Nanocarriers enhance doxorubicin uptake in drug-resistant ovarian cancer cells

Hans C. Arora, Mark P. Jensen, Ye Yuan, Aiguo Wu, Stefan Vogt, Tatjana Paunesku*, Gayle E. Woloschak

*Corresponding author for this work

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Resistance to anthracyclines and other chemotherapeutics due to P-glycoprotein (pgp)-mediated export is a frequent problem in cancer treatment. Here, we report that iron oxide-titanium dioxide core-shell nanocomposites can serve as efficient carriers for doxorubicin to overcome this common mechanism of drug resistance in cancer cells. Doxorubicin nanocarriers (DNC) increased effective drug uptake in drug-resistant ovarian cells. Mechanistically, doxorubicin bound to the TiO 2 surface by a labile bond that was severed upon acidification within cell endosomes. Upon its release, doxorubicin traversed the intracellular milieu and entered the cell nucleus by a route that evaded pgp-mediated drug export. Confocal and X-ray fluorescence microscopy and flow cytometry were used to show the ability of DNCs to modulate transferrin uptake and distribution in cells. Increased transferrin uptake occurred through clathrin-mediated endocytosis, indicating that nanocomposites and DNCs may both interfere with removal of transferrin from cells. Together, our findings show that DNCs not only provide an alternative route of delivery of doxorubicin to pgp-overexpressing cancer cells but also may boost the uptake of transferrin-tagged therapeutic agents.

Original languageEnglish (US)
Pages (from-to)769-778
Number of pages10
JournalCancer Research
Volume72
Issue number3
DOIs
StatePublished - Feb 1 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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