title: Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro.
abstract: Multidrug resistance (MDR) is characterized by the overexpression of ATP-binding cassette (ABC) transporters that actively pump a broad class of hydrophobic chemotherapeutic drugs out of cancer cells. MDR is a major mechanism of treatment resistance in a variety of human tumors, and clinically applicable strategies to circumvent MDR remain to be characterized. Here we describe the fabrication and characterization of a drug-loaded iron oxide nanoparticle designed to circumvent MDR. Doxorubicin (DOX), an anthracycline antibiotic commonly used in cancer chemotherapy and substrate for ABC-mediated drug efflux, was covalently bound to polyethylenimine via a pH sensitive hydrazone linkage and conjugated to an iron oxide nanoparticle coated with amine terminated polyethylene glycol. Drug loading, physiochemical properties and pH lability of the DOX-hydrazone linkage were evaluated in vitro. Nanoparticle uptake, retention, and dose-dependent effects on viability were compared in wild-type and DOX-resistant ABC transporter over-expressing rat glioma C6 cells. We found that DOX release from nanoparticles was greatest at acidic pH, indicative of cleavage of the hydrazone linkage. DOX-conjugated nanoparticles were readily taken up by wild-type and drug-resistant cells. In contrast to free drug, DOX-conjugated nanoparticles persisted in drug-resistant cells, indicating that they were not subject to drug efflux. Greater retention of DOX-conjugated nanoparticles was accompanied by reduction of viability relative to cells treated with free drug. Our results suggest that DOX-conjugated nanoparticles could improve the efficacy of chemotherapy by circumventing MDR.
authors.affiliation: Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA.
authors.forename: Forrest M
authors.initials: FM
authors.lastname: Kievit
authors.forename: Freddy Y
authors.initials: FY
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Fang
authors.forename: Hyejung
authors.initials: H
authors.lastname: Mok
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
authors.forename: John R
authors.initials: JR
authors.lastname: Silber
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ellenbogen
authors.forename: Miqin
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005290:Ferric Compounds / Q000008:administration & dosage* / Q000737:chemistry; D005910:Glioma / Q000188:drug therapy*; D006863:Hydrogen-Ion Concentration; D053768:Metal Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D051381:Rats; D012995:Solubility; D014018:Tissue Distribution
chemical_list: D000903:Antibiotics, Antineoplastic; D005290:Ferric Compounds; C000499:ferric oxide; D011092:Polyethylene Glycols; D004317:Doxorubicin; D011094:Polyethyleneimine