromatic compound, such as one of the amino-substituted polyiodinated aromatic compounds described above, may be protected with a suitable protecting agent to modify the solubility of the amino-substituted polyiodinated aromatic compound for compatibility with other reactants in the subsequent amide coupling reaction (described below). For example, the hydroxy groups of an amino-substituted polyiodinated aromatic compound containing a monocyclic or polycyclic aromatic structure substituted with one or more hydrophilic functional groups including an amino group, multiple iodine groups, and a C1-C4-dihydroxyalkyl group can be protected with 2,2-dimethoxypropane to obtain an acetal-protected amino-substituted polyiodinated aromatic compound.

[0025] In a specific example shown in FIG. 1 using 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (110) (CAS number 76801-93-9) as the primary iodinated structure, the 2,3-dihydroxypropyl group of 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (110) is protected using 2,2-dimothoxypropane (112) in the presence of DMF (dimethylformamide) and p-toluenesulfonic acid (PTSA) at room temperature to give the acetal-protected iodinated molecule, 5-amino-N1,N3-bis[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2,4,6-triiodo-benzene-1,3-dicarboxamide (114).

[0026] In the second method, the amino group of a carboxy-substituted polyamino compound is protected to form a protected carboxy-substituted polyamino compound. Examples of carboxy-substituted polyamino compounds are described above and include polylysine and various carboxy-terminated polyamines, a specific example being trilysine. Referring to Figure 2, the amino group of trilysine (210) is protected using di-tert-butyl dicarbonate (112), thereby forming tBoc-protected trilysine (214). This leaves the carboxy group of the protected compound (tBoc-protected trilysine) available for amide coupling.

[0027] In the third method, the acetal-protected amino-substituted polyiodinated aromatic compound prepared as described in the first method is coupled (e.g., with a carbodiimide coupling agent) with the protected carboxy-substituted polyamino compound described in the second method in an amide coupling reaction to form a protected polyiodinated polyamino compound, which is then deprotected (e.g., under acidic conditions) to form the final polyiodinated polyamino compound. Referring to Figure 3A, the acetal-protected iodinated molecule of Figure 1, 5-amino-N1,N3-bis[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2,4,6-triiodo-benzene-1,3-dicarboxamide (114), is coupled with tBoc-protected trilysine (214) of Figure 2 in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) to form protected polyiodinated polyamino compound (314). Protected polyiodinated polyamino compound (314) is then deprotected to form the final polyiodinated polyamino compound (316), as shown in Figure 3B.

[0028] As another example, the above-described hydroxy-substituted polyiodinated aromatic compound, e.g., iodixanol, can be coupled with the above-described protected carboxy-substituted polyamino compound in an ester coupling reaction (e.g., using a carbodiimide coupling reagent) to form a protected polyiodinated polyamino compound, which can then be deprotected (e.g., under acidic conditions) to form the final polyiodinated polyamino compound. As noted above, some aspects of the present disclosure provide radiopaque crosslinked hydrogels comprising the crosslinked reaction product of (a) a polyiodinated polyamino compound, such as those 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 polyiodinated polyamino compound. In various embodiments, such crosslinked products are visible under fluoroscopy. In various embodiments, such crosslinked products have a radiopacity greater than 250 Hounsfield Units (HU), advantageously ranging from 250 HU to 500 HU, 750 HU, 1000 HU, or more. Such crosslinked products may be formed in vivo (e.g., using a delivery device such as those described below), or they may be formed ex vivo and subsequently administered to a subject. Such crosslinked products may be used in a wide range of biomedical applications, including medical devices, implants, and pharmaceutical compositions.

[0029] In various embodiments, the reactive end groups of the reactive multi-arm polymer and the amino groups of the polyiodinated polyamino compound react with each other via an amide coupling reaction 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), wherein two or more polymer arms of the multi-arm polymer contain one or more reactive end groups. In some embodiments, compositions containing reactive multi-arm polymers can be provided in which the percentage of polymer arms containing one or more reactive end groups can represent between 50% and 100% of the total number of polymer arms (e.g., between 50%, 70%, 80%, 90%, 95%, 99%, or 100% of the total number of polymer arms) (in other words, a range between any two of the aforementioned values). Typical average molecular weights of reactive multi-arm polymers for use herein range from 5 to 50 kDa. 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 polymeric arms are hydrophilic polymeric arms. Such hydrophilic polymeric arms can be comprised of any of a variety of synthetic polymers, natural polymers, or hybrid synthetic-natural polymers, including, for example, poly(ethylene oxide) (also referred to as polyethylene glycol or PEG), poly(alkylene oxides) such as poly(ethylene oxide-co-propylene oxide), poly(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), poly(ethyleneimine), poly(allylamine), poly(vinylamine), poly(amino acids), 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 cycloaliphatic polyols, including linear, branched, and cyclic polyhydroxyalkanes; linear, branched, and cyclic polyhydroxyethers, including polyhydroxypolyethers; linear, branched, and cyclic polyhydroxyalkylethers, including polyhydroxyalkylpolyethers; glycerol, mannitol, sorbitol, inositol, xylitol, querachitol, threitol, arabitol, erythritol, adonitol, dulcitol, fucose, ribose, arabinose, xylose, lyxose, rhamnose, galactose, glucose, fructose, sorbose, mannose, pyranose, altrose, taro. The polyol may be selected from linear, branched, and cyclic sugars and sugar alcohols such as sucrose, tagatose, pyranoside, sucrose, lactose, and maltose; oligomers (defined herein as two or more units, including dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, nonamers, and decamers) of linear, branched, and cyclic sugars and sugar alcohols, including the above sugars and sugar alcohols, starch, amylose, dextrin, cyclodextrin; and polymers (defined herein as two or more units), of linear, branched, and cyclic sugars and sugar alcohols, including polyhydroxy crown ethers and polyhydroxyalkyl 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, among others.

