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Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro

Author:
Kievit, Forrest M., Wang, Freddy Y., Fang, Chen, Mok, Hyejung, Wang, Kui, Silber, John R., Ellenbogen, Richard G., Zhang, Miqin
Source:
Journal of controlled release 2011 v.152 no.1 pp. 76-83
ISSN:
0168-3659
Subject:
ABC transporters, antibiotics, dose response, doxorubicin, drug therapy, humans, hydrophobicity, iron oxides, multiple drug resistance, nanoparticles, neoplasm cells, neoplasms, pH, polyethylene glycol, rats, varietal resistance, viability
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.
Agid:
1009877