Roles of Interstitial Albumin in the Subcutaneous Delivery of Therapeutic Peptides

Abstract

Subcutaneous administration of biotherapeutics is increasingly favoured for better safety profile, improved stability, and patient compliance compared with intravenous administration. Despite these advantages, the roles of extracellular matrix (ECM) components and interstitial proteins, particularly albumin, in the mechanisms governing therapeutic pharmacokinetics and bioavailability remain poorly understood. We present a versatile and customizable hydrogel platform resembling native ECM in composition, charge density, and microstructure, enabling systematic investigation of transport mechanisms in the subcutaneous space. Using this platform, we studied peptides with different net charges and albumin affinities. Based on results from confocal microscopy combined with measurements of diffusivities by means of FRAP, we propose a role for albumin beyond that of transport vehicle for drugs. We show that reversible peptide-albumin binding can both increase bioavailability by removing peptides bound to the ECM biopolymers and modulate peptide diffusivity and distribution, as albumin was found to have an affinity for matrix glycosaminoglycans. For cationic peptides, albumin had a major influence on diffusivity and distribution in the matrix, with more pronounced effects over time in vitro. These findings, complemented by exploratory in vivo observations in a limited cohort, highlight realistic ECM structure and albumin inclusion as key considerations for predictive in vitro subcutaneous models.