Anti-tumor efficacy and biodistribution of intravenous polymeric micellar paclitaxel.
The purpose of this study was to evaluate the diblock copolymer poly(DL-lactide)-block-methoxy polyethylene glycol as an i.v. delivery vehicle for paclitaxel. Nude mice were implanted s.c. with fragments of MV-522 lung carcinomas and treated with paclitaxel on a daily x 5 schedule when tumors were approximately 5 x 5 mm in size. Cremophor paclitaxel or polymeric micellar paclitaxel were given i.p. or i.v. at the maximum tolerated dose (Cremophor paclitaxel MTD: 20 mg/kg/day i.v. or i.p.; micellar paclitaxel MTD: 25 mg/kg/day i.v. or 100 mg/kg/day i.p.). The tumors were measured using callipers during the experiment and accurately weighted at the end. Two biodistribution studies were carried out. In one study, the nude mice were given micellar paclitaxel at a dose of 25 mg/kg i.v. or 100 mg/kg i.p. in another study, BDF-1 mice were given either micellar paclitaxel or Cremophor paclitaxel at a dose of 20 mg/kg i.v. The mice were sacrificed after a given time and the organs were harvested. Paclitaxel in the organs was extracted with acetonitrile and analyzed using HPLC. Tumor growth inhibitions of 98.5 and 98.7% were obtained from i.v. administered micellar paclitaxel and Cremophor paclitaxel at their MTDs, respectively. Micellar paclitaxel was more efficacious i.p. (98.7% tumor growth inhibition) than Cremophor paclitaxel i.p. (83.0% tumor growth inhibition) at their MTDs. The highest concentrations of paclitaxel were found in the liver after administration of paclitaxel formulations. Paclitaxel was also found in spleen, kidney, lung and blood, in order of decreasing concentration. The preliminary results indicate that polymeric micellar paclitaxel could be a clinically useful chemotherapeutic formulation.
Zhang
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X
Angiotech Pharmaceuticals, Inc., Vancouver, BC, Canada.
Burt
H M
HM
Mangold
G
G
Dexter
D
D
Von Hoff
D
D
Mayer
L
L
Hunter
W L
WL
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004337:Drug Carriers; D006207:Half-Life; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011091:Polyesters; D011092:Polyethylene Glycols; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D011092:Polyethylene Glycols; C083464:poly(ethyleneglycol-lactide); D017239:Paclitaxel