Aliphatic copolyesters consisting of diester, diol, and glycolate repeat units were enzymatically synthesized for the first time via lipase-catalyzed polycondensation reactions. Copolymerization of ethyl glycolate (EGA) with diethyl sebacate (DES) and 1,4-butanediol (BD) in the presence of Candida antarctica lipase B (CALB) resulted in the formation of poly(butylene-co-sebacate-co-glycolate) (PBSG) copolyesters with molecular weight (M-w) up to 28000 and typical polydispersity between 1.2 and 1.8. The synthesized copolymers contained 10-40 mol % glycolate (GA) units depending on the monomer feed ratio employed. DSC analyses show that the copolyesters with 12-38% GA content are semicrystalline materials that melt between 43 and 59 degrees C. Free standing nanoparticles with an average size ranging from 250 to 400 nm were successfully fabricated from these PBSG copolymers using a single emulsification solvent evaporation process. PBSG copolyesters were found to be hydrolytically degradable and doxorubicin- (DOX-) encapsulated PBSG nanoparticles exhibited slow and sustained release of the drug in PBS solution at 37 degrees C over an extended period of time (60 days). Cellular uptake studies indicate that the drug-loaded PBSG particles are absorbed by a large percentage (up to 95%) of Hela cancer cells within 4 h incubation time. In vitro cytotoxicity investigations reveal that at a same DOX concentration (0.125-2.0 mu M), DOX-encapsulated PBSG nanoparticles possess either higher or comparable cytotoxicity toward He la cells than the free drug DOX center dot HCl. These results suggest that the PBSG nanoparticles are promising carriers for controlled release delivery of DOX to treat cancers.