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

Forrest M. Kievit, Freddy Y. Wang, Chen Fang, Hyejung Mok, Kui Wang, John R. Silber, Richard G. Ellenbogen, Miqin Zhang

Research output: Contribution to journalArticlepeer-review

224 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)76-83
Number of pages8
JournalJournal of Controlled Release
Volume152
Issue number1
DOIs
StatePublished - May 30 2011
Externally publishedYes

Keywords

  • Brain tumors
  • Chemotherapy
  • Drug efflux
  • Glioma
  • Theranostics

ASJC Scopus subject areas

  • Pharmaceutical Science

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