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

JOURNAL OF CONTROLLED RELEASE

卷:152

Article

Kievit, Forrest M.¹  Wang, Freddy Y.¹  Fang, Chen¹  Mok, Hyejung¹  Wang, Kui¹  Silber, John R.²  Ellenbogen, Richard G.²  Zhang, Miqin^1,2 

[1] Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA

[2] Univ Washington, Dept Neurol Surg, Seattle, WA 98195 USA

关键词: Brain tumors;    Chemotherapy;    Drug efflux;    Theranostics;    Glioma;   

DOI  :  10.1016/j.jconrel.2011.01.024

来源: Elsevier

【 摘 要 】

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. (C) 2011 Elsevier B.V. All rights reserved.

【 授权许可】

Free