Self-assembling methoxypoly(ethylene glycol)-b-poly(carbonate-co-L-lactide) block copolymers for drug delivery

Bicalutamide is the most widely used non-steroidal antiandrogen for treating early stage prostate cancer, but suffers variable oral absorption due to its limited aqueous solubility. Thus, our objective was to synthesize novel biodegradable copolymers for the systemic micellar delivery of bicalutamide. Flory-Huggins interaction parameter (chi(FH)) was used to assess compatibility between bicalutamide and poly(L-lactide) or poly(carbonate-co-lactide) polymer pairs. Polyethylene glycol-b-poly(carbonate-co-lactide) [PEG-b-P(CB-co-LA)] copolymers were synthesized and characterized by NMR and gel permeation chromatography. These micelles had average diameter of 100 nm and had a smooth surface and distinct spherical shape. Drug loading studies revealed that adding the carbonate monomer could increase bicalutamide loading. Among the series, drug loading of micelles formulated with PEG-b-P(CB-co-LA) copolymer containing 20 mol% carbonate was about four-fold higher than PEG-b-PLLA and aqueous solubility of bicalutamide increased from 5 to 4000 mu g/mL. CIVIC values for PEG-b-P(CB-co-LA) copolymers was up to 10-fold lower than those of PEG-b-PLLA. In vitro release experiments showed PEG-b-P(CB-co-LA) copolymers to be more efficient in sustaining the release of bicalutamide compared to PEG-b-PLLA. Bicalutamide-loaded PEG-b-P(CB-co-LA) micelles showed significant inhibition of LNCaP cell growth in a dose-dependent manner which was similar to the methanol solution of free drug. (C) 2009 Elsevier Ltd. All rights reserved.