Development of copolymers of poly(D,L-lactide) and methoxypolyethylene glycol as micellar carriers of paclitaxel

Diblock copolymers containing one block of methoxypolyethylene glycol (MePEG) and one block of either poly(D,L-lactide) (PDLLA), copolymers of poly(D,L-lactide-co-caprolactone) (PDLLACL) or poly(glycolide-co-caprolactone) (PGACL) were synthesized by a ring opening bulk polymerization in the presence of stannous octoate. The copolymer molecular weight and composition were controlled by changing the monomer weight ratios. The copolymers dissolved in aqueous media to form polymeric micelles with a hydrophobic polyester core and a water soluble MePEG shell. Micellar solutions of paclitaxel in the PGACL-MePEG copolymers showed poor physical stability and were the least able to maintain paclitaxel in solution. Micellar paclitaxel solutions with the greatest physical stability were obtained using PDLLA-MePEG copolymers, probably due to the decreased fluidity of the micellar core environment of PDLLA-MePEG compared to PDLLACL-MePEG copolymer micelles. The PDLLA-MePEG; diblock copolymer was considered to be the optimal copolymer for the solubilization of paclitaxel. The results of a range of in vitro and in vivo biocompatibility / toxicology tests in animals showed the PDLLA-MePEG micelles to be biocompatible and non-toxic. Biodistribution studies using radiolabelled paclitaxel loaded PDLLA-MePEG micelles in rats showed that paclitaxel rapidly dissociated from the micellar components in the blood and that greater than 95% of the administered micellar diblock copolymer dose was eliminated within 15 h. There was also evidence to suggest that the diblock copolymer was cleaved into its two polymer components in the blood. (C) 1999 Elsevier Science B.V. All rights reserved.