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WO-2026096739-A1 - RADIOPAQUE MULTI-ARM POLYMERS FOR MEDICAL APPLICATIONS

WO2026096739A1WO 2026096739 A1WO2026096739 A1WO 2026096739A1WO-2026096739-A1

Abstract

In some aspects, the present disclosure pertains to multi-arm polymers that comprise a core region, a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising a hydrophilic polymer segment and an amino-alcohol residue that is attached to the hydrophilic polymer segment through an ether group, an electrophilic group attached to each amino-alcohol residue through a linkage that comprises a hydrolysable ester group, and a residue of a carboxylic-acid-containing iodinated molecule attached to each amino-alcohol residue through a linkage comprising an amide group. Other aspects of the present disclosure pertain to systems for forming hydrogels that are based on such multi-arm polymers, to crosslinked products that are formed from such systems, and to methods of treatment that use such systems.

Inventors

  • DORN, Rick William
  • DELANEY, JR., Joseph Thomas
  • PARISI, Cristian

Assignees

  • BOSTON SCIENTIFIC SCIMED, INC.

Dates

Publication Date
20260507
Application Date
20251030
Priority Date
20241031

Claims (15)

  1. 1. A multi-arm polymer comprising a core region, a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising a hydrophilic polymer segment and an amino-alcohol residue that is attached to the hydrophilic polymer segment through an ether group, an electrophilic group attached to each amino-alcohol residue through a linkage that comprises a hydrolysable ester group, and a residue of a carboxylic-acid-containing iodinated molecule attached to each amino-alcohol residue through a linkage comprising an amide group.
  2. 2. The multi-arm polymer of claim 1, wherein the amino-alcohol residue comprises an amino group and a hydroxyl group on adjacent carbon atoms.
  3. 3. The multi-arm polymer of any of claims 1-2, wherein the electrophilic group is a cyclic-imidyl ester group and/or wherein the carboxylic-acid- containing iodinated molecule comprises a carboxylic acid group and a monocyclic or multicyclic aromatic structure that is substituted with one or more iodine atoms and/or wherein the carboxylic-acid-containing iodinated molecule is a carboxyalkylamido-modified, iodinated aminoacid ester and a residue of an iodinated amino-acid ester is attached to the amino-alcohol residue through a linkage that contains two amide groups.
  4. 4. The multi-arm polymer of any of claims 1-3, wherein the multi-arm polymer is made by a process comprising (a) reacting the carboxylic-acid- containing iodinated molecule in an amide coupling reaction with a multiarm polymer comprising the core region and a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising the hydrophilic polymer segment and an amino-alcohol end group that is attached to the hydrophilic polymer segment through an ether group; (b) reacting the product of step (a) with a cyclic anhydride compound in a ring opening reaction; (c) reacting the product of step (b) in an ester-forming reaction with an N-hydroxy cyclic imide compound.
  5. 5. The multi-arm polymer of claim 4, wherein the carboxylic-acid-containing iodinated molecule is made by a process that comprises reacting a cyclic PCT/US25/53294 30 October 2025 (30.10.2025) BSC File No. 24-0448W001 Aty. Docket No. 2001.3744111 anhydride compound in a ring opening reaction with an amino group of an iodinated amino-acid alkyl ester to form a carboxyalkylamido-modified iodinated amino-acid alkyl ester.
  6. 6. A multi-arm polymer comprising a core region, a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising a hydrophilic polymer segment and a residue of a halogensubstituted cyclic anhydride that is attached to the hydrophilic polymer segment through a hydrolysable ester group, an electrophilic group attached to each halogen-substituted cyclic anhydride residue, and at least one residue of a hydroxyl-containing iodinated molecule attached to each halogen- substituted cyclic anhydride residue through a linkage comprising an ether group, wherein the halogen is selected from bromine and iodine.
  7. 7. The multi-arm polymer of claim 6, wherein the halogen- substituted cyclic anhydride comprises two or more halogen groups.
  8. 8. The multi-arm polymer of any of claims 6-7, wherein the electrophilic group is a cyclic-imidyl ester group that is directly attached to a carbon atom of each halogen-substituted cyclic anhydride residue and/or wherein the hydroxyl-containing iodinated molecule comprises a hydroxyl group and a monocyclic or multicyclic aromatic structure that is substituted with one or more iodine atoms.
