Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound.

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.

[1]  L. Seymour,et al.  Adenovirus type 5 interactions with human blood cells may compromise systemic delivery. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[2]  Katherine W Ferrara,et al.  Ultrasound increases nanoparticle delivery by reducing intratumoral pressure and increasing transport in epithelial and epithelial-mesenchymal transition tumors. , 2012, Cancer research.

[3]  D. Kirn,et al.  Systemic efficacy with oncolytic virus therapeutics: clinical proof-of-concept and future directions. , 2007, Cancer research.

[4]  A. Brayman,et al.  Ultrasound with microbubbles enhances gene expression of plasmid DNA in the liver via intraportal delivery , 2008, Gene Therapy.

[5]  Victor Frenkel,et al.  Ultrasound mediated delivery of drugs and genes to solid tumors. , 2008, Advanced drug delivery reviews.

[6]  K. Schughart,et al.  Effect of liposome-encapsulated clodronate pretreatment on synthetic vector-mediated gene expression in mice , 1999, Gene Therapy.

[7]  R. Jain,et al.  Delivering nanomedicine to solid tumors , 2010, Nature Reviews Clinical Oncology.

[8]  J. Gong,et al.  High‐intensity focused ultrasound combined with herpes simplex virus thymidine kinase gene‐loaded ultrasound‐targeted microbubbles improved the survival of rabbits with VX2 liver tumor , 2012, The journal of gene medicine.

[9]  H. Katus,et al.  Augmentation of AAV-mediated cardiac gene transfer after systemic administration in adult rats , 2008, Gene Therapy.

[10]  R. Iggo,et al.  RAD001 (everolimus) improves the efficacy of replicating adenoviruses that target colon cancer. , 2005, Cancer research.

[11]  R. Alemany,et al.  Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[12]  Tom Leslie,et al.  Spatiotemporal monitoring of high-intensity focused ultrasound therapy with passive acoustic mapping. , 2012, Radiology.

[13]  C. Arvanitis,et al.  Cavitation-enhanced extravasation for drug delivery. , 2011, Ultrasound in medicine & biology.

[14]  T. Leighton.  The Acoustic Bubble , 1994 .

[15]  Ronald A. Roy,et al.  Applications of Acoustics and Cavitation to Noninvasive Therapy and Drug Delivery , 2008 .

[16]  M. Samoszuk,et al.  Improved Immunohistochemical Method for Detecting Hypoxia Gradients in Mouse Tissues and Tumors , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[17]  Samir Mitragotri,et al.  Healing sound: the use of ultrasound in drug delivery and other therapeutic applications , 2005, Nature Reviews Drug Discovery.

[18]  Douglas L. Miller,et al.  Tumor growth reduction and DNA transfer by cavitation-enhanced high-intensity focused ultrasound in vivo. , 2003, Ultrasound in medicine & biology.

[19]  R. Alemany,et al.  Replacement of adenovirus type 5 fiber shaft heparan sulfate proteoglycan-binding domain with RGD for improved tumor infectivity and targeting. , 2009, Human gene therapy.

[20]  Miklós Gyöngy,et al.  Passive Spatial Mapping of Inertial Cavitation During HIFU Exposure , 2010, IEEE Transactions on Biomedical Engineering.

[21]  B. Harvey,et al.  Enhancement of in vivo adenovirus-mediated gene transfer and expression by prior depletion of tissue macrophages in the target organ , 1997, Journal of virology.

[22]  Costas D Arvanitis,et al.  Ultrasound-induced cavitation enhances the delivery and therapeutic efficacy of an oncolytic virus in an in vitro model. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[23]  M. Clarke,et al.  New oncolytic adenoviruses with hypoxia- and estrogen receptor-regulated replication. , 2002, Human gene therapy.

[24]  R. Iggo,et al.  Comparison of molecular strategies for breast cancer virotherapy using oncolytic adenovirus. , 2008, Human gene therapy.

[25]  K. Ulbrich,et al.  Passive tumour targeting of polymer-coated adenovirus for cancer gene therapy , 2007, Journal of drug targeting.

[26]  V. Šubr,et al.  Tumour necrosis factor-alpha increases extravasation of virus particles into tumour tissue by activating the Rho A/Rho kinase pathway. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[27]  Aaron Fenster,et al.  Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans , 2011, Nature.

[28]  B. Raju,et al.  Focused ultrasound and microbubbles for enhanced extravasation. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[29]  P. Fisher,et al.  Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[30]  R. Carlisle,et al.  Factors influencing retention of adenovirus within tumours following direct intratumoural injection , 2008, Gene Therapy.