title: Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound.
abstract: Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery.
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford OX3 7DQ, UK. miriam.bazan-peregrino@balliol.oxon.org
authors.forename: Miriam
authors.initials: M
authors.lastname: Bazan-Peregrino
authors.forename: Bassel
authors.initials: B
authors.lastname: Rifai
authors.forename: Robert C
authors.initials: RC
authors.lastname: Carlisle
authors.forename: James
authors.initials: J
authors.lastname: Choi
authors.forename: Costas D
authors.initials: CD
authors.lastname: Arvanitis
authors.forename: Leonard W
authors.initials: LW
authors.lastname: Seymour
authors.forename: Constantin C
authors.initials: CC
authors.lastname: Coussios
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004867:Equipment Design; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D045423:Microbubbles; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000295:instrumentation*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D019076:Transgenes; D014465:Ultrasonics / Q000295:instrumentation*