Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro
Forrest M Kievit1, Freddy Y Wang, Chen Fang
1Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, USA.
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.
Insights
This study developed iron oxide nanoparticles loaded with doxorubicin (DOX) to overcome multidrug resistance (MDR) in cancer. These nanoparticles effectively delivered DOX to resistant cells, improving chemotherapy efficacy by bypassing drug efflux pumps.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Multidrug resistance (MDR) in cancer involves ATP-binding cassette (ABC) transporters that expel chemotherapy drugs.
- Developing strategies to circumvent MDR is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To fabricate and characterize iron oxide nanoparticles loaded with doxorubicin (DOX) to overcome MDR.
- To evaluate the efficacy of these nanoparticles in drug-resistant cancer cells.
Main Methods:
- Conjugating DOX to iron oxide nanoparticles via a pH-sensitive hydrazone linkage.
- Assessing nanoparticle drug release, uptake, retention, and cytotoxicity in wild-type and DOX-resistant rat glioma cells.
Main Results:
- DOX release was pH-dependent, with increased release at acidic pH.
- DOX-conjugated nanoparticles were taken up by both wild-type and resistant cells.
- Nanoparticles persisted in resistant cells, unlike free DOX, leading to reduced cell viability.
Conclusions:
- DOX-conjugated iron oxide nanoparticles can circumvent MDR by preventing drug efflux.
- This nanoparticle-based approach shows potential for enhancing chemotherapy efficacy in resistant cancers.
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