[0033] In certain advantageous embodiments, the core region comprises the residue of a polyol containing 2, 3, 4, 5, 6, 7, 8, 9, 10 or more hydroxyl groups. In certain advantageous 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, among others. 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 linked to the polymer arm by a hydrolyzable ester group. For example, the polymer arm may be terminated with the following reactive hydrolyzable groups, among others: succinimidyl glutarate group, succinimidyl succinate group, succinimidyl carbonate group, or succinimidyl adipate group.

[0034] 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, there is provided a system comprising: (a) a first composition comprising a polyiodinated polyamino compound as described hereinabove; and (b) a second composition comprising a reactive multi-arm polymer as described hereinabove. Such a system can be used to form a crosslinked hydrogel either in vivo or ex vivo.

[0035] For example, as shown schematically in FIG. 4, a second composition comprising a reactive multi-arm polymer (410), such as those described above, comprising a core region and a plurality of hydrophilic polymer arms having reactive end groups (i.e., succinimidyl glutarate groups) (R is a core region such as a polyol residue, and n is, for example, in the range of 15 to 45), is crosslinked with a first composition comprising a polyiodinated polyamino compound (316), such as those described above, comprising amino groups reactive with the reactive groups (i.e., succinimidyl glutarate groups) of the reactive multi-arm polymer (410), to form a crosslinked product 412, which, when hydrated, may be in the form of a hydrogel. The first composition may be a first fluid composition comprising a polyiodinated polyamino compound or a first dry composition comprising a polyiodinated polyamino compound, to which a suitable fluid such as water for injection or saline may be added to form the first fluid composition. In addition to the polyiodinated polyamino compound, the first composition may further comprise an additive, such as those described below.

[0036] The second composition may 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 may further comprise additional agents, such as those described below.

[0037] In various embodiments, the system includes one or more delivery devices for delivering a first composition and a second composition to a subject. For example, the system may include a delivery device with a first reservoir containing a first composition (e.g., a first fluid composition or a first dry composition, to which a suitable fluid can be added to form the first fluid composition) and a second reservoir containing a second composition (e.g., a second fluid composition or a second dry composition, to which a suitable fluid, such as water for injection or saline, can be added to form the second fluid composition). In operation, once the first composition and the second composition are dispensed from the first and second reservoirs, the first composition and the second composition interact and crosslink with each other to form a hydrogel. In certain embodiments, the system can include a delivery device comprising a double-barrel syringe, the double-barrel syringe including a first barrel having a first barrel outlet, the first barrel containing a first composition, a first plunger movable within the first barrel, a second barrel having a second barrel outlet, the second barrel containing a second composition, and a second plunger movable within the second barrel.

[0038] In some embodiments, the device can 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 can further include a cannula or catheter tubing configured to receive the first and second fluid compositions from the first and second barrels. For example, the cannula or catheter tubing can be configured to form a fluid connection with the mixing section outlet by attaching the cannula or catheter tubing to the mixing section outlet via a suitable fluid connector, such as a Luer connector. As another example, the catheter may be a multi-lumen catheter comprising 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 can comprise 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.

[0039] During operation, the first and second plungers are depressed, and the first and second fluid compositions are dispensed from the first and second barrels, whereupon the first and second fluid compositions interact and crosslink to form a hydrogel, which is administered to a subject or into a tissue thereof. For example, the first and second fluid compositions can pass from the first and second barrels to the mixing section via the first and second mixing section inlets, whereupon the first and second fluid compositions mix to form a mixture, which exits the mixing section via the mixing section outlet. In some embodiments, a cannula or catheter tube is attached to the mixing section outlet, allowing the mixture to 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 via first and second mixing section inlets, whereupon the first and second fluid compositions mix in the mixing section to form a mixture, which exits the mixing section via a mixing section outlet.

