Engineering Extended Release Profiles for Biologic Formulations via Chemical Cross-Linking of Poloxamer 407 Hydrogels.

Abstract

Hydrogels, networks of hydrophilic polymers known for their water retention capacity, biodegradability, and biocompatibility, are ideal for the sustained and extended delivery of biologics. Because in situ hydrogels can form at the administration site in response to external stimuli, they can provide noninvasive and localized delivery of biotherapeutics. In particular, poloxamer 407 (P407), an "A-B-A" triblock copolymer, composed of hydrophilic poly-(ethylene oxide) (block A) and hydrophobic poly-(propylene oxide) (block B), exhibits reversible thermal property: liquid at room temperature and gelling at elevated temperatures. This characteristic, combined with its low toxicity and excellent chemical compatibility, makes P407 an attractive polymer for drug delivery applications. However, its low mechanical strength and weak gel stability have limited its broader use in therapeutic applications. To address this challenge, chemically cross-linked P407 hydrogels were developed using acrylate-modified P407 and thiol-terminated eight-arm polyethylene glycol with two different molecular weights (MWs) via Michael-type addition. Chemical cross-linking enhanced the mechanical strength of P407 hydrogels, enabling extended in vitro release of bovine serum albumin (BSA), human plasma immunoglobulin G antibody (IgG), and adalimumab for up to 70 days with tunable release kinetics profile. Biophysical and functional characterization via circular dichroism, size exclusion chromatography, capillary electrophoresis-sodium dodecyl sulfate, and enzyme-linked immunosorbent assay indicated that the hydrogels did not adversely affect the structural conformation, stability, and in vitro potency of the encapsulated biologics. This study highlights improved P407 hydrogel stability and tunable release profiles by incorporating acrylate reactive cross-linkers with two different MWs, providing insights for the application of sustained and controlled release of biologic.