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

Authors Xu WH, Han M, Dong Q, Fu ZX, Diao YY, Liu H, Xu J, Jiang HL, Zhang SZ, Zheng S, Gao JQ, Wei QC

Received 1 February 2012

Accepted for publication 17 April 2012

Published 29 May 2012 Volume 2012:7 Pages 2661—2671

DOI https://doi.org/10.2147/IJN.S30445

Review by Single-blind

Peer reviewer comments 3

Wen-Hong Xu,1 Min Han,2 Qi Dong,3 Zhi-Xuan Fu,3 Yuan-Yuan Diao,2 Hai Liu,3 Jing Xu,3 Hong-Liang Jiang,4 Su-Zhan Zhang,3 Shu Zheng,3 Jian-Qing Gao,2 Qi-Chun Wei1
1Department of Radiation Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 2Institute of Pharmaceutics, College of Pharmaceutical Sciences, 3Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, School of Medicine, 4Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, China

Background: The purpose of this study is to evaluate the efficacy of composite doxorubicin-loaded micelles for enhancing doxorubicin radiosensitivity in multicellular spheroids from a non-small cell lung cancer cell line.
Methods: A novel composite doxorubicin-loaded micelle consisting of polyethylene glycol-polycaprolactone/Pluronic P105 was developed, and carrier-mediated doxorubicin accumulation and release from multicellular spheroids was evaluated. We used confocal laser scanning microscopy and flow cytometry to study the accumulation and efflux of doxorubicin from A549 multicellular spheroids. Doxorubicin radiosensitization and the combined effects of irradiation and doxorubicin on cell migration and proliferation were compared for the different doxorubicin delivery systems.
Results: Confocal laser scanning microscopy and quantitative flow cytometry studies both verified that, for equivalent doxorubicin concentrations, composite doxorubicin-loaded micelles significantly enhanced cellular doxorubicin accumulation and inhibited doxorubicin release. Colony-forming assays demonstrated that composite doxorubicin-loaded micelles are radiosensitive, as shown by significantly reduced survival of cells treated by radiation + composite micelles compared with those treated with radiation + free doxorubicin or radiation alone. The multicellular spheroid migration area and growth ability verified higher radiosensitivity for the composite micelles loaded with doxorubicin than for free doxorubicin.
Conclusion: Our composite doxorubicin-loaded micelle was demonstrated to have radiosensitization. Doxorubicin loading in the composite micelles significantly increased its cellular uptake, improved drug retention, and enhanced its antitumor effect relative to free doxorubicin, thereby providing a novel approach for treatment of cancer.

Keywords: doxorubicin, lung cancer, micelles, radiosensitivity, spheroids

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