Sonodynamic therapy, the ultrasound dependent enhancement of cytotoxic activities of certain compounds (sonosensitizers) in studies with cells in vitro and in tumor bearing animals, is reviewed. The attractive features of this modality for cancer treatment emerges from the ability to focus the ultrasound energy on malignancy sites buried deep in tissues and to locally activate a preloaded sonosensitizer. Possible mechanisms of sonodynamic therapy include generation of sonosensitizer derived radicals which initiate chain peroxidation of membrane lipids via peroxyl and/or alkoxyl radicals, the physical destabilization of the cell membrane by the sonosensitizer thereby rendering the cell more susceptible to shear forces or ultrasound enhanced drug transport across the cell membrane (sonoporation). Evidence against the role of singlet oxygen in sonodynamic therapy is discussed. The mechanism of sonodynamic therapy is probably not governed by a universal mechanism, but may be influenced by multiple factors including the nature of the biological model, the sonosensitizer and the ultrasound parameters. The current review emphasizes the effect of ultrasound induced free radicals in sonodynamic therapy.

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Phthalocyanines, porphyrin-like compounds with maximum absorption in the red, which were previously reported to localize selectively in tumours, have been shown to be efficient photosensitizers of mammalian cells in culture, thus making them possible candidates to replace haematoporphyrin derivatives in cancer phototherapy.

The presence of molecular oxygen is a determinant in the phototoxicity of phthalocyanines, and photosensitized oxidation is the accepted chemical mechanism for photo-dynamic action. However, it is difficult to establish whether the process is initiated by a type I electron transfer, or by a type II energy transfer reaction to form singlet oxygen. Usually, the involvement of singlet oxygen in photodamage has been indicated by the inhibition of the biological effect by a competitive physical or chemical singlet oxygen quencher, or by a rate increase in D2O, in which singlet oxygen has a longer lifetime than in H2O. Unfortunately, these techniques are not completely specific for singlet oxygen. Moreover, thermodynamic considerations suggest that photoinduced electron abstraction from appropriate biomaterials could compete with singlet oxygen production under in vivo conditions. This likely source of one electron-oxidized primary radicals, which can provide the precursors of the oxidative damage in phthalocyanine photosensitization, suggests the possibility of modulated toxicity by interaction with chemical additives. Examples of such additives recently studied are ascorbate, tocopherol and quercetin, all of which are natural antioxidants.

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