title: Novel self-assembling PEG-p-(CL-co-TMC) polymeric micelles as safe and effective delivery system for paclitaxel.
abstract: Paclitaxel (PTX) is an effective anti-cancer drug currently used to treat a wide variety of cancers. Unfortunately, nonaqueous vehicle containing Cremophor EL is associated with serious clinical side effects. This work aimed to evaluate the ability of polymeric micelles to (i) solubilize PTX without Cremophor EL and to be used as a (ii) safe and (iii) effective delivery system for PTX. Hence, we developed novel self-assembling poly(ethyleneglycol)(750)-block-poly(epsilon-caprolactone-co-trimethylenecarbonate) (PEG-p-(CL-co-TMC)) polymeric micelles which form micelles spontaneously in aqueous solution. The solubility of PTX increased up to three orders of magnitude. The PTX-loaded micelles showed a slow release of PTX with no burst effect. The HeLa cells viability assessed by the MTT test was lower for PTX-loaded micelles than for Taxol (IC(50) 10.6 vs. 17.6 microg/ml). When solubilized in micelles, PTX induced apoptosis comparable with Taxol. The maximum tolerated doses (MTD) of PTX-loaded micelles and Taxol in mice were 80 mg/kg and 13.5mg/kg, respectively, after intraperitoneal administration; and 45 mg/kg and 13.5mg/kg, respectively, after intravenous administration. Similar anti-tumor efficacy of PTX-loaded micelles and Taxol was observed at the dose of 13.5mg/kg on TLT-tumor-bearing mice, while the body weight loss was only observed in Taxol group. However, as higher dose was tolerated (80 mg/kg - IP), a higher growth delay was induced with PTX-loaded micelles. These results demonstrated that PTX-loaded self-assembling micelles present a similar anti-tumor efficacy as Taxol, but significantly reduced the toxicity allowing the increase in the dose for better therapeutic response.
authors: Université Catholique de Louvain, Unité de Pharmacie Galénique, Brussels B-1200, Belgium.
authors: Fabienne
authors: F
authors: Danhier
authors: Nicolas
authors: N
authors: Magotteaux
authors: Bernard
authors: B
authors: Ucakar
authors: Nathalie
authors: N
authors: Lecouturier
authors: Marcus
authors: M
authors: Brewster
authors: Véronique
authors: V
authors: Préat
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004339:Drug Compounding; D006367:HeLa Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011091:Polyesters / Q000737:chemistry* / Q000633:toxicity; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000633:toxicity; D012995:Solubility; D014018:Tissue Distribution
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; C513506:monomethyletherpoly(oxyethylene glycol(750))-poly(caprolactone-co-trimethylene carbonate); D011092:Polyethylene Glycols; D017239:Paclitaxel