Ultrasound and Microbubble for Oncolytic Virus Delivery
Ultrasound and Microbubble System
Ultrasound is an inexpensive, readily available artificial trigger that can achieve tissue penetration depths of 15 cm. It allows easily directing to desired locations in the body for pinpoint accuracy of carrier activation. Ultrasound has been used diagnostically and therapeutically for decades, and its safety is well established. However, the ultrasound system lacks the suitable delivery vehicles which could respond to focused ultrasound and release their payload. The microbubbles are very sensitive to ultrasound and undergo size oscillations in response to the ultrasound pressure waves. This induces microstreaming of fluid around the microbubble to disrupt and penetrate nearby membranes. Indeed, ultrasound application in the presence of microbubbles induces these disturbances to the membrane, which can facilitate the rapid delivery and release of drugs into cells in response to a localized trigger.
Many delivery schemes use microbubbles as a delivery vehicle and ultrasound as a physical stimulus to offer a means of achieving enhanced transport. The ability of ultrasound to be tightly focused into small tissue volumes provides a physical means of localizing microbubble activity and releasing the drug. Meanwhile, microbubbles represent excellent vehicles for this type of application, as drugs or DNA can be incorporated into the microbubble coating, traced through the body using low-intensity ultrasound, and then released by destroying them microbubbles with high-intensity ultrasound at target sites.
Fig.1 Mechanism of the microbubble. (Nande, 2015)
Ultrasound and Microbubble for Oncolytic Virus Delivery
Oncolytic viruses (OVs) are among the most potent and selective cancer therapeutics under development and are showing robust activity in clinical trials. However, one of the significant challenges for OV therapy is the delivery of OV directly into the affected tumor tissue, which limits the intravenous delivery and antitumor activity of OVs. In particular, ultrasound and microbubbles have been developed as a potential method for enhancing the systemic delivery of a variety of agents such as OVs. Ultrasound-targeted destruction of the microbubbles resulting in the shockwaves and microstreaming allows the focused release of OVs at the tumor site and increased transient and localized cellular viral extravasation. Besides, the microbubbles protect the viruses from rapid degradation by the immune system, thus allowing for intravenous injection. The microbubbles may also limit the amount of inflammatory response to the viruses and may allow repeated injections. Ultrasound-induced cavitation may ultimately enhance the efficacy of a range of powerful therapeutics, thereby improving the treatment of a particular disease.
Oncolytic adenoviruses (Ads) selectively replicate and destroy cancer cells, making them one of the most potent therapeutics available. External stimuli have been applied to improve Ads uptake into and spread through the tumors, in which focused ultrasound is the safest and most clinically applