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EP-4739362-A1 - CROSSLINKED HYDROGELS WITH ENHANCED RADIOPACITY FOR MEDICAL APPLICATIONS

EP4739362A1EP 4739362 A1EP4739362 A1EP 4739362A1EP-4739362-A1

Abstract

The present disclosure pertains to systems for forming hydrogel compositions that comprise a reactive polymer comprising a plurality of hydrophilic polymer segments and a plurality of first reactive moieties and gold nanoparticles, wherein the system is configured to deliver the reactive polymer and the gold nanoparticles under conditions such that covalent crosslinks are formed between the reactive polymer and the gold nanoparticles. The present disclosure also pertains to methods of treatment that comprise administering to a subject a mixture that comprises a reactive polymer comprising a plurality of hydrophilic polymer segments and a plurality of first reactive moieties and gold nanoparticles, under conditions such that the reactive polymer and the gold nanoparticles crosslink after administration, and to radiopaque crosslinked hydrogel compositions that comprise a crosslinked reaction product of a reactive polymer comprising a plurality of hydrophilic polymer segments and a plurality of first reactive moieties and gold nanoparticles.

Inventors

  • DORN, Rick
  • DELANEY, JR., Joseph, Thomas

Assignees

  • Boston Scientific Scimed, Inc.

Dates

Publication Date
20260513
Application Date
20240703

Claims (15)

  1. 1. A system for forming a hydrogel composition that comprises (a) a reactive polymer comprising a plurality of hydrophilic polymer segments and a plurality of first reactive moieties and (b) gold nanoparticles, wherein the system is configured to deliver the reactive polymer and the gold nanoparticles under conditions such that covalent crosslinks are formed between the reactive polymer and the gold nanoparticles.
  2. 2. The system of claim 1, wherein the reactive polymer is a multi-arm polymer that comprises three or more polymer arms linked to a core region, each arm comprising one of the plurality of hydrophilic polymer segments and one of the plurality of first reactive moieties.
  3. 3. The system of claim 1, wherein the reactive polymer is a multi-arm polymer that comprises three or more polymer arms linked to a core region, each arm comprising a cyclic anhydride residue disposed between one of the plurality of hydrophilic polymer segments and one of the plurality of first reactive moieties.
  4. 4. The system of any one of claims 2-3, wherein the core region comprises a polyol residue.
  5. 5. The system of any one of claims 1-4, wherein the hydrophilic polymer segments are selected from polyalkylene oxide segments, polyester segments, polyoxazoline segments, polydioxanone segments, and polypeptide segments.
  6. 6. The system of any one of claims 1-5, wherein each of the hydrophilic polymer segments contains between 10 and 1000 monomer residues.
  7. 7. The system of any one of claims 1-6, wherein the gold nanoparticles range from 1 nm to 2 micrometers in longest dimension.
  8. 8. The system of any one of claims 1-7, wherein the first reactive moieties comprise thiol groups and the gold nanoparticles comprise a stabilization agent that exhibits a lower affinity for gold than the thiol groups.
  9. 9. The system of claim 8, wherein the stabilization agent is a surfactant.
  10. 10. The system of any one of claims 1-7, wherein the gold nanoparticles comprise a plurality of second reactive moieties that form covalent crosslinks with the first reactive moieties.
  11. 11. The system of claim 10, wherein the first reactive moieties comprise a cyclic imide ester group and the second reactive moieties comprise a primary amine, thiol or hydroxyl group, or wherein the first reactive moieties comprise a primary amine, thiol or hydroxyl group and the second reactive moieties comprise a cyclic imide ester group.
  12. 12. The system of claim 10, wherein the first reactive moieties comprise a strained alkyne group and the second reactive moieties comprise an azide group, or wherein the first reactive moieties comprise an azide group and the second reactive moieties comprise a strained alkyne group.
  13. 13. The system of claim 10, wherein the first reactive moieties comprise a strained alkene group and the second reactive moieties comprise tetrazine a group, or wherein the first reactive moieties comprise a tetrazine group and the second reactive moieties comprise a strained alkene group.
  14. 14. A method of treatment comprising administering to a subject a mixture that comprises the reactive polymer and the gold nanoparticles of any one of claims 1- 13 under conditions such that the reactive polymer and the gold nanoparticles crosslink after administration.
  15. 15. A radiopaque crosslinked hydrogel composition comprising a crosslinked reaction product of the reactive polymer and the gold nanoparticles of any one of claims 1- 13.

