title: Nanocarriers enhance Doxorubicin uptake in drug-resistant ovarian cancer cells.
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.
authors.affiliation: Department of Radiation Oncology and Radiology, Northwestern University Feinberg School of Medicine, Chicago, USA.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Arora
authors.forename: Mark P
authors.initials: MP
authors.lastname: Jensen
authors.forename: Ye
authors.initials: Y
authors.lastname: Yuan
authors.forename: Aiguo
authors.initials: A
authors.lastname: Wu
authors.forename: Stefan
authors.initials: S
authors.lastname: Vogt
authors.forename: Tatjana
authors.initials: T
authors.lastname: Paunesku
authors.forename: Gayle E
authors.initials: GE
authors.lastname: Woloschak
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D002232:Carbocyanines / Q000737:chemistry; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm; D011992:Endosomes / Q000378:metabolism; D005260:Female; D052203:Ferrosoferric Oxide / Q000737:chemistry; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence / Q000379:methods; D053761:Nanocomposites / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D014025:Titanium / Q000737:chemistry; D014168:Transferrin / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C569686:Alexa Fluor 647; D000903:Antibiotics, Antineoplastic; D002232:Carbocyanines; D004337:Drug Carriers; D005456:Fluorescent Dyes; D014168:Transferrin; C009495:titanium dioxide; D004317:Doxorubicin; D014025:Titanium; D052203:Ferrosoferric Oxide