The main thrust of the proposed research is to combine the advantages of ultrasonic drug delivery and micellar drug carriers into a novel technology that will deliver high local concentrations of drugs to tissues exposed to localized acoustic energy. Ultrasound is non-invasive, can be carefully controlled and focused on the target tissue; it induces drug release from micelles and enhances the intracellular drug uptake and it can simultaneously create a hyperthermic condition. Micellar drug carriers prevent unwanted drug interaction with healthy tissues while sensitizing multidrug resistant (MDR) cells to the action of drugs. The foundation of this proposal is the hypothesis that micellar drug delivery combined lwith ultrasonic activation can target drugs to tumors, enhance the cytotoxicity of drugs in sensitive and MDR tumors, and suppress tumor growth.
Specific aims of the project include: 1. To extend a panel of /cell fines, drugs, and polymeric micelles for which the above technology may prove beneficial, In particular, to include taxol into the panel of drugs since it has low solubility in commonly used media and low activity in multidrug resistant cells. The cytotoxicity of Doxorubicin (DOX) and taxol in vitro will be measured in A2780 ovarian carcinoma, MCF7 breast cancer, and P388 leukemia cell lines (both dwg-sensitive and MDR), and in DHD/KlZ/TRb colon cancer cell line. 2. To test the hypothesis that micelfar drug delivery combined with ultrasound suppresses tumor growth in vivo and increases survival rates of tumor-bearing mice. Experiments will be performed with drug-sensitive and MDR A2780 and MCF7 tumors grown subcutaneously, and P388 internal tumors grown in the peritoneal cavity of mice; micellar-encapsutated DOX and taxol will be delivered with and without 20-kHz ultrasound applied to the tumors at various duty cycles and power densities. 3. To extend and scale up in vivo experiments using the DHDMZFRb colon cancer model in rats. Experiments will be performed with micellar encapsulated DOX combined with 20-kHz and 70-kHz ultrasound. All three specific aims are focused on clinically relevant targets.
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