title: Mixed molecular weight copolymer nanoparticles for the treatment of drug-resistant tumors: formulation development and cytotoxicity.
abstract: Nanoparticles composed of both high- and low-molecular-weight methoxy poly(ethylene glycol)-block-poly(caprolactone) (MePEG-b-PCL) diblock copolymers (termed "mixed molecular weight nanoparticles") were investigated for the encapsulation and delivery of the taxane drugs paclitaxel (PTX) and docetaxel (DTX). These nanoparticles were prepared using nanoprecipitation and emulsion methods. These 80 nm nanoparticles were prepared with high yields, efficiently solubilized PTX and DTX up to 500 and 1300 μg/mL, respectively, and demonstrated controlled release of these drugs over 14 days. The taxane-sensitive (MDCKII) and taxane-resistant [P-glycoprotein (P-gp) overexpressing] MDCKII-MDR cell lines were used to establish the cytotoxic profiles of these nanoparticles. Because of the coencapsulation of the previously demonstrated P-gp inhibitor, a low-molecular-weight MePEG-b-PCL copolymer (MePEG17 -b-PCL5 ), these drug-loaded mixed molecular weight nanoparticles dramatically reduced the viability of P-gp overexpressing MDCKII-MDR cells and restored sensitivity to taxane drugs in these cells.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: leonwan@mail.ubc.ca.
authors.forename: Chung Ping Leon
authors.initials: CPL
authors.lastname: Wan
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Letchford
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Donna
authors.initials: D
authors.lastname: Leung
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: John K
authors.initials: JK
authors.lastname: Jackson
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Burt
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000008:administration & dosage / Q000737:chemistry; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D000077143:Docetaxel; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008823:Micelles; D008970:Molecular Weight; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry; D010316:Particle Size; D011091:Polyesters / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry*; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001952:Bridged-Ring Compounds; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D011108:Polymers; D043823:Taxoids; C439611:methoxy poly(ethylene glycol-co-epsilon-caprolactone); D000077143:Docetaxel; C080625:taxane; D011092:Polyethylene Glycols; D017239:Paclitaxel
keywords: Controlled release/delivery; P-glycoprotein; cancer; efflux pumps; multidrug resistance