Description

CROSSLINKED HYDROGELS WITH ENHANCED RADIOPACITY FOR MEDICAL APPLICATIONS CROSS REFERENCE TO RELATED APPLICATIONS [0001] The application claims the benefit of U.S. Provisional Patent Application Serial No. 63/512,263 filed on July 6, 2023, the disclosure of which is incorporated herein by reference. FIELD [0002] The present disclosure relates radiopaque hydrogels and to crosslinkable systems for forming radiopaque hydrogels, among other aspects. The radiopaque hydrogels and crosslinkable systems for forming the same are useful, for example, in various medical applications. BACKGROUND [0003] Bioresorbable hydrogels with rapid crosslinking reaction rate in vivo, known by the trade name of SpaceOAR®, have become a prominent biomaterial and obtained clinical success in creating the space between prostate and rectum, tremendously improving patient safety during the cancer therapies. A further improvement based on this application is that some of 8-Arm PEG branches are functionalized with 2,3,5-triiiodobenzamide (TIB) groups, replacing part of the activated ester end groups, succinimidyl glutarate (SG), in order to provide intrinsic radiopacity to the hydrogels themselves for CT-visibility. This hydrogel, known by the trade name of SpaceOAR Vue®, is the next generation of SpaceOAR® for prostate medical applications. [0004] Alternative strategies for forming iodine-labelled crosslinked hydrogels that provide enhanced radiopacity while maintaining or improving crosslink density per polymer molecule are desired. SUMMARY [0005] In some aspects, the present disclosure pertains to systems for forming hydrogel compositions that comprise (a) a reactive polymer comprising a plurality of hydrophilic polymer segments and a plurality of first reactive moieties and (b) gold nanoparticles, wherein the system is configured to deliver the reactive polymer and the gold nanoparticles under conditions such that covalent crosslinks are formed between the reactive polymer and the gold nanoparticles. [0006] In some embodiments, the reactive polymer is a multi-arm polymer that comprises three or more polymer arms linked to a core region, each arm comprising one of the plurality of hydrophilic polymer segments and one of the plurality of first reactive moieties. In some of these embodiments, the reactive polymer is a multi-arm polymer that comprises three or more polymer arms linked to a core region, each arm comprising a cyclic anhydride residue disposed between one of the plurality of hydrophilic polymer segments and one of the plurality of first reactive moieties. The core region may comprise, for example, polyol residue, among other possibilities. [0007] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the hydrophilic polymer segments are selected from polyalkylene oxide segments, polyester segments, polyoxazoline segments, polydioxanone segments, and polypeptide segments. [0008] In some embodiments, which can be used in conjunction with the above aspects and embodiments, each of the hydrophilic polymer segments contains between 10 and 1000 monomer residues. [0009] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the gold nanoparticles range from 1 nm to 2 micrometers in longest dimension. [0010] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the first reactive moieties comprise thiol groups and the gold nanoparticles comprise a stabilization agent that exhibits a lower affinity for gold than the thiol groups. In some of these embodiments, the stabilization agent is a surfactant. [0011] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the gold nanoparticles comprise a plurality of second reactive moieties that form covalent crosslinks with the first reactive moieties. For example, (a) the first reactive moieties may comprise a cyclic imide ester group and the second reactive moieties may comprise a primary amine, thiol or hydroxyl group, (b) the first reactive moieties may comprise a primary amine, thiol or hydroxyl group and the second reactive moieties may comprise a cyclic imide ester group, (c) the first reactive moieties may comprise a strained alkyne group and the second reactive moieties may comprise an azide group, (d) the first reactive moieties may comprise an azide group and the second reactive moieties may comprise a strained alkyne group, (e) the first reactive moieties may comprise a strained alkene group and the second reactive moieties may comprise tetrazine a group, or (f) the first reactive moieties may comprise a tetrazine group and the second reactive moieties may comprise a strained alkene group. [0012] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the system further comprises a delivery device. [0013] In some aspects, the present disclosure provides methods of treatment that compr