title: The combined use of paclitaxel-loaded nanoparticles with a low-molecular-weight copolymer inhibitor of P-glycoprotein to overcome drug resistance.
abstract: Two types of nanoparticles were prepared using the diblock copolymer methoxy poly(ethylene glycol)-block-poly(caprolactone) (MePEG-b-PCL), with either a short PCL block length, which forms micelles, or with a longer PCL block length, which forms kinetically "frozen core" structures termed nanospheres. Paclitaxel (PTX)-loaded micelles and nanospheres were evaluated for their cytotoxicity, cellular polymer uptake, and drug accumulation in drug-sensitive (Madin-Darby Canine Kidney [MDCK]II) and multidrug-resistant (MDR) P-glycoprotein (P-gp)-overexpressing (MDCKII-MDR1) cell lines. Both types of PTX-loaded nanoparticles were equally effective at inhibiting proliferation of MDCKII cells, but PTX-loaded micelles were more cytotoxic than nanospheres in MDCKII-MDR1 cells. The intracellular accumulation of both PTX and the diblock copolymers were similar for both nanoparticles, suggesting that the difference in cytotoxicity might be due to the different drug-release profiles. Furthermore, the cytotoxicity of these PTX-loaded nanoparticles was enhanced when these systems were subsequently or concurrently combined with a low-molecular-weight MePEG-b-PCL diblock copolymer, which we have previously demonstrated to be an effective P-gp inhibitor. These results suggest that the dual functionality of MePEG-b-PCL might be useful in delivering drug intracellularly and in modulating P-gp in order to optimize the cytotoxicity of PTX in multidrug-resistant cells.
authors: University of British Columbia, Vancouver, BC, Canada.
authors: Chung Ping Leon
authors: CP
authors: Wan
authors: Kevin
authors: K
authors: Letchford
authors: John K
authors: JK
authors: Jackson
authors: Helen M
authors: HM
authors: Burt
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D042541:Intracellular Space / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008823:Micelles; D018613:Microscopy, Confocal; D008970:Molecular Weight; D054118:Nanospheres / Q000008:administration & dosage* / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011091:Polyesters / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; C439611:methoxy poly(ethylene glycol-co-epsilon-caprolactone); D011092:Polyethylene Glycols; D017239:Paclitaxel
keywords: P-glycoprotein; micelles; multidrug resistance; nanoparticles; nanospheres; paclitaxel
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