Hydrogels with biodegradable crosslinking
Inventors
Ashley, Gary W. • Santi, Daniel V. • Henise, Jeffrey C.
Assignees
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Publication Number
US-11181803-B2
Publication Date
2021-11-23
Expiration Date
Abstract
Hydrogels that degrade under appropriate conditions of pH and temperature by virtue of crosslinking compounds that cleave through an elimination reaction are described. The hydrogels may be used for delivery of various agents, such as pharmaceuticals.
Core Innovation
The invention relates to a drug-releasing degradable hydrogel prepared by an orthogonal assembly method using a first multi-armed polyethylene glycol (PEG) polymer with orthogonal first and second functional groups on each arm. The first multi-armed PEG polymer reacts with a linker-drug conjugate in which a third functional group reacts only with the first orthogonal functional group to obtain a derivatized first polymer, and the derivatized first polymer reacts with a crosslinker coupled to a second multi-armed PEG polymer in which a fourth functional group reacts only with the second orthogonal functional group to obtain the drug-releasing degradable hydrogel.
The order of reaction may be swapped by reacting the first multi-armed PEG polymer with the crosslinker to form a crosslinked polymer followed by reaction with the linker-drug conjugate. The crosslinker and the linker-drug conjugate are defined by chemical formulas with structural constraints that require that neither the third functional group nor the fourth functional group participates in the wrong orthogonal coupling, and the claims further specify allowable orthogonal functional group types and compatibility constraints.
The claims further include a requirement that both the linker-drug conjugate and the crosslinker are degradable by a β-elimination reaction. The hydrogel network couples the first and second PEG polymers through orthogonal group-specific reactions and supports selective and orthogonal drug conjugation and crosslinking.
Claims Coverage
The provided material includes two independent claims. The inventive coverage centers on orthogonal first and second functional groups on multi-armed PEG polymers, selective reaction of a linker-drug conjugate and a crosslinker, formula-based constraints on both components, and β-elimination degradability of both the linker-drug conjugate and the crosslinker.
Orthogonal first and second functional groups on multi-armed PEG
A first multi-armed polyethylene glycol (PEG) polymer has orthogonal first and second functional groups on each arm, with the first orthogonal functional group different from the second orthogonal functional group.
Linker-drug conjugate reacts only with the first orthogonal functional group
The first multi-armed PEG polymer reacts with a linker-drug conjugate that comprises a third functional group that reacts only with the first orthogonal functional group to obtain a derivatized first polymer.
Crosslinker reacts only with the second orthogonal functional group and couples to second multi-armed PEG
The derivatized first polymer reacts with a crosslinker coupled to a second multi-armed PEG polymer, and the crosslinker comprises a fourth functional group that reacts only with the second orthogonal functional group to obtain the drug-releasing degradable hydrogel.
Crosslinker and linker-drug conjugate defined by formulas with orthogonal-functional-group compatibility constraints
The crosslinker and the linker-drug conjugate are defined by chemical formulas with structural constraints and orthogonal-functional-group type rules, including compatibility constraints among N3, NH2, NH-CO2tBu, SH, StBu, maleimide, CO2H, CO2tBu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate, and acrylamide.
Β-elimination degradability of both linker-drug conjugate and crosslinker
The linker-drug conjugate and the crosslinker are degradable by a β-elimination reaction.
Across the independent claims, the inventive coverage centers on forming a drug-releasing degradable hydrogel by orthogonal, group-specific reactions: a derivatized first multi-armed PEG polymer is created via a linker-drug conjugate that reacts only with a first orthogonal functional group, and then crosslinked via a crosslinker that reacts only with a second orthogonal functional group on a second multi-armed PEG polymer, with the order optionally swapped. The crosslinker and linker-drug conjugate are further constrained by formula definitions and orthogonal-functional-group compatibility rules, and an additional independent refinement requires β-elimination degradability of both the linker-drug conjugate and the crosslinker.
Stated Advantages
Enables enzyme-independent biodegradation via non-enzymatic elimination under physiological pH and physiological temperature.
Produces smaller soluble fragments through elimination-based degradation.
Supports drug release from a degradable hydrogel via degradation of the linker and/or crosslinking connections.
Documented Applications
Drug-releasing hydrogel formulations for drug delivery, including hydrogels enabling drug release controlled by hydrogel degradation; drug loading described as entrapped and/or drug conjugated via elimination linkers.
Example drug-releasing hydrogel embodiments include linker-drug conjugates associated with drug examples such as exenatide (exendin-4).
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