title: Polymeric Cups for Cavitation-mediated Delivery of Oncolytic Vaccinia Virus.
abstract: Oncolytic viruses (OV) could become the most powerful and selective cancer therapies. However, the limited transport of OV into and throughout tumors following intravenous injection means their clinical administration is often restricted to direct intratumoral dosing. Application of physical stimuli, such as focused ultrasound, offers a means of achieving enhanced mass transport. In particular, shockwaves and microstreaming resulting from the instigation of an ultrasound-induced event known as inertial cavitation can propel OV hundreds of microns. We have recently developed a polymeric cup formulation which, when delivered intravenously, provides the nuclei for instigation of sustained inertial cavitation events within tumors. Here we report that exposure of tumors to focused ultrasound after intravenous coinjection of cups and oncolytic vaccinia virus , leads to substantial and significant increases in activity. When cavitation was instigated within SKOV-3 or HepG2 xenografts, reporter gene expression from vaccinia virus was enhanced 1,000-fold (P < 0.0001) or 10,000-fold (P < 0.001), respectively. Similar increases in the number of vaccinia virus genomes recovered from tumors were also observed. In survival studies, the application of cup mediated cavitation to a vaccinia virus expressing a prodrug converting enzyme provided significant (P < 0.05) retardation of tumor growth. This technology could improve the clinical utility of all biological therapeutics including OV.
authors.affiliation: Department of Engineering Science, University of Oxford, BUBBL, IBME, Oxford, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Myers
authors.affiliation: OxSonics Ltd, The Magdalen Centre, Oxford, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Coviello
authors.affiliation: Transgene SA, Boulevard Gonthier d'Andernach, Illkirch-Graffenstaden, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Erbs
authors.affiliation: Transgene SA, Boulevard Gonthier d'Andernach, Illkirch-Graffenstaden, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Foloppe
authors.affiliation: OxSonics Ltd, The Magdalen Centre, Oxford, UK.
authors.forename: Cliff
authors.initials: C
authors.lastname: Rowe
authors.affiliation: Department of Engineering Science, University of Oxford, BUBBL, IBME, Oxford, UK.
authors.forename: James
authors.initials: J
authors.lastname: Kwan
authors.affiliation: Department of Engineering Science, University of Oxford, BUBBL, IBME, Oxford, UK.
authors.forename: Calum
authors.initials: C
authors.lastname: Crake
authors.affiliation: OxSonics Ltd, The Magdalen Centre, Oxford, UK.
authors.forename: Seán
authors.initials: S
authors.lastname: Finn
authors.affiliation: Department of Engineering Science, University of Oxford, BUBBL, IBME, Oxford, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Jackson
authors.affiliation: Transgene SA, Boulevard Gonthier d'Andernach, Illkirch-Graffenstaden, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Balloul
authors.affiliation: OxSonics Ltd, The Magdalen Centre, Oxford, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Story
authors.affiliation: Department of Engineering Science, University of Oxford, BUBBL, IBME, Oxford, UK.
authors.forename: Constantin
authors.initials: C
authors.lastname: Coussios
authors.affiliation: Department of Engineering Science, University of Oxford, BUBBL, IBME, Oxford, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Carlisle
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics*; D014161:Transduction, Genetic; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D014616:Vaccinia virus / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D005472:Fluorouracil