Biomaterials 24 (2003) 5037–5044 Preparation and characterization of poly(lactic acid)–poly(ethylene glycol)–poly(lactic acid) (PLA–PEG–PLA) microspheres for controlled release of paclitaxel Gang Ruan a , Si-Shen Feng a,b, * a Department of Chemical and Environmental Engineering, Faculty of Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore b Division of Bioengineering, Faculty of Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore Received 19 December 2002; accepted 30 May 2003 Abstract Microspheres of a new kind of copolymer, poly(lactic acid)–poly(ethylene glycol)–poly(lactic acid) (PLA–PEG–PLA), are proposed in the present work for clinical administration of an antineoplastic drug paclitaxel with hypothesis that incorporation of a hydrophilic PEG segment within the hydrophobic PLA might facilitate the paclitaxel release. Paclitaxel-loaded PLA–PEG–PLA microspheres of various compositions were prepared by the solvent extraction/evaporation method. Characterization of the microspheres was then followed to examine the particle size and size distribution, the drug encapsulation efficiency, the colloidal stability, the surface chemistry, the surface and internal morphology, the drug physical state and its in vitro release behavior. The effects of polymer types, solvents and drug loading were investigated. It was found that in the microspheres the PEG segment was homogeneously distributed and caused porosity. SignificantlyfasterreleasefromPLA–PEG–PLAmicrospheresresultedincomparisonwiththePLGAcounterpart.Incorporation of water-soluble solvent acetone in the organic solvent phase further increased the porosity of the PLA–PEG–PLA microspheres and facilitated the drug release. A total of 49.6% sustained release of paclitaxel within 1 month was achieved. Potentially, the presence of PEG on the surface of PLA–PEG–PLA microspheres could improve their biocompatibility. PLA–PEG–PLA microspheres could thus be promising for the clinical administration of highly hydrophobic antineoplastic drugs such as paclitaxel. r 2003 Elsevier Ltd. All rights reserved. Keywords: Anticancer drugs; Biodegradable polymers; Drug delivery; Surface modification; Taxol s 1. Introduction Paclitaxel is believed to be one of the best antineo- plastic drugs discovered from nature (see Fig. 1(A) for its molecular structure). No other chemotherapeutic agent except penicillin has generated so much interest [1]. It has been widely applied to treat various cancers, especially breast cancer and ovarian cancer [2,3]. Its unique action mechanism involves binding to micro- tubules, forming dysfunctional microtubules and thus leading to cell death [4]. However, the clinical applica- tion of paclitaxel is limited by its limited natural source [5] andthedifficultyinclinicaladministration.Thelatter is the focus of this paper. Due to the low aqueous solubilityofthedrug,anadjuvantCremophorELhasto be used. Paclitaxel in Cremophor EL is called Taxol s which is the only available clinical dosage form of paclitaxel. Cremorphor EL has been reported to be responsible for various serious side effects such as hypersensitivity reactions, nephrotoxicity, neurotoxicity and cardiotoxicity [6].Inrecentyears,variouscontrolled deliveryforms,suchaspolymericmicro/nanospheres [7], liposomes [8], micelles [9], parenteral emulsion [10], ARTICLE IN PRESS Abbreviations: DCM, Dichloromethane; EE, Encapsulation efficiency; PBS, Phosphate-buffered saline; PEG, Poly(ethylene glycol); PLA, Poly(lactic acid); PLA–PEG, Poly(lactic acid)–Poly(ethylene glycol); PLA–PEG–PLA, Poly(lactic acid)–Poly(ethylene glycol)–Poly(lactic acid); PLGA, Poly(lactide-co-glycolide); PVA, Poly(vinyl alcohol); SEM, Scanning electron microscope. *Corresponding author. Department of Chemical and Environ- mental Engineering, Faculty of Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore. Tel.: +65-6874-3835; fax: +65-6779-1936. E-mail address: chefss@nus.edu.sg (S.-S. Feng). 0142-9612/03/$-see front matter r 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0142-9612(03)00419-8