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

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 DOXresistant 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. DOXconjugated 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.

Superparamagnetic iron oxide nanoparticles: magnetic nanoplatforms as drug carriers

“…The doxorubicin-loaded nanoparticles were taken up by both wild-type and drug-resistant cells, and were retained for longer in the drug-resistant cells due to lack of drug efflux. 94 The development of multifunctional magnetic nanoparticle formulations further boosts the potential use of SPIONs in medicine. These formulations not only serve the purpose of being drug delivery vectors but also have applications in MRI imaging, 95 targeted thermosensitive chemotherapy, 96 magnetically targeted photodynamic therapy, 97 and fluorescent/luminescence imaging.…”

pH-Responsive therapeutic solid lipid nanoparticles for reducing P-glycoprotein-mediated drug efflux of multidrug resistant cancer cells

“…40 In this work, the drug release behavior of the SLNs was studied at pH characteristic of the blood circulation (pH 7.4), the acidic tumor microenvironment (pH 6.0), and the subcellular acidic organelles (4.7) with succinate and PBS buffers. 41 As shown in Figure 3, all SLNs tested exhibited pH-dependent drug release behaviors, with the highest drug release of ~55% at pH 4.7, followed by a moderate drug release of ~40% at pH 6.0, and the lowest drug release of ~25% at pH 7.4. The release of DOX under acidic conditions was facilitated by the protonation of the carboxyl group of laurate (pKa =5.34), leading to the reduction of the electrostatic attractions between the negatively charged laurate and the positively charged DOX.…”

Doxorubicin-mediated radiosensitivity in multicellular spheroids from a lung cancer cell line is enhanced by composite micelle encapsulation

“…New strategies, such as developing radiosensitizers, are clinically important and have become an important research focus. Doxorubicin is a tetracycline antibiotic commonly used in the treatment of cancer 19 and induces DNA damage by inhibition of topoisomerase II and free radical generation as an anticancer mechanism. 20 Doxorubicin can also bind covalently to DNA, leading to formation of doxorubicin-DNA adducts and interstrand cross-links.…”