[0040] In some embodiments, the first composition comprising the polyiodinated polyamino compound, the second composition comprising the reactive multi-arm polymer, or the crosslinked product of the polyiodinated polyamino compound and the reactive multi-arm polymer may comprise one or more additional agents. Examples of such additional agents include therapeutic agents and additional imaging agents (other than the iodine groups present in the polyiodinated polyamino compound).

[0041] Examples of additional imaging agents include: (a) fluorescent dyes such as fluorescein, indocyanine green, or fluorescent proteins (e.g., green, blue, cyan fluorescent proteins); (b) Gd (III) , Mn (II) , Fe (III) and gadolinium ions chelated with diethylenetriaminepentaacetic acid. (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 anechogenic particles (i.e., particles that result in a decrease in reflected ultrasound energy); (d) clinically significant isotopes 99m Tc-based, as well as, inter alia, 123 I, 125 I, 131 I, 111 In, 57 Co, 153 Sm, 133 Xe, 51 Cr, 81m Kr, 201 Tl, 67 Ga and 75 (e) radiocontrast agents such as other gamma emitters such as Se, which are used to obtain functionalized radiotracer coatings, among others 18 F, 11 C. 13 N, 15 O and 68(f) contrast agents for use in connection with near-infrared (NIR) imaging, such as NIR-sensitive nanoparticles (gold nanoshells, carbon nanotubes (e.g., nanotubes derivatized with hydroxyl or carboxyl groups, e.g., partially oxidized carbon nanotubes), dye-containing nanoparticles (e.g., dye-doped nanofibers and dye-encapsulated nanoparticles), and semiconductor quantum dots, which can be selected to impart near-infrared fluorescence to the coatings of the present disclosure, enabling deep tissue imaging and device marking. NIR-sensitive dyes include cyanine dyes, squaraines, phthalocyanines, porphyrin derivatives, and boron dipyrromethane (BODIPY) analogs, among others.

[0042] Crosslinked hydrogel compositions according to the present disclosure include lubricious compositions for medical applications, compositions for releasing therapeutic agents (e.g., by including one or more therapeutic agents in the matrix of the crosslinked hydrogel), and implants (which may be formed ex vivo 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.).

Claims

1. 1. A hydrogel-forming system comprising: (a) a first composition comprising a polyiodinated polyamino compound comprising a polyamino moiety linked to a polyiodinated aromatic moiety by an amide group; and (b) a second composition comprising a reactive multi-arm polymer comprising a plurality of hydrophilic polymer arms having reactive end groups reactive with the amino groups of the polyiodinated polyamino compound.

2. 10. The system of claim 1, wherein the polyiodinated aromatic moiety comprises a residue of an amino-substituted polyiodinated aromatic compound.

3. 2. The system of claim 1, wherein the polyiodinated aromatic moiety comprises a residue of an amino-substituted polyiodinated aromatic compound comprising a monocyclic or polycyclic aromatic moiety substituted with (a) an amino group, (b) a plurality of iodine groups, and (c) one or more hydrophilic functional groups.

4. 2. The system of claim 1, wherein the polyiodinated aromatic moiety comprises a monocyclic or polycyclic aromatic moiety substituted with (a) a plurality of iodine groups and (b) one or more hydrophilic functional groups.

5. The system according to any one of claims 3 to 4, wherein the monocyclic or polycyclic aromatic moiety is selected from benzene and naphthalene, and the hydrophilic functional group comprises a hydroxyalkyl group.

6. 10. The system of claim 1, wherein the polyiodinated aromatic moiety is a 1,3-substituted-2,4,6-triiodobenzene moiety, and the substituents at each of the 1- and 3-positions comprise dihydroxyalkyl groups.

7. The system of any one of claims 1 to 6, wherein the polyamino moiety comprises a residue of a carboxy-substituted polyamino compound comprising a carboxy group and a polyamino moiety.

8. 8. The system of claim 7, wherein the carboxy-substituted polyamino compound is selected from polylysine compounds, carboxy-substituted carboxy-terminated poly(allylamine) compounds, carboxy-terminated polyvinylamine compounds, and carboxy-terminated chitosan compounds.

9. The polyamino moiety may have a plurality of —(CH 2 ) x -NH 2 8. The system of claim 1, comprising a group, wherein x is 0, 1, 2, 3, 4, 5, or 6.

10. Multiple -(CH 2 ) x -NH 2 The system of claim 9 , wherein the groups are disposed along the polymer segment.

11. 11. The system of any of claims 1 to 10, 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, PEG methyl ether methacrylate, or PNIPAAM.

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

13. 13. The system of claim 12, wherein the electrophilic group is selected from an imidazole ester, an imidazole carboxylate, a benzotriazole ester, or an imidoester.

14. The system of any preceding claim, further comprising a delivery device.

15. 15. The system of claim 14, wherein the delivery device comprises a first reservoir containing the first composition and a second reservoir containing the second composition, and wherein during operation, the first composition and the second composition interact and crosslink with each other to form a hydrogel upon being dispensed from the first and second reservoirs.

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