title: In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy.
abstract: Although the current clinical formulation of paclitaxel (Taxol) 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)-containing biodegradable polymeric micellar system (Genexol-PM) in comparison to Taxol. Genexol-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, Samyang Genex Co., Seoul, Korea). In a human cancer cell line model, Genexol-PM and Taxol 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-PM and Taxol in nude mice was determined to be 60 and 20 mg/kg, respectively. The median lethal dose (LD(50)) in Sprague--Dawley rats was 205.4 mg/kg (male) and 221.6 mg/kg (female) for Genexol-PM, while 8.3 mg/kg (male) and 8.8 mg/kg (female) for Taxol. After intravenous administration of Genexol-PM in murine B16 melanoma-induced female SPF C57BL/6 mice at a dose of 50 mg/kg, the area under the plasma concentration-time curve (AUC) was similar to Taxol((R)) at a dose of 20 mg/kg, but biodistribution of paclitaxel after administration of Genexol-PM showed 2 to 3-fold higher levels in tissues including liver, spleen, kidneys, lungs, heart and tumor as compared to Taxol. The in vivo antitumor efficacy of Genexol-PM as measured by reduction in tumor volume of SKOV-3 human ovarian cancer implanted in nude (nu/nu) athymic mice and MX-1 human breast cancer implanted in Tac:Cr:(NCr)-nu athymic mice was significantly greater than that of Taxol. The results of cytotoxicity, MTD, LD(50) and antitumor efficacy suggest that Genexol-PM may have a great advantage over present-day chemotherapy with Taxol.
authors.affiliation: Particulate Drug Delivery, Samyang Pharmaceuticals R&D, Taejeon 305-348, South Korea.
authors.forename: S C
authors.initials: SC
authors.lastname: Kim
authors.forename: D W
authors.initials: DW
authors.lastname: Kim
authors.forename: Y H
authors.initials: YH
authors.lastname: Shim
authors.forename: J S
authors.initials: JS
authors.lastname: Bang
authors.forename: H S
authors.initials: HS
authors.lastname: Oh
authors.forename: S
authors.initials: S
authors.lastname: Wan Kim
authors.forename: M H
authors.initials: MH
authors.lastname: Seo
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D004337:Drug Carriers; D004339:Drug Compounding; D005260:Female; D006801:Humans; D019344:Lactic Acid; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D011092:Polyethylene Glycols; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D017239:Paclitaxel