Hydrogel drug delivery system with predictable and tunable drug release and degradation rates

TLDR

Many drugs, especially peptides and proteins, suffer from short serum half‑lives, and conjugation to carriers such as PEG is a common strategy to extend their duration of action. The authors aim to develop a biodegradable subcutaneous implant that uses self‑cleaving β‑eliminative linkers to attach drugs to PEG hydrogels, thereby extending drug half‑life beyond the limits of circulating carriers. They employ β‑eliminative linkers that tether drugs to PEG hydrogels and, with a second linker of longer half‑life, control polymer degradation so that drug release precedes complete gel erosion. The system achieves tunable drug release and hydrogel erosion over a wide range, as demonstrated by a PEG hydrogel‑exenatide conjugate capable of once‑monthly dosing, suggesting a generic platform for ultralong half‑life therapeutics.

Abstract

Many drugs and drug candidates are suboptimal because of short duration of action. For example, peptides and proteins often have serum half-lives of only minutes to hours. One solution to this problem involves conjugation to circulating carriers, such as PEG, that retard kidney filtration and hence increase plasma half-life of the attached drug. We recently reported an approach to half-life extension that uses sets of self-cleaving linkers to attach drugs to macromolecular carriers. The linkers undergo β-eliminative cleavage to release the native drug with predictable half-lives ranging from a few hours to over 1 y; however, half-life extension becomes limited by the renal elimination rate of the circulating carrier. An approach to overcoming this constraint is to use noncirculating, biodegradable s.c. implants as drug carriers that are stable throughout the duration of drug release. Here, we use β-eliminative linkers to both tether drugs to and cross-link PEG hydrogels, and demonstrate tunable drug release and hydrogel erosion rates over a very wide range. By using one β-eliminative linker to tether a drug to the hydrogel, and another β-eliminative linker with a longer half-life to control polymer degradation, the system can be coordinated to release the drug before the gel undergoes complete erosion. The practical utility is illustrated by a PEG hydrogel-exenatide conjugate that should allow once-a-month administration, and results indicate that the technology may serve as a generic platform for tunable ultralong half-life extension of potent therapeutics.