Abstract
Systemically administered chemotherapeutic agents are, firstly limited by their inability to penetrate across the blood brain barrier (BBB). Site-specific disruption of the BBB using focused ultrasound (FUS) has been demonstrated in experimental animal glioma models and in a small number of patients. Secondly, many highly effective chemotherapeutic agents are large and water soluble and are actively transported into tumor cells by endocytosis. Their poor ability to escape from the resulting intracellular endosomes leads to their inactivation via lysosome-endosome fusion. Activation of sonosensitizers via focused ultrasound (FUS), i.e. sonodynamic therapy (SDT) has been proposed as an extension to light activated photodynamic therapy for the treatment of brain as well as other tumors. The use of focused FUS, as opposed to light, allows treatment to tumor sites buried deep within tissues as well as through the intact skull. We have examined ultrasonic activation of sonosensitizers to enhance the efficacy of the anti-cancer agent bleomycin (BLM). The combination of sonosensitizers drug and FUS is termed sonochemical internalization (SCI), as an extension of light based photochemical internalization (PCI). SCI is a technique which utilizes FUS for the enhanced delivery of endo-lysosomal trapped macromolecules into the cell cytoplasm. The released agent can therefore exert its full biological activity, in contrast to being degraded by lysosomal hydrolases. Our results indicate that, compared to drug or FUS treatment alone, FUS activation of the sonosensitizer AlPcS2a together with BLM significantly inhibits glioma growth. SCI is a promising new technology that, like PCI, may potentiate the efficacy of a wide variety of therapeutic compounds. However, unlike PCI, SCI is not limited by the poor tissue penetration inherent to light-based approaches and, as such, this ultrasound-based technology is ideally suited for the treatment of deep seated or intracranial lesions like gliomas.