Radiolysis, Photolysis, Sonolysis and Sonoprotection of

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Summary of work:Sonodynamic therapy is a promising new modality for cancer treatment based on the synergistic effects of cell killing by a combination of sonosensitzer and ultrasound. Ultrasound can penetrate deeply into tissue and can be focused in a small region of tumor to activate non-toxic molecules (e.g. porphyrins ) thus minimizing undesirable side effects. The experimental evidence suggests that sonosensitization is due to the chemical activation of sonosensitizers inside or in close vicinity of hot collapsing cavitation bubbles to form sensitizer-derived radicals either by direct pyrolysis of the sensitizer at the water-gas interface or due to the reactions of hydrogen atoms and hydroxyl radicals formed by the pyrolysis of water. The free radicals derived from the sonosensitizer (mostly carbon-centered) react with oxygen to form peroxyl and alkoxyl radicals. Unlike OH radicals and H atoms which are formed by pyrolysis inside cavitation bubbles, the reactivity of alkoxyl and peroxyl radicals with organic compounds in biological media is much lower and hence they have a higher probability of reaching critical cellular sites.The mechanism(s) responsible for sudden cytolysis observed when cells are exposed to ultrasound could be mechanical and/or free radical in nature. Free radical reactions are initiated in the core and in the interfacial regions of collapsing acoustic cavitation bubbles. Since cyclic sugars are known to inhibit free radical chain reactions, we investigated the effect of n-alkyl a-D glucopyranosides of varying hydrophobicity on ultrasound (1.057 MHz) induced cytolysis of HL-60 cells in vitro. n-alkyl glucopyranosides with hexyl- (HGP, 5 mM), heptyl- (3 mM) or octyl- (2 mM) n-alkyl chains protected 100% of the cell population from ultrasound induced cytolysis under conditions where 35% to 100% cytolysis occurred in the absence of glucopyranosides. The protected cell populations also possessed long-term reproductive viability. However, the hydrophilic methyl-a-D glucopyranoside could not protect cells, even up to a concentration of 30 mM. Furthermore, none of the glucopyranosides could prevent cytolysis of cells from a mechanically induced shear stress. Spin trapping and electron spin resonance experiments confirmed the presence of inertial cavitation in cell suspensions both in the presence and absence of the surfactants. It is concluded that surface active glucopyranosides efficiently quench cytotoxic radicals at the gas/solution interface of collapsing cavitation bubbles.1. Feril, L.B., Tsuda, Y., Kondo, T., Zhao, Q.L., Ogawa, R., Cui, Z.G., Tsukada, K. & Riesz P., Ultrasound-induced killing of monocytic U937 cells enhanced by 2,2'-azobis(2-amidinopropane) dihydrochloride. Cancer Science 95, 181-185 (2004).2. Feril, L., Kondo, T., Takaya, K. & Riesz, P., Enhanced ultrasound-induced apoptosis and cell lysis by a hypotonic medium. International Journal Of Radiation Biology 80, 165-175 (2004).3. Rosenthal, I., Sostaric, J. & Riesz, P., Sonodynamic therapy - a review of the synergistic effects of drugs and ultrasound. Ultrasonics Sonochemistry 11, 349-363 (2004).4. Rosenthal, I., Sostaric, J. & Riesz, P., Enlightened sonochemistry. Research On Chemical Intermediates 30, 685-701 (2004).5. Sostaric, J., Miyoshi, N., Riesz, P., De Graff, W.G., Mitchell, J.B., n-Alkyl glucopyranosides completely inhibit ultrasound induced cytolysis. (Free Radicals Biology and Medicine, In Press, 2005)