2003 Summer Bioengineering Conference, June 25-29, Sonesta Beach Resort in Key Biscayne, Florida INTRODUCTION Paclitaxel, a naturally occurring diterpenoid originally extracted from the Pacific Yew tree, is one of the best antineoplastic drugs, which has been used against a wide spectrum of cancers, including breast cancer, ovarian cancer, lung cancer, head and neck carcinomas, and acute leukemia. However, the success of its clinical application is limited by its low therapeutic index and low solubility in most pharmaceutical solvents. More effective chemotherapy using paclitaxel is relying on development of its new dosage forms, among which nanoparticles of biodegradable polymers and lipid bilayer vesicles (liposome) seem the most prospective. Currently, the only available dosage form of paclitaxel is Taxol® for intravenous (i.v.) infusion, which is a solution of paclitaxel in an adjuvant called Cremophor EL, which causes serious side effects such as hypersensitivity reactions, nephrotoxicity, neurotoxicity and cardiotoxicity [1-4]. Also, Taxol® infusion is cumbersome for the patients and limits the use of frequent dosing schedule for a prolonged systemic exposure to the drug. Thus, the development of successful paclitaxel delivery system devoid of Cremophor EL is essential for a better clinical administration. Moreover, it would be ideal solution to achieve best therapeutic efficacy and least side effects and to greatly improve the quality of life of the patients if oral paclitaxel could become bioavailable. Nanoparticles of biodegradable polymers could provide such an ideal solution for intravenous or oral delivery of paclitaxel as well as of other anticancer drugs. Bioadhesive nanoparticles with appropriate coating have been shown to increase oral bioavailablity of drugs due to the increased residence time of the nanoparticles within the gastrointestinal (GI) tract and the increased contact time with the intestinal epithelium cells and hence the increased uptake. Moreover, appropriate coating of nanoparticles may provide engineering make- ups to escape from the recognition of P-glycoproteins, which have been found to be responsible for the oral unavailability and the multidrug resistance of paclitaxel. The objective of this study was to develop a new polymeric delivery system of paclitaxel for clinical administration with higher therapeutic efficacy and less side effects, and with further development, to promote oral chemotherapy. This system developed can also be applied to other anti-cancer drugs. EXPERIMENTAL METHODS Nanoparticle Preparation Nanoparticles were prepared by the solvent extraction/ evaporation method. In brief, an oil phase solution of di- chloromethane (DCM) or other organic solvents containing poly (DL- lactide-co-glycolide) (PLGA, 50:50) and paclitaxel was emulsified in an aqueous solution containing PVA or vitamin E TPGS using a microtip probe sonicator. The polymer solution also contained 0.05%(w/v) Coumarin 6 as a fluorescent marker. The resulted emulsion was then stirred to evaporate DCM and particles were collected by centrifugation followed by freeze-drying. Characterization of Nanoparticles Nanoparticle size and size distribution were determined by laser light scattering with particle size analyzer (90 Plus, Brookhaven Inst, Huntsville, NY) at a fixed angle of 90° and at a temperature of 25°C. The size distribution was given by the polydispersity index. The morphology of nanoparticles was investigated by scanning electron microscopy (SEM) (Jeol JSM 5600LV). The zeta potential as an indicator of surface charge and particle stability in dispersion was determined by a zeta potential analyzer (Zeta Plus, Brookhaven Instruments, Huntsville, NY). The encapsulation efficiency of paclitaxel in particles was analyzed by HPLC system. In Vitro Release Studies The amount of paclitaxel released from particles into phosphate buffered saline (PBS, pH 7.4), under in vitro conditions, was measured by high performance liquid chromatography (HPLC). In Vitro Cytotoxicity Human colon adenocarcinoma cell lines, HT-29 cells and Caco-2 cells, were used for cytotoxicity study. The cells were incubated with NANOPARTICLES OF BIODEGRADABLE POLYMERS FOR CANCER CHEMOTHARAPY Khin Yin Win (1), Li Mu (2), Chi-Hwa Wang (1), Si-Shen Feng (1, 2) (1) Chemical and Environmental Engineering Department National University of Singapore Singapore (2) Bioengineering Division National University of Singapore Singapore 117576 (2) Bioengineering Division National University of Singapore Singapore Starting page #: 0917