Ultrasound-Gene Delivery Applications in Cancer Research:
AN INTERNATIONAL JOURNEY
Dr. Howard Leong-Poi, MD, FRCPC, FACC, FASE (Left) Staff Cardiologist, St. Michael’s Hospital Associate Scientist, Keenan Research Centre for Biomedical Sciences Associate Professor, Department of Medicine, University of Toronto Dr. Pratiek Matkar, PhD (Right) Previously a PhD student at Institute of Medical Science, University of Toronto Photo by Grace Jacobs
By Priscilla Chan
hat do microbubbles—miniscule gas filled bubbles just three micrometres (μm) across—have to do with the future of non-invasive cancer treatment? Originally used as a contrast media to improve ultrasound images, microbubbles are now being harnessed for their novel therapeutic properties. Specifically, microbubbles may be used in targeted gene delivery to treat a variety of conditions, from cardiovascular diseases to cancer. I sat down with Dr. Howard Leong-Poi, a clinician-scientist at St. Michael’s Hospital, to talk about his work in non-invasive cancer therapy, specifically the application of ultrasound and microbubbles. “Essentially, it’s the use of gas-filled microbubbles for a variety of purposes,” explains Dr. Leong-Poi. Microbubbles can be administered intravenously into the systemic circulation. Ultrasound waves cause these microbubbles to expand and 20 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS
contract, resonating strongly at high frequencies. Importantly, compared to soft tissue, microbubbles have a greater capacity to reflect ultrasound waves. In other words, microbubbles can be used to enhance the resolution of greyscale ultrasound images.1 This approach can be used for more than just diagnostics; it can also be applied for therapeutics. With sufficient excitation, microbubbles are ready to burst, opening up the vascular endothelium. As Dr. Leong-Poi describes it, “it’s a mechanical form of gene transfection.” Ultrasound-targeted microbubble destruction exploits this property to increase the efficiency of drug, protein, and gene delivery. Dr. Leong-Poi’s lab has used ultrasound and microbubbles for targeted gene delivery to treat peripheral artery disease, heart failure, and acute myocardial infarction. More recently, his team started looking into ultrasound-mediated gene therapies for cancer.
Currently, cancers are treated using a combination of surgery, chemotherapy, and radiation. Tumours can be partially or completely removed through surgery, but the procedure is invasive and mainly applicable to localized tumours that have not spread. Chemotherapy and radiation are also reasonably effective, but patients are left to deal with the many systemic side effects associated with the treatments. “They work on cancer for a reason,” says Dr. Leong-Poi, “they’re toxic.” In contrast, ultrasound-mediated gene therapy may provide a non-invasive alternative. Dr. Leong-Poi and his colleagues have shown that microbubble delivery of a short hairpin (sh)RNA specific to VEGFR2, a gene contributing to neovascularization—the formation of new blood vessels—reduces angiogenesis (blood vessel formation) in an in vivo tumour model.3 His team also optimized the ultrasound pulse rate to achieve maximal
The fall issue of the IMS Magazine for 2017, with a feature on Cancer Therapeutics.