High-intensity focused ultrasound (HIFU) emerges as a powerful technology for noninvasive or minimally invasive non-ionizing treatment of cancer. HIFU deposits a large amount of acoustic energy at the focal region within the target tissue (i.e., tumor), causing localized heating and necrosis. HIFU treatment also causes pores in the cellular membrane, an effect known as sonoporation. The objective of this study is to combine the HIFU treatment with the triggered release of a chemotherapeutic agent (Sorafenib). The rise in temperature caused by HIFU was used to trigger the release of Sorafenib from temperature sensitive liposomes (TSLs). TSLs are self-assembled lipid based nano-carriers which can be triggered to rapidly release their contents above a certain temperature. HIFU alone can be used to effectively kill tumor cells at high enough intensities but even if few cells survive, they can grow back into a tumor. Thus, to effectively treat the tumor, a chemotherapeutic agent is used in synergy with the ablative effect of the HIFU treatment. The HIFU waves were administered at moderate intensities, enough to raise the temperature above the transition temperature of the TSLs to quickly release the drug. The HIFU treatment of cells also causes sonoporation, which increases the cell permeability to the chemotherapeutic drug allowing for increased treatment efficacy.
Liposomes were characterized for particle size (DLS), morphology (Cryo-TEM) and encapsulation efficiency (UV-VIS assay). The sensitivity of the liposomes to temperature was confirmed by monitoring the release of a dye at elevated temperatures. Cryogenic Scanning Electron Microscopy (Cryo-SEM) was used to visualize sonoporation in the cancer cell membranes. Pellets of DU145 human prostate cancer cells were placed in thin-wall PCR tubes to mimic dense tumor aggregation. Confocal microscopy confirmed the uptake of liposomes by the cells. The cell viability was found to be significantly lower for the cells exposed to both HIFU and Sorafenib encapsulating TSLs (SFTSLs) as compared to the cells exposed to Sorafenib only or SFTSLs only. The DU145 cell viability when treated with both HIFU and SFTSLs was greatly reduced post treatment. The results from a cell proliferation assay showed no significant regrowth of the tumor after the synergistic treatment. This implies that the sonoporation which increased the permeability of the cells, resulted in more bioavailability of the drug to the cells, effectively containing the tumor.
Acknowledgments: Authors acknowledge funding from National Science Foundation, Department of Defense, Louisiana Board of Regents, Newcomb-Tulane College, and Tulane Center for Engaged Learning and Teaching.
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