In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy

Abstract

Although the current clinical formulation of paclitaxel (Taxol(R)) has a promising clinical activity against a wide variety of tumors, it has significant toxic side effects, some of which are associated with its formulation in a 1:1 (v/v) mixture of Cremophor EL and dehydrated alcohol. One of the problems associated with the intravenous administration of paclitaxel is its low solubility in water. Our study was designed to evaluate the pharmacokinetics, tissue distribution, toxicity and efficacy of a paclitaxel (Genexol(R))-containing biodegradable polymeric micellar system (Genexol(R)-PM) in comparison to Taxol(R). Genexol(R)-PM was newly developed by using a low molecular weight, nontoxic and biodegradable amphiphilic diblock copolymer, monomethoxy poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA) and paclitaxel (Genexol(R), Samyang Genex Co., Seoul, Korea). In a human cancer cell line model, Genexol(R)-PM and Taxol(R) showed comparable in vitro cytotoxicity against human ovarian cancer cell line OVCAR-3 and human breast cancer cell line MCF7. The maximum tolerated dose (MTD) of Genexol(R)-PM and Taxol(R) in nude mice was determined to be 60 and 20 mg/kg, respectively. The median lethal dose (LD50) in Sprague-Dawley rats was 205.4 mg/kg (male) and 221.6 mg/kg (female) for Genexol(R)-PM, while 8.3 mg/kg