Yoshinori Kakizawa

pH-responsive release of proteins from biocompatible and biodegradable reverse polymer micelles

A reverse polymer micelle with a diameter of 100nm was prepared for a protein carrier releasing payloads in a pH-dependent manner. The reverse polymer micelle was made from an amphiphilic diblock copolymer of biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) and biocompatible poly(ethylene glycol) (PEG). PLGA having a terminal carboxyl group was additionally embedded in the micelles PLGA layer via hydrophobic interaction. The micelles encapsulating bovine serum albumin and streptavidin released the proteins under neutral and basic conditions, whereas the proteins remained in the interior at acidic pH. Using erythropoietin as a protein drug, it was also exemplified that the released protein retained its cell proliferation activity even after rigorous formulation processes, including water-in-oil emulsion. The present reverse polymer micelle could potentially find application as an oral protein drug delivery carrier.

Controlled release of protein drugs from newly developed amphiphilic polymer-based microparticles composed of nanoparticles

A novel formulation of biodegradable microparticles was developed for the sustained release of peptide and protein drugs. The microparticles were formed by the aggregation of protein nanoparticles through water-in-oil (W/O) emulsion-lyophilization and subsequent solid-in-oil-in-water (S/O/W) emulsion-solvent evaporation. Amphiphilic copolymers were used as an emulsifier in the W/O emulsion and matrix of the microparticles. Among the various copolymers investigated, poly(lactide-co-glycolide)-grafted dextran (Dex-g-PLGA) was chosen as the best candidate on the basis of the encapsulation efficiency and in vitro release profile, the near zero-order release without a significant initial burst, of human growth hormone (hGH). The release rate of hGH was controllable by changing the composition of Dex-g-PLGA. The in vivo release studies using normal mice revealed that the plasma concentration of hGH was maintained for 1week without a significant initial burst. The enhancement of biological activity of hGH by sustained release was confirmed by measuring the IGF-1 concentration and body weight of hypophysectomized mice. These results suggest the high potential of the newly developed microparticles for the sustained release of biopharmaceuticals.