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A physiological barrier protecting the brain, the blood\u2013brain barrier (BBB), functions as a deterrent to effective therapies. To enhance cancer therapy, we developed a cancer terminator virus (\n                    <jats:italic>CTV<\/jats:italic>\n                    ), a unique tropism\u2010modified adenovirus consisting of serotype 3 fiber knob on an otherwise Ad5 capsid that replicates in a cancer\u2010selective manner and simultaneously produces a potent therapeutic cytokine, melanoma differentiation\u2010associated gene\u20107\/interleukin\u201024\u00a0(MDA\u20107\/IL\u201024). A limitation of the\n                    <jats:italic>CTV<\/jats:italic>\n                    and most other viruses, including adenoviruses, is an inability to deliver systemically to treat brain tumors because of the BBB, nonspecific virus trapping, and immune clearance. These obstacles to effective viral therapy of brain cancer have now been overcome using focused ultrasound with a dual microbubble treatment, the focused ultrasound\u2010double microbubble\u00a0(FUS\u2010DMB) approach. Proof\u2010of\u2010principle is now provided indicating that the BBB can be safely and transiently opened, and the\n                    <jats:italic>CTV<\/jats:italic>\n                    can then be administered in a second set of complement\u2010treated microbubbles and released in the brain using focused ultrasound. Moreover, the FUS\u2010DMB can be used to deliver the\n                    <jats:italic>CTV<\/jats:italic>\n                    multiple times in animals with glioblastoma\u00a0 growing in their brain thereby resulting in a further enhancement in survival. This strategy permits efficient therapy of primary and secondary brain tumors enhancing animal survival without promoting harmful toxic or behavioral side effects. Additionally, when combined with a standard of care therapy, Temozolomide, a further increase in survival is achieved. The FUS\u2010DMB approach with the\n                    <jats:italic>CTV<\/jats:italic>\n                    highlights a noninvasive strategy to treat brain cancers without surgery. This innovative delivery scheme combined with the therapeutic efficacy of the\n                    <jats:italic>CTV<\/jats:italic>\n                    provides a novel potential translational therapeutic approach for brain cancers.\n                  <\/jats:p>","DOI":"10.1002\/jcp.31302","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T05:38:30Z","timestamp":1716356310000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Noninvasive therapy of brain cancer using a unique systemic delivery methodology with a cancer terminator virus"],"prefix":"10.1002","volume":"239","author":[{"given":"Praveen","family":"Bhoopathi","sequence":"first","affiliation":[{"name":"Department of Human and Molecular Genetics Virginia Commonwealth University, School of Medicine Richmond Virginia USA"},{"name":"VCU Institute of Molecular Medicine Virginia Commonwealth University, School of Medicine 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