Bypassing multidrug resistance in human breast cancer cells with lipid/polymer particle assemblies

Bo Li1 College of Pharmaceutical sciences, Zhejiang University, Hangzhou

Hui Xu2 No. 202 Hospital of People’s Liberation Army, Shenyang, China

Zhen Li1 College of Pharmaceutical sciences, Zhejiang University, Hangzhou

Mingfei Yao1 College of Pharmaceutical sciences, Zhejiang University, Hangzhou

Meng Xie1 College of Pharmaceutical sciences, Zhejiang University, Hangzhou

Haijun Shen1 College of Pharmaceutical sciences, Zhejiang University, Hangzhou

Song Shen1 College of Pharmaceutical sciences, Zhejiang University, Hangzhou

Xinshi Wang1 College of Pharmaceutical sciences, Zhejiang University, Hangzhou

Yi Jin1 College of Pharmaceutical sciences, Zhejiang University, HangzhouCorrespondence[email protected]

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Abstract

Background

Multidrug resistance (MDR) mediated by the overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), remains one of the major obstacles to effective cancer chemotherapy. In this study, lipid/particle assemblies named LipoParticles (LNPs), consisting of a dimethyldidodecylammonium bromide (DMAB)-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticle core surrounded by a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) shell, were specially designed for anticancer drugs to bypass MDR in human breast cancer cells that overexpress P-gp.

Methods

Doxorubicin (DOX), a chemotherapy drug that is a P-gp substrate, was conjugated to PLGA and encapsulated in the self-assembled LNP structure. Physiochemical properties of the DOX-loaded LNPs were characterized in vitro. Cellular uptake, intracellular accumulation, and cytotoxicity were compared in parental Michigan Cancer Foundation (MCF)-7 cells and P-gp-overexpressing, resistant MCF-7/adriamycin (MCF-7/ADR) cells.

Results

This study found that the DOX formulated in LNPs showed a significantly increased accumulation in the nuclei of drug-resistant cells relative to the free drug, indicating that LNPs could alter intracellular traffic and bypass drug efflux. The cytotoxicity of DOX loaded-LNPs had a 30-fold lower half maximal inhibitory concentration (IC₅₀) value than free DOX in MCF-7/ADR, measured by the colorimetric cell viability (MTT) assay, correlated with the strong nuclear retention of the drug.

Conclusion

The results show that this core-shell lipid/particle structure could be a promising strategy to bypass MDR.

Keywords:

Acknowledgments

Support from the National Natural Science Foundation of China (NSFC: 30973647) and National Basic Research Program of China (973 Program, 2009 CB930300) are acknowledged.

Disclosure

The authors report no conflicts of interest in this work.

Supplementary Data

Figure S1 Gel Permeation chromatogram of DOX-PLGA conjugate (solid line) and unconjugated PLGA (dotted line)

Abbreviations: DOX, doxorubicin; PLGA, poly(lactic-co-glycolic) acid.

Figure S2 In vitro drug release profiles of DOX-loaded PLGA nanoparticles (without DPPC shell) in different pH (5.5, 6.5, and 7.4) at 37°C. Error bars indicate mean ± SD.

Abbreviations: DOX, doxorubicin; DPPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; PLGA, poly(lactic-co-glycolic) acid; SD, standard deviation.

Figure S3 Cytotoxicity of Free-DOX against MCF-7 and MCF-7/ADR cells. Error bars indicate mean ± SD.

Abbreviations: DOX, doxorubicin; MCF-7, Michigan Cancer Foundation-7; MCF-7/ADR, MCF-7/adriamycin; SD, standard deviation.