Enhancement of sustained and controlled protein release using polyelectrolyte complex-loaded injectable and thermosensitive hydrogel

Abstract

In this study, we aimed at developing controlled and sustained protein release formulations using a combination system of polyelectrolyte complexes (PECs) and thermosensitive poly(organophosphazene) hydrogels as an injectable gel-depot system. In the protein-loaded hydrogel system, the loaded proteins were released rapidly through diffusion regardless of viscosities and mass loss of the gels because of the small hydrodynamic size of the proteins. To suppress protein diffusion and increase protein size, we induced PECs between negatively charged proteins (BSA, gelatin-type B 75 bloom, α-amylase, and hGH) and polycations (protamine, polyethylenimine, poly-l-lysine, and poly-l-arginine (PLA)) via an electrostatic interaction and loaded the PECs into the hydrogels. The formations of PECs were affected by molecular weight, pI (or pK(a)), and types of amine group of the used polycations. Unlike other polycations, PLA formed a large uniform complex with BSA, and the PLA/protein complex-loaded hydrogel showed the slowest protein release behavior. In the PEC-loaded hydrogel system, the protein release could also be controlled by viscosities of the gel and weight ratios of polycations and proteins, although the activities of the proteins were decreased in proportion to the PLA amounts. These results suggest that the PEC-loaded injectable and thermosensitive poly(organophosphazene) hydrogel has considerable potential for creating a sustained protein delivery system by using the PEC via electrostatic interaction.