Hydrogels with biodegradable crosslinking
Inventors
Ashley, Gary W. • Santi, Daniel V. • Henise, Jeffrey C.
Assignees
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Publication Number
US-10398779-B2
Publication Date
2019-09-03
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 biodegradable hydrogels in which crosslinkers cleave via a non-enzymatic elimination reaction under physiological pH and temperature conditions. The elimination yields soluble fragments and therefore supports hydrogel degradation.
The crosslinkers are defined by chemical formulas (1) and (2) and include modulator groups that influence elimination kinetics. By selecting substituents and structural features, the crosslinker is degradable by elimination reaction to obtain desired degradation and drug release kinetics.
In some embodiments, the hydrogel is formed from multi-arm polymer architectures, including a first four-armed polyethylene glycol (PEG) polymer and a second four-armed PEG polymer. Orthogonal functional groups are used so that a crosslinker reacts only with a selected functional group on the second polymer.
Claims Coverage
The document contains one independent claim. It centers on a biodegradable crosslinked hydrogel formed from orthogonally functionalized four-armed PEG polymers, with a crosslinker that is degradable by elimination reaction and reacts only with the second orthogonal functional group, together with explicit functional-group compatibility exclusions.
Orthogonal four-armed peg polymer coupling
Providing a first four-armed polyethylene glycol (PEG) polymer wherein each arm is terminated by a group comprising orthogonal first and second functional groups, wherein said first orthogonal functional group is different from said second orthogonal functional group.
Crosslinker selective reaction with second orthogonal group
Reacting said first four-armed polymer with a crosslinker coupled to a second four-armed PEG polymer wherein said crosslinker comprises a functional group that reacts only with the second orthogonal functional group to obtain a crosslinked polymer as said hydrogel.
Elimination reaction degradable crosslinker of formula (1)
The crosslinker is degradable by an elimination reaction and is of Formula (1) with constraints including m=0 or 1, R1 defined as CN or SO2R3, R3 defined as H or alkyl, aryl, or arylalkyl, or NR2-based and related ring-forming possibilities, R2 being H, and R5 independently being H, alkyl, alkenylalkyl, or alkynylalkyl, with X or one of R1 and R5 comprising a functional group and being coupled to the second four-armed polymer under the stated proviso.
Enumerated orthogonal end functional groups with explicit pairing exclusions
Each functional group independently comprises N3, NH2, NH—CO2tBu, SH, S-tBu, maleimide, CO2H, CO2tBu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate, or acrylamide, and pairing compatibility rules are imposed: when one orthogonal functional group comprises N3 the other does not comprise alkyne or cyclooctyne; when one comprises SH the other does not comprise maleimide, acrylate, or acrylamide; when one comprises NH2 the other does not comprise CO2H; and when one comprises 1,3-diene or cyclopentadiene the other does not comprise furan.
Overall, the claim coverage centers on a biodegradable crosslinked hydrogel built by orthogonally functionalized four-armed PEG polymers using a crosslinker that reacts selectively with one orthogonal group, where the crosslinker is defined structurally to be degradable by an elimination reaction and subject to defined functional-group constraints and incompatibility exclusions.
Stated Advantages
Biodegradability of the hydrogel via a crosslinker degradable by an elimination reaction.
Enables biodegradation of the hydrogel via non-enzymatic elimination reaction under physiological pH and temperature conditions.
Produces soluble fragments through elimination cleavage.
Provides tunable elimination half-life to control hydrogel degradation and drug release kinetics.
Documented Applications
Hydrogel/drug delivery applications using drug-loaded hydrogels with linker-drugs that release drug and optionally contribute to gel degradation.
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