Activation of sonosensitizers via focused ultrasound (FUS), i.e., sonodynamic therapy has been proposed as an extension to light-activated photodynamic therapy for the treatment of brain as well as other tumors. The use of 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 together with the anticancer agent bleomycin (BLM), i.e., sonochemical internalization (SCI). SCI is a technique that utilizes FUS for the enhanced delivery of endo-lysosomal trapped macromolecules into the cell cytoplasm in a similar manner to light-based photochemical internalization. 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 the ability of treated glioma cells to grow as three-dimensional tumor spheroids in vitro.
Photochemical internalization (PCI) is a technique that uses the photochemical properties of photodynamic therapy (PDT) for the enhanced delivery of endolysosomal-trapped macromolecules into the cell cytoplasm. The released agent can therefore exert its full biological activity, in contrast to being degraded by lysosomal hydrolases. Activation of photosensitizers via ultrasound (US), called sonodynamic therapy (SDT), has been proposed as an alternative to light-activated PDT for the treatment of cancerous tumors. The use of focused US (FUS) to activate photosensitizers allows treatment at tumor sites buried deep within tissues, overcoming one of the main limitations of PDT/PCI. We have examined ultrasonic activation of photosensitizers together with the anticancer agent bleomycin (BLM) using sonochemical internalization (SCI), as an alternative to light-activated PCI. Our results indicate that, compared to drug or US treatment alone, US activation of the photosensitizer AlPcS2a together with BLM significantly inhibits the ability of treated glioma cells to form clonogenic colonies.
Combination therapies of photochemical internalization (PCI) and moderate hyperthermia (MHT) were investigated in an in vitro system consisting of human and rat glioma spheroids. PCI using the amphiphilic photosensitizer, AlPcS2a and two anti cancer agents BLM or 5-FU were used. Spheroids were irradiated with λ = 670 nm laser light in an incubator at temperatures ranging from 37 to 44°C. For each temperature investigated, spheroids were divided into 4 groups: control, drug-only, photodynamic therapy (PDT), and PCI. PDT and PCI spheroids were exposed to radiant exposures ranging from 0.3 to 2.5 J cm −2 using an irradiance of 5 mW cm −2 . Toxicity was evaluated from spheroid growth kinetics. The combination of PCI and MHT resulted in significant increases in BLM efficacy at 44°C for both cell line derived spheroids compared to controls at 37°C over the range of radiant exposures examined. 5-FU PCI was ineffective for the human cell line at both 37 and 44°C. L. West, "Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance," Proc. Natl. Acad. Sci. U.S.A. 100(23), 13549-13554 (2003). 31. X. Huang, P. K. Jain, I. H. El-Sayed, and M. A. El-Sayed, "Determination of the minimum temperature required for selective photothermal destruction of cancer cells with the use of immunotargeted gold nanoparticles," Photochem. Photobiol. 82(2), 412-417 (2006). 32.
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