Surfactin-based nanoparticles loaded with doxorubicin to overcome multidrug resistance in cancers

Wenjing Huang1 Department of Nanomedicine and Biopharmaceuticals, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China

Yan Lang1 Department of Nanomedicine and Biopharmaceuticals, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China

Abdul Hakeem1 Department of Nanomedicine and Biopharmaceuticals, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China

Yan Lei2 Pharmacy of School Hospital, Huazhong University of Science and Technology, Wuhan 430074, China

Lu Gan1 Department of Nanomedicine and Biopharmaceuticals, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, ChinaCorrespondence[email protected]

Xiangliang Yang1 Department of Nanomedicine and Biopharmaceuticals, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China

Abstract

Background

Multidrug resistance (MDR) is one of the major obstacles to successful cancer chemotherapy. Developing efficient strategies to reverse MDR remains a major challenge. Surfactin (SUR), a cyclic lipopeptide biosurfactant, has been found to display anticancer activity.

Methods

In this paper, SUR was assembled by solvent-emulsion method to load the anticancer drug doxorubicin (DOX). The cytotoxicity of DOX-loaded SUR nanoparticles (DOX@SUR) against DOX-resistant human breast cancer MCF-7/ADR is measured by MTT assay. The cellular uptake and intracellular retention of DOX@SUR are determined by flow cytometry. The tumor accumulation and anticancer activity of DOX@SUR are evaluated in MCF-7/ADR-bearing nude mice.

Results

DOX@SUR induce stronger cytotoxicity against DOX-resistant human breast cancer MCF-7/ADR cells compared to free DOX. DOX@SUR nanoparticles exhibit enhanced cellular uptake and decreased cellular efflux, which might be associated with reduced P-glycoprotein expression. After internalization into MCF-7/ADR cells by macropinocytosis- and caveolin-mediated endocytosis, DOX@SUR nanoparticles are colocalized with the lysosomes and translocated to the nucleus to exert cytotoxicity. Furthermore, in vivo animal experiment shows that the DOX@ SUR nanoparticles are accumulated more efficiently in tumors than free DOX. Meanwhile, DOX@SUR nanoparticles display stronger tumor inhibition activity and fewer side effects in MCF-7/ADR-bearing nude mice.

Conclusion

This study indicates that SUR-based nanocarrier might present a promising platform to reverse MDR in cancer chemotherapy.

Keywords:

Supplementary materials

Figure S1 Confocal microscopic images of the intracellular DOX localization of MCF-7/ADR cells treated with free DOX or DOX@SUR nanoparticles at a DOX concentration of 5 μg/mL for 8 h.

Note: Scale bar: 25 μm.

Abbreviations: DAPI, 4,6-diamidino-2-phenylindole; DOX, doxorubicin; SUR, surfactin; DOX@SUR, DOX-loaded SUR.

Figure S1 Confocal microscopic images of the intracellular DOX localization of MCF-7/ADR cells treated with free DOX or DOX@SUR nanoparticles at a DOX concentration of 5 μg/mL for 8 h.Note: Scale bar: 25 μm.Abbreviations: DAPI, 4,6-diamidino-2-phenylindole; DOX, doxorubicin; SUR, surfactin; DOX@SUR, DOX-loaded SUR.

Figure S2 Confocal microscopic images of the intracellular DOX localization of MCF-7/ADR cells treated with DOX@SUR nanoparticles at a DOX concentration of 5 μg/mL for different time courses.

Note: Scale bar: 25 μm.

Abbreviations: DAPI, 4,6-diamidino-2-phenylindole; DOX, doxorubicin; SUR, surfactin; DOX@SUR, DOX-loaded surfactin.

Figure S2 Confocal microscopic images of the intracellular DOX localization of MCF-7/ADR cells treated with DOX@SUR nanoparticles at a DOX concentration of 5 μg/mL for different time courses.Note: Scale bar: 25 μm.Abbreviations: DAPI, 4,6-diamidino-2-phenylindole; DOX, doxorubicin; SUR, surfactin; DOX@SUR, DOX-loaded surfactin.

Figure S3 Serological analysis of MCF-7/ADR-bearing nude mice at the end of tumor inhibition experiments, including ALT, AST, BUN and CRE.

Note: Data are represented as mean value ± SD (n=6).

Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRE, creatinine; DOX, doxorubicin; SUR, surfactin; DOX@SUR, DOX-loaded surfactin.

Figure S3 Serological analysis of MCF-7/ADR-bearing nude mice at the end of tumor inhibition experiments, including ALT, AST, BUN and CRE.Note: Data are represented as mean value ± SD (n=6).Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRE, creatinine; DOX, doxorubicin; SUR, surfactin; DOX@SUR, DOX-loaded surfactin.

Acknowledgments

This work was supported by National Basic Research Program of China (2015CB931802), National Natural Science Foundation of China (81672937, 81473171, 81773653 and 81627901) and Program for Changjiang Scholars and Innovative Research Team in University (IRT13016). We thank the Analytical and Testing Center of Huazhong University of Science and Technology for related analysis.

Disclosure

The authors report no conflicts of interest in this work.