  9. 9. The multi-arm polymer of any of claims 6-8, wherein the multi-arm polymer is made by a process comprising (a) reacting a hydroxylterminated multi-arm polymer, which comprises the core region and a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising the hydrophilic polymer segment and a hydroxyl end group, with a halogen- substituted cyclic anhydride compound to form a multi-arm polymer, which comprises the core region and a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising the hydrophilic polymer segment and a carboxyhaloalkyl end group that is attached to the hydrophilic polymer segment through a hydrolysable ester group; (b) reacting the product of PCT/US25/53294 30 October 2025 (30.10.2025) BSC File No. 24-0448W001 Aty. Docket No. 2001.3744111 step (a) with at least one hydroxyl-containing iodinated molecule in a substitution reaction to form a multi-arm polymer, which comprises the core region and a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising the hydrophilic polymer segment and at least one residue of the hydroxyl-containing iodinated molecule attached to a residue of the carboxyhaloalkyl end group through a linkage comprising an ether group; and (c) reacting the product of step (b) in an ester-forming reaction with an N-hydroxy cyclic imide compound.
  10. 10. A multi-arm polymer comprising a core region, a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising a hydrophilic polymer segment and a residue of a carboxylic- acid-substituted cyclic anhydride that is atached to the hydrophilic polymer segment through a hydrolysable ester group, a residue of a hydroxyl-containing iodinated molecule attached to each carboxylic-acid- substituted cyclic anhydride residue through a linkage that comprises a urethane group and an amide group, and an electrophilic group attached to each carboxylic-acid-substituted cyclic anhydride residue.
  11. 11. The multi-arm polymer of claim 10, wherein the electrophilic group is a cyclic-imidyl ester group that is directly attached to a carbon atom of each carboxylic-acid-substituted cyclic anhydride residue and/or wherein the hydroxyl-containing iodinated molecule comprises a hydroxyl group and a monocyclic or multicyclic aromatic structure that is substituted with one or more iodine atoms.
  12. 12. The multi-arm polymer of any of claims 10-11, wherein the linkage that comprises a urethane group and an amide group contains a residue of compound that comprises an amine group and an isocyanate group.
  13. 13. The multi-arm polymer of any of claims 10-12, wherein the carboxylic- acid-substituted cyclic anhydride comprises two or more carboxylic acid groups. PCT/US25/53294 30 October 2025 (30.10.2025) BSC File No. 24-0448W001 Aty. Docket No. 2001.3744111
  14. 14. The multi-arm polymer of any of claims 10-13, wherein the multi-arm polymer is made by a process comprising (a) reacting a hydroxylterminated multi-arm polymer, which comprises the core region and a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising the hydrophilic polymer segment and a hydroxyl end group, in a ring opening reaction with carboxylic-acid- substituted cyclic anhydride compound, in which the carboxylic acid is protected, to form a multi-arm polymer that comprises the core region and a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising the hydrophilic polymer segment and an end group that comprises the protected carboxylic acid group and an unprotected protected carboxylic acid group; (b) reacting a hydroxylcontaining iodinated molecule with a compound that comprises a protected amine group and an isocyanate group and then deprotecting the amine group to form a molecule in which an amine group is attached to a residue of the hydroxyl-containing iodinated molecule through a urea-containing linkage; (c) reacting the product of step (a) with the product of step (b) in an amide coupling reaction; (d) deprotecting the protected carboxylic acid group; and (e) reacting the product of step (d) in an ester-forming reaction with an N-hydroxy cyclic imide compound.
  15. 15. A system for forming a hydrogel that comprises (a) the multi-arm polymer of any of claims 1-14 and (b) a polyamino compound comprising at least two amino (-NH2) groups, wherein the reactive multi-arm polymer and the polyamino compound react to form a crosslinked hydrogel.

Description

PCT/US25/53294 30 October 2025 (30.10.2025) BSC File No. 24-0448W001 Aty. Docket No. 2001.3744111 RADIOPAQUE MULTI-ARM POLYMERS FOR MEDICAL APPLICATIONS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63/714,657 filed on October 31, 2024, the disclosure of which is incorporated herein by reference. FIELD [0002] The present disclosure relates to radiopaque multi -arm polymers, to methods of making such multi-arm polymers, to crosslinkable systems for radiopaque hydrolysable hydrogels, and to methods of treatment using such radiopaque hydrolysable hydrogels. BACKGROUND [0003] SpaceOAR®, a rapid crosslinking hydrogel that polymerizes in vivo within seconds, is based on a multi-arm polyethylene glycol (PEG) polymer with a polyol core functionalized with succinimidyl glutarate as reactive end groups which further react with trilysine 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 replaced 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 of SpaceOAR® and SpaceOAR Vue® will rapidly react with the trilysine crosslinker in vivo to form a hydrogel. The hydrogel breaks down in-vivo over the course of about 6-9 months. The breakdown occurs primarily through the hydrolysis of the ester linkages in the glutarate groups. [0004] An alternative approach to the synthesis of an iodinated multi-arm polymer is described herein, which enables water-soluble iodinated species to be provided in some or all reactive arms of the multi-arm polymer. PCT/US25/53294 30 October 2025 (30.10.2025) BSC File No. 24-0448W001 Aty. Docket No. 2001.3744111 SUMMARY [0005] In some aspects, the present disclosure pertains to a multi-arm polymer comprising a core region, a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising a hydrophilic polymer segment and an amino-alcohol residue that is attached to the hydrophilic polymer segment through an ether group, an electrophilic group attached to each amino-alcohol residue through a linkage that comprises a hydrolysable ester group, and a residue of a carboxylic-acid-containing iodinated molecule attached to each aminoalcohol residue through a linkage comprising an amide group. [0006] In some embodiments, the amino-alcohol residue comprises an amino group and a hydroxyl group on adjacent carbon atoms. [0007] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the electrophilic group is a cyclic-imidyl ester group. [0008] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the carboxylic-acid-containing iodinated molecule comprises a carboxylic acid group and a monocyclic or multicyclic aromatic structure that is substituted with one or more iodine atoms. [0009] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the carboxylic-acid-containing iodinated molecule is a carboxyalkylamido-modified, iodinated amino-acid ester, and wherein a residue of an iodinated amino-acid ester is attached to the amino-alcohol residue through a linkage that contains two amide groups [0010] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the multi-arm polymer is made by a process comprising (a) reacting the carboxylic-acid-containing iodinated molecule in an amide coupling reaction with a multi-arm polymer comprising the core region and a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising the hydrophilic polymer segment and an amino-alcohol end group that is attached to the hydrophilic polymer segment through an ether group; (b) reacting the product of step (a) with a cyclic anhydride compound in a ring opening reaction; (c) reacting the product of step (b) in an ester-forming reaction with an N-hydroxy cyclic imide compound. In some of these embodiments, the PCT/US25/53294 30 October 2025 (30.10.2025) BSC File No. 24-0448W001 Aty. Docket No. 2001.3744111 carboxylic-acid-containing iodinated molecule is made by a process that comprises reacting a cyclic anhydride compound in a ring opening reaction with an amino group of an iodinated amino-acid alkyl ester to form a carboxyalkylamido-modified iodinated amino-acid alkyl ester. [0011] In some aspects, the present disclosure pertains to a multi-arm polymer comprising a core region, a plurality of polymer arms linked to the core region, at least three of the polymer arms each comprising a hydrophilic polymer segment and a residue of a halogen-su