ACTIVATION OF ANTI-CANCER AGENTS WITH ULTRASOUND

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The overall goal of this research is to develop a new therapeutic modality for cancer based on activation and/or delivery of anticancer agents by intense ultrasound exposure. Preliminary evidence has shown that it is possible to "activate" the anticancer agent hematoporphyrin by ultrasound in a manner analogous to light activation in photodynamic therapy . Since ultrasound can be localized deep into tissues with precision, particularly using the phased array technology currently under development, the technique promises numerous advantages over optical techniques for drug activation. In addition, there exists the attractive possibility of acoustically activating, or chemically modifying, a wide range of pharmaceuticals in situ as well as creating highly reactive drugs from inert protopharmaceuticals encapsulated with cavitation nuclei. This approach to drug delivery for cancer treatment has been called sonodynamic therapy (SDT). In addition to hematoporphyrin, additional oxygen active compounds including other porphyrins, adriamycin, chlorins, phthalocyanines, bacteriochlorophylls, and cationic dyes, will be assayed for ultrasound induced cytotoxicity by colony formation assays using rat 9L gliosarcoma and human HL 60 promyelocytic cell culture systems. In vivo tumoricidal activity of the most promising agents will be assayed using the rat 9L and the rabbit VX2 carcinoma both introduced into the thigh of host animals. Tumor growth of various control and treatment groups will be determined along with drug kinetics, tissue distribution, and tumor blood flow. The possibility of enhancing SDT with injected cavitation nuclei (stabilized microbubbles) will be explored as a test of the hypothesis that sonochemical interactions related to acoustic cavitation is the primary mechanism to explain the promising preliminary results which have been obtained with SDT. Of particular interest will be the determination of tissue and cellular sites of drug concentration and sonochemical interaction.