Key result
Hyperthermia at 42°C increased glutathione-mediated release of doxorubicin from nanocontainers and markedly potentiated clonogenic and apoptotic cell death in human lung cancer cells.
Hyperthermia enhances the efficacy of doxorubicin-loaded mesoporous silica nanocontainers in lung cancer cells by increasing glutathione-mediated drug release.
Hyperthermia with doxorubicin nanocontainers warrants in vivo testing in lung cancer; leaves open any clinical translation or practice change.
PURPOSE: We investigated the use of hyperthermia to improve the anti-cancer efficacy of doxorubicin (DOX)-loaded mesoporous silica nanocontainer Si-SS-CD-PEG. The hypothesis was that heat stimulates glutathione-mediated degradation of cyclodextrin gatekeeper, thereby causing the release of DOX from the carrier and DOX-induced cell death. MATERIALS AND METHODS: The release of DOX from DOX-loaded Si-SS-CD-PEG suspended in PBS containing glutathione (GSH) was studied by assessing the changes in DOX fluorescence intensity. The effect of heating at 42°C on the release of DOX from the intracellular carriers was determined with confocal microscopy. The extents of clonogenic and apoptotic cell death caused by DOX-loaded Si-SS-CD-PEG were determined. RESULTS: The release of DOX from DOX-loaded Si-SS-CD-PEG in PBS occurred only when GSH presented in the suspension, and heating at 42°C slightly increased the release of DOX from the carriers. Heating significantly elevated the GSH content in A549 cells and increased the release of DOX from the internalised carriers. Heating the cancer cells treated with the carriers at 42°C markedly increased the clonogenic death and apoptosis. The GSH content in A549 cells was greater than that in L-132 cells, and A549 cells were far more sensitive than L-132 cells to DOX-loaded Si-SS-CD-PEG at both 37°C and 42°C. CONCLUSIONS: Hyperthermia increased the GSH-mediated release of DOX from DOX-loaded Si-SS-CD-PEG. Furthermore, hyperthermia markedly elevated the GSH content in cancer cells, thereby increasing the release of DOX from the internalised carriers and potentiating the DOX-induced clonogenic and apoptotic cell death.
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Lee et al. (2011) studied human lung cancer. Hyperthermia (42°C) vs. 37°C was evaluated on Release of doxorubicin and cell death (clonogenic and apoptotic). Hyperthermia at 42°C increased glutathione-mediated release of doxorubicin from nanocontainers and markedly potentiated clonogenic and apoptotic cell death in human lung cancer cells.
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