US-20260125517-A1 - IODINATED MULTI-FUNCTIONAL COMPOUNDS WITH ENHANCED HYDROLYTIC STABILITY IN RADIOPAQUE HYDROGELS

Abstract

In some aspects, the present disclosure provides a hydrolytically stable iodinated multi-functional compound comprising: a multi-functional compound having functional groups that are reactive with a reactive group of a multi-arm polymer; an iodinated polyol having reactive moieties including two or more hydroxyl groups, and one or more iodinated aromatic groups; and a linker between a reactive moiety of the iodinated polyol and a functional group of the multi-functional compound, where the linker includes a carbamate linkage or a carbonate linkage.

Inventors

• Joseph Thomas Delaney, JR.
• Cristian Parisi
• Yen-Hao Hsu
• Rick William Dorn
• Nicolas Ball-Jones

Assignees

• BOSTON SCIENTIFIC SCIMED, INC.

Dates

Publication Date

20260507

Application Date

20251105

Claims (20)

1. 1 . A hydrolytically stable iodinated multi-functional compound comprising: a multi-functional compound having functional groups that are reactive with a reactive group of a multi-arm polymer; an iodinated polyol having reactive moieties including two or more hydroxyl groups, and one or more iodinated aromatic groups; and a linker between a reactive moiety of the iodinated polyol and a functional group of the multi-functional compound, wherein the linker includes a carbamate linkage or a carbonate linkage.
2. 2 . The hydrolytically stable iodinated multi-functional compound of claim 1 , wherein the linker has a hydrolytic stability in the presence of water that is greater than a hydrolytic stability of a comparative ester bond in the presence of water.
3. 3 . The hydrolytically stable iodinated multi-functional compound of claim 1 , wherein the linker is a residue of a heteropolyfunctional linker, and wherein the linker is linked between a hydroxyl group of the iodinated polyol and a functional group of the functional groups of the multi-functional compound.
4. 4 . The hydrolytically stable iodinated multi-functional compound of claim 3 , wherein the heteropolyfunctional linker is represented by the Formula 1: ( A ) ⁢ m - R - ( B ) ⁢ n ; ( Formula ⁢ 1 ) where “R” is an organic segment; where “A” is a first terminal functional group comprising a protected amine; where “B” is a second terminal functional group comprising at least one of an isocyanate and a chloroformate ester; where “m” is 1; and where “n” is 1, 2, or 3.
5. 5 . The hydrolytically stable iodinated multi-functional compound of claim 3 , wherein the heteropolyfunctional linker is a linear heterobifunctional linker.
6. 6 . The hydrolytically stable iodinated multi-functional compound of claim 5 , wherein the linear heterobifunctional linker is a protected amino chloroformate.
7. 7 . The hydrolytically stable iodinated multi-functional compound of claim 6 , wherein the protected amino chloroformate is selected from a group consisting of 4-(t-butoxycarbonylamino)butyl carbonochloridate, 2-(benzyloxycarbonylamino)ethyl carbonochloridate, 2-[2-(tbutoxycarbonylamino)ethyldisulfanyl]ethyl carbonochloridate, 3-(t-butoxycarbonylamino)propyl carbonochloridate, 2-[2-(tbutoxycarbonylamino) ethoxy]ethyl carbonochloridate, 6-(9H-fluoren-9-ylmethoxycarbonylamino)hexyl carbonochloridate, 2-(9H-fluoren-9-ylmethoxycarbonylamino)ethyl carbonochloridate, and chlorocarbonyl 2-(tritylamino)acetate.
8. 8 . The hydrolytically stable iodinated multi-functional compound of claim 3 , wherein the heteropolyfunctional linker is a branched heteropolyfunctional linker.
9. 9 . The hydrolytically stable iodinated multi-functional compound of claim 8 , wherein the branched heteropolyfunctional linker is a benzyloxycarbonyl (Cbz)-protected bis-chloroformate.
10. 10 . The hydrolytically stable iodinated multi-functional compound of claim 9 , wherein the benzyloxycarbonyl (Cbz)-protected bis-chloroformate is: benzyloxycarbonyl(2-chlorocarbonyloxyethyl)amino]ethyl carbonochloridate or 6-[2-[benzyloxycarbonyl-[2-[6-chlorocarbonyloxyhexyl(methyl)carbamoyl]oxyethyl]amino]ethoxycarbonylmethyl-amino]hexyl carbonochloridate.
11. 11 . The hydrolytically stable iodinated multi-functional compound of claim 1 , wherein the multi-functional compound is a polyamine.
12. 12 . The hydrolytically stable iodinated multi-functional compound of claim 1 , wherein the multi-functional compound comprises trilysine acetate (TLA).
13. 13 . The hydrolytically stable iodinated multi-functional compound of claim 1 , wherein the iodinated polyol is biocompatible iodinated contrast agent.
14. 14 . The hydrolytically stable iodinated multi-functional compound of claim 1 , wherein the iodinated polyol is selected from a group including: iopromide, 5-Acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, Metrizamide, 1,3-Benzenedicarboxamide, 5-(acetylamino)-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-N1-methyl- (ACI), iopamidol, Iomeprol, 1,3-Benzenedicarboxamide, N1,N3-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo- (ACI), ioxilan, isopentyl, ioversol, iohexol, iobitridol, iodixanol, and [1,3-Benzenedicarboxamide, 5,5′-[(1,3-dioxo-1,3-propanediyl)bis(methylimino)]bis[N,N′-bis[2,3-dihydroxy-1-(hydroxymethyl)propyl]-2,4,6-triiodo-(9CI, ACI)].
15. 15 . The hydrolytically stable iodinated multi-functional compound of claim 1 , wherein the iodinated polyol is an azide-functionalized iodinated polyol including an azide functional group, and wherein the linker is formed between the azide functional group and a functional group of the functional groups of the multi-functional compound.
16. 16 . A radiopaque hydrogel formed by covalently crosslinking (a) a hydrolytically stable iodinated multi-functional compound comprising: a multi-functional compound having functional groups that are reactive with a reactive group of a multi-arm polymer; an iodinated polyol having reactive moieties including two or more hydroxyl groups, and one or more iodinated aromatic groups; and a linker between a reactive moiety of the iodinated polyol and a functional group of the multi-functional compound, wherein the linker includes a carbamate linkage or a carbonate linkage, with (b) a multi-arm polymer comprising a core, a plurality of polymer segments having a first end that is covalently attached to the core and a second end comprising a moiety that comprises a reactive group that is reactive with the functional groups of the hydrolytically stable iodinated multi-functional compound.
17. 17 . The radiopaque hydrogel of claim 16 , wherein the reactive moieties of the multi-arm polymer include moieties that comprise electrophilic groups.
18. 18 . The radiopaque hydrogel of claim 17 , wherein the electrophilic groups comprise succinimide ester groups; and wherein the plurality of polymer segments comprises polyethylene glycol segments.
19. 19 . The radiopaque hydrogel of claim 17 , wherein the radiopaque hydrogel is formed in-vivo.
20. 20 . A kit for forming a radiopaque hydrogel comprising: a reactive multi-arm polymer comprising a core, a plurality of polymer segments having a first end that is covalently attached to the core and a second end comprising a moiety that comprises a reactive group; a multi-functional compound that comprises functional groups that are reactive with the reactive group of the reactive high molecular weight multi-arm polymer; an iodinated polyol having two or more hydroxyl groups, and one or more iodinated aromatic groups; and a heteropolyfunctional linker comprising a first terminal functional group that is reactive with a hydroxyl group of the iodinated polyol and at least one second terminal functional group that is reactive with the functional groups of the multi-functional compound to form a linker between the iodinated polyol and the multi-functional compound, wherein the heteropolyfunctional linker has is represented by Formula 1: ( A ) ⁢ m - R - ( B ) ⁢ n ; ( Formula ⁢ 1 ) where “R” is an organic segment; where “A” is a first terminal functional group comprising a protected amine; where “B” is a second terminal functional group comprising at least one of an isocyanate and a chloroformate ester; where “m” is 1; and where “n” is 1, 2, or 3.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application Ser. No. 63/717,396 filed on Nov. 7, 2024, the disclosure of which is incorporated herein by reference. FIELD The present disclosure relates to iodinated multi-functional compounds for forming radiopaque hydrogels (e.g., radiopaque hydrogel networks), more specifically to iodinated multi-functional compounds with enhanced hydrolytic stability in the radiopaque hydrogels and methods of formation of the iodinated multi-functional compounds. The radiopaque hydrogels and systems for forming the same are useful, for example, in various medical applications. BACKGROUND SpaceOAR®, a rapid crosslinking hydrogel that polymerizes in vivo within seconds, is based on a multi-arm polyethylene glycol (PEG) polymer functionalized with succinimidyl glutarate as reactive end groups which further react with trilysine acetate (TLA) to form crosslinks. This product has become a very successful, clinically used biomaterial in prostate cancer therapy. A further improvement based on this structure is that a portion of the succinimidyl glutarate end groups have been functionalized with 2,3,5-triiiodobenzamide groups, providing radiopacity. This hydrogel, known by the trade name of SpaceOAR Vue®, is the radiopaque version of SpaceOAR® for prostate medical applications. Above a specific pH, the succinimidyl glutarate groups will rapidly react with the trilysine crosslinker in vivo to form a hydrogel. The hydrogels breakdown in-vivo over the course of ca. 6-9 months. The breakdown occurs primarily through the hydrolysis of the ester linkages on the glutarate groups. Future versions of SpaceOAR® products family may include formulations containing iodine atoms onto the trilysine molecule structure. When enhanced hydrolytic stability of the covalent bond connecting the trilysine to the iodinated species may be desired, ester linkages may not be desired. However, many iodinated species, and especially commercialized and approved iodinated contrast agents, contain alcohols which can undergo straightforward condensation/esterification reactions with the carboxylic acid group of trilysine. Nonetheless, inclusion of these approved iodinated contrast agents is desired as they are readily available, manufactured on large scales, well-studied from a toxicology/biological standpoint, and commonly used in clinical practice. SUMMARY The present disclosure provides an alternative approach to the SpaceOAR® products described above. For instance, in some embodiments herein a linker or moiety is employed in conjunction with contrast agents (e.g., iodinated polyols) that has increased hydrolytic stability, as compared to a hydrolytic stability of the most hydrolytically labile group (e.g., glutaric ester linkages) employed with respect to other components (e.g., a multi-arm polymer) in the SpaceOAR® products described above. Thus, the resultant rate of hydrolysis of a crosslinked gel network in a hydrogel herein is higher than the rate of hydrolysis of the contrast agent-to-crosslinker to maintain radiopacity of the cross-linked gel network (e.g., at least until hydrolysis of the most hydrolytically labile groups) and hence improves performance (e.g., imaging performance remains unchanged or suitable for a longer time) of the crosslinked gel network. That is, the linkers herein (e.g., heterobifunctional linkers) can include a reactive moiety or functional group (e.g., isocyanates, chloroformate esters, etc.) that can form hydrolytically stable covalent bonds with traditional components such as iodinated polyols (e.g., iodixanol, etc.) that remain hydrolytically stable longer than hydrolysable bonds (e.g., those formed via the glutaric ester linkages) in the hydrogel. Yet, the linkers herein (e.g., heterobifunctional linkers) also include a reactive moiety or functional group (e.g., an amine) that can couple with traditional components such as traditional cross-linkers (e.g., trilysine) which permit the formation of the crosslinked gel networks via the traditional cross-linkers. In some aspects, a hydrolytically stable iodinated multi-functional compound comprises a multi-functional compound having functional groups that are reactive with a reactive group of a multi-arm polymer; an iodinated polyol having reactive moieties including two or more hydroxyl groups, and one or more iodinated aromatic groups; and a linker between a reactive moiety of the iodinated polyol and a functional group of the multi-functional compound, wherein the linker includes a carbamate linkage or a carbonate linkage. In some aspects, a radiopaque hydrogel is formed by covalently crosslinking (a) a hydrolytically stable iodinated multi-functional compound comprising: a multi-functional compound having functional groups that are reactive with a reactive group of a multi-arm polymer; an iodinated polyol having reactive moieties including two or more hydroxyl groups, an