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: Forrest M Kievit, Freddy Y Wang, Chen Fang, Hyejung Mok, Kui Wang, John R Silber, Richard G Ellenbogen, Miqin Zhang
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 152 Issue 1 Pg. 76-83 (May 30 2011) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 21277920 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Ferric Compounds
• ferric oxide
• Polyethylene Glycols
• Doxorubicin
• Polyethyleneimine

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage)
• Brain Neoplasms (drug therapy)
• Cell Line, Tumor
• Doxorubicin (administration & dosage, chemistry, pharmacokinetics)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Ferric Compounds (administration & dosage, chemistry)
• Glioma (drug therapy)
• Hydrogen-Ion Concentration
• Metal Nanoparticles (administration & dosage, chemistry)
• Particle Size
• Polyethylene Glycols (chemistry)
• Polyethyleneimine (chemistry)
• Rats
• Solubility
• Tissue Distribution