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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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Confocal laser scanning microscopy of cellular incorporation and release of doxorubicin in A549 multicellular spheroids. (A1) A549 spheroid cells incubated in free doxorubicin for 4 hours. (A2) Free doxorubicin released from the spheroid for one hour. (B1) A549 spheroid cells incubated in composite doxorubicin-loaded micelles with the same doxorubicin densities for 4 hours. (B2) Composite doxorubicin-loaded micelles released from the spheroid for one hour. (B3) Composite doxorubicin-loaded micelles released from the spheroid for 2.5 hours.
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f3-ijn-7-2661: Confocal laser scanning microscopy of cellular incorporation and release of doxorubicin in A549 multicellular spheroids. (A1) A549 spheroid cells incubated in free doxorubicin for 4 hours. (A2) Free doxorubicin released from the spheroid for one hour. (B1) A549 spheroid cells incubated in composite doxorubicin-loaded micelles with the same doxorubicin densities for 4 hours. (B2) Composite doxorubicin-loaded micelles released from the spheroid for one hour. (B3) Composite doxorubicin-loaded micelles released from the spheroid for 2.5 hours.

Mentions: Intracellular incorporation and release of doxorubicin in A549 multicellular spheroids was measured by confocal laser scanning microscopy (Figure 3). After 4 hours of incubation, A549 multicellular spheroids incubated with MIX (Figure 3B1) were more intensely fluorescent and showed deeper penetration of fluorescence than multicellular spheroids treated with free doxorubicin (Figure 3A1), which had barely detectable levels of intracellular fluorescence. Only very weak fluorescence was observed for multicellular spheroids treated with free doxorubicin for 4 hours followed by a one-hour recovery period (Figure 3A2). In contrast, multicellular spheroids treated with MIX were strongly fluorescent one hour after withdrawal of the drug ( Figure 3B2). Moreover, levels of fluorescence remained high at 2.5 hours (Figure 3B3).


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)

Confocal laser scanning microscopy of cellular incorporation and release of doxorubicin in A549 multicellular spheroids. (A1) A549 spheroid cells incubated in free doxorubicin for 4 hours. (A2) Free doxorubicin released from the spheroid for one hour. (B1) A549 spheroid cells incubated in composite doxorubicin-loaded micelles with the same doxorubicin densities for 4 hours. (B2) Composite doxorubicin-loaded micelles released from the spheroid for one hour. (B3) Composite doxorubicin-loaded micelles released from the spheroid for 2.5 hours.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368509&req=5

f3-ijn-7-2661: Confocal laser scanning microscopy of cellular incorporation and release of doxorubicin in A549 multicellular spheroids. (A1) A549 spheroid cells incubated in free doxorubicin for 4 hours. (A2) Free doxorubicin released from the spheroid for one hour. (B1) A549 spheroid cells incubated in composite doxorubicin-loaded micelles with the same doxorubicin densities for 4 hours. (B2) Composite doxorubicin-loaded micelles released from the spheroid for one hour. (B3) Composite doxorubicin-loaded micelles released from the spheroid for 2.5 hours.
Mentions: Intracellular incorporation and release of doxorubicin in A549 multicellular spheroids was measured by confocal laser scanning microscopy (Figure 3). After 4 hours of incubation, A549 multicellular spheroids incubated with MIX (Figure 3B1) were more intensely fluorescent and showed deeper penetration of fluorescence than multicellular spheroids treated with free doxorubicin (Figure 3A1), which had barely detectable levels of intracellular fluorescence. Only very weak fluorescence was observed for multicellular spheroids treated with free doxorubicin for 4 hours followed by a one-hour recovery period (Figure 3A2). In contrast, multicellular spheroids treated with MIX were strongly fluorescent one hour after withdrawal of the drug ( Figure 3B2). Moreover, levels of fluorescence remained high at 2.5 hours (Figure 3B3).

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