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

Xu WH, Han M, Dong Q, Fu ZX, Diao YY, Liu H, Xu J, Jiang HL, Zhang SZ, Zheng S, Gao JQ, Wei QC - Int J Nanomedicine (2012)

Bottom Line: Doxorubicin radiosensitization and the combined effects of irradiation and doxorubicin on cell migration and proliferation were compared for the different doxorubicin delivery systems.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

ABSTRACT

Background: The purpose of this study is to evaluate the efficacy of composite doxorubicinloaded 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 glycolpolycaprolactone/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.

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Flow cytometric histograms of multicellular spheroids incubated with MIX or free doxorubicin that achieved the same doxorubicin incorporation after 3 hours of exposure, at 2 and 4 hours following drug withdrawal.Notes: DOX for 2 hours, multicellular spheroids incubated in free doxorubicin for 3 hours, then compounds removed for 2 hours; DOX for 4 hours, multicellular spheroids incubated in free doxorubicin for 3 hours, then compounds removed for 4 hours; MIX for 2 hours, multicellular spheroids incubated in MIX for 3 hours, then compounds removed for 2 hours; MIX for 4 hours, multicellular spheroids incubated in MIX for 3 hours, then compounds removed for 4 hours.Abbreviations: DOX, free doxorubicin; MIX, composite doxorubicin-loaded micelles.
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f5-ijn-7-2661: Flow cytometric histograms of multicellular spheroids incubated with MIX or free doxorubicin that achieved the same doxorubicin incorporation after 3 hours of exposure, at 2 and 4 hours following drug withdrawal.Notes: DOX for 2 hours, multicellular spheroids incubated in free doxorubicin for 3 hours, then compounds removed for 2 hours; DOX for 4 hours, multicellular spheroids incubated in free doxorubicin for 3 hours, then compounds removed for 4 hours; MIX for 2 hours, multicellular spheroids incubated in MIX for 3 hours, then compounds removed for 2 hours; MIX for 4 hours, multicellular spheroids incubated in MIX for 3 hours, then compounds removed for 4 hours.Abbreviations: DOX, free doxorubicin; MIX, composite doxorubicin-loaded micelles.

Mentions: Multicellular spheroid intracellular doxorubicin uptake and release by MIX and free doxorubicin was investigated by flow cytometry. As shown in Figure 4, after 2 and 3 hours, the intensity of cellular fluorescence was 14.14 and 13.61 times higher in MIX-treated multicellular spheroids than in free doxorubicin-treated multicellular spheroids for equivalent 2.5 μg/mL drug treatments. For multicellular spheroids incubated with MIX or free doxorubicin that achieved the same amount of doxorubicin incorporation after 3 hours of exposure, the intensity of cellular fluorescence in MIX-treated A549 cells at 2 and 4 hours following drug withdrawal was 9.53 and 14.93 times that of the free doxorubicin-treated cells, respectively (Figure 5). Overall, the quantitative results obtained by flow cytometry are in good agreement with those obtained by confocal laser scanning microscopy (Figure 3).


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

Xu WH, Han M, Dong Q, Fu ZX, Diao YY, Liu H, Xu J, Jiang HL, Zhang SZ, Zheng S, Gao JQ, Wei QC - Int J Nanomedicine (2012)

Flow cytometric histograms of multicellular spheroids incubated with MIX or free doxorubicin that achieved the same doxorubicin incorporation after 3 hours of exposure, at 2 and 4 hours following drug withdrawal.Notes: DOX for 2 hours, multicellular spheroids incubated in free doxorubicin for 3 hours, then compounds removed for 2 hours; DOX for 4 hours, multicellular spheroids incubated in free doxorubicin for 3 hours, then compounds removed for 4 hours; MIX for 2 hours, multicellular spheroids incubated in MIX for 3 hours, then compounds removed for 2 hours; MIX for 4 hours, multicellular spheroids incubated in MIX for 3 hours, then compounds removed for 4 hours.Abbreviations: DOX, free doxorubicin; MIX, composite doxorubicin-loaded micelles.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368509&req=5

f5-ijn-7-2661: Flow cytometric histograms of multicellular spheroids incubated with MIX or free doxorubicin that achieved the same doxorubicin incorporation after 3 hours of exposure, at 2 and 4 hours following drug withdrawal.Notes: DOX for 2 hours, multicellular spheroids incubated in free doxorubicin for 3 hours, then compounds removed for 2 hours; DOX for 4 hours, multicellular spheroids incubated in free doxorubicin for 3 hours, then compounds removed for 4 hours; MIX for 2 hours, multicellular spheroids incubated in MIX for 3 hours, then compounds removed for 2 hours; MIX for 4 hours, multicellular spheroids incubated in MIX for 3 hours, then compounds removed for 4 hours.Abbreviations: DOX, free doxorubicin; MIX, composite doxorubicin-loaded micelles.
Mentions: Multicellular spheroid intracellular doxorubicin uptake and release by MIX and free doxorubicin was investigated by flow cytometry. As shown in Figure 4, after 2 and 3 hours, the intensity of cellular fluorescence was 14.14 and 13.61 times higher in MIX-treated multicellular spheroids than in free doxorubicin-treated multicellular spheroids for equivalent 2.5 μg/mL drug treatments. For multicellular spheroids incubated with MIX or free doxorubicin that achieved the same amount of doxorubicin incorporation after 3 hours of exposure, the intensity of cellular fluorescence in MIX-treated A549 cells at 2 and 4 hours following drug withdrawal was 9.53 and 14.93 times that of the free doxorubicin-treated cells, respectively (Figure 5). Overall, the quantitative results obtained by flow cytometry are in good agreement with those obtained by confocal laser scanning microscopy (Figure 3).

Bottom Line: Doxorubicin radiosensitization and the combined effects of irradiation and doxorubicin on cell migration and proliferation were compared for the different doxorubicin delivery systems.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

ABSTRACT

Background: The purpose of this study is to evaluate the efficacy of composite doxorubicinloaded 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 glycolpolycaprolactone/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.

Show MeSH
Related in: MedlinePlus