Parenteral protein delivery systems using biodegradable polyesters of ABA block structure, containing hydrophobic poly(lactide-co-glycolide) A blocks and hydrophilic poly(ethylene oxide) B blocks

Abstract

Parenteral delivery systems for proteins, based on biodegradable polyesters present significant problems with respect to modulation of release properties. Frequently proteins are more sensitive to environmental factors than peptides, leading to a loss in biological activity. We have investigated the release properties of ABA block copolymers, which contain hydrophilic poly(ethylene oxide) B blocks. Microspheres prepared from these biodegradable polyesters show striking differences in their release behaviour for the macromolecular model compounds, such as FITC-dextrans (molecular mass 4-500 kDa), when compared to poly(DL-lactide-co-glycolide). While the release from PLG is biphasic and almost independent of the molecular mass of FITC-dextran, ABA polymers show a continuous and molecular mass dependent release, reminiscent of cross-linked hydrogels. Several model proteins were studied, such as cytochrome c (13 kDa), ovalbumin (43 kDa), bovine serum albumin (67 kDa) and tetanus toxoid (150 kDa) confirming this release pattern under in- vitro conditions. We attribute this change in the release behaviour to a combined mechanism of swelling and erosion, leading to a hydrogel-like structure, also observed by scanning electron microscopy. Preliminary data from studies in mice demonstrate that tetanus toxoid is also released under in vivo conditions, leading to a prolonged antibody response. Effects of ABA block copolymer composition and molecular mass on the release, degradation and compatibility of proteins are under investigation. ABA block copolymers may offer advantages over PLG for parenteral protein delivery systems.