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

• Published in: Journal of controlled release Vol. 152; no. 1; pp. 76 - 83
• Main Authors: Kievit, Forrest M., Wang, Freddy Y., Fang, Chen, Mok, Hyejung, Wang, Kui, Silber, John R., Ellenbogen, Richard G., Zhang, Miqin
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Kidlington Elsevier B.V 30.05.2011; Elsevier
• Subjects: ABC transporter; ABC transporters; amines; Animals; Anthracycline; Antibiotics; Antibiotics, Antineoplastic - administration & dosage; Biological and medical sciences; Brain Neoplasms - drug therapy; Brain tumors; Cell Line, Tumor; Chemotherapy; Controlled release; dose response; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Doxorubicin - pharmacokinetics; Drug efflux; Drug resistance; Drug Resistance, Multiple; Drug Resistance, Neoplasm; drug therapy; Drugs; Ferric Compounds - administration & dosage; Ferric Compounds - chemistry; General pharmacology; Glioma; Glioma - drug therapy; Glioma cells; humans; Hydrogen-Ion Concentration; Hydrophobicity; iron oxides; Lability; Medical sciences; Metal Nanoparticles - administration & dosage; Metal Nanoparticles - chemistry; Multidrug resistance; multiple drug resistance; nanoparticles; neoplasm cells; neoplasms; Particle Size; pH effects; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyethylene glycol; Polyethylene Glycols - chemistry; Polyethyleneimine - chemistry; Rats; Solubility; Theranostics; Tissue Distribution; Tumors; varietal resistance; viability; ABC; NP; Chemotherapy; NP-DOX; Glioma; Brain tumors; MDR; Drug efflux; DOX; SPION; Theranostics; Antineoplastic agent; Iron oxide; Nanoparticle; Doxorubicin; Isomerases; Multiple resistance; Microparticle; Drug; DNA topoisomerase (ATP-hydrolysing); Intracranial; Nervous system diseases; Pharmaceutical technology; Enzyme; Enzyme inhibitor; Topoisomerase II inhibitor; Malignant tumor; In vitro; Intracranial tumor; Cerebral disorder; Antibiotic; Treatment; Central nervous system disease; Anthracyclins; Cancer
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2011.01.024

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. Doxorubicin (DOX) efflux from multi-drug resistance C6 glioma cells (C6-ADR) is overcome through conjugation to superparamagnetic iron oxide nanoparticles (NP-DOX), and corresponds to improved cell kill. [Display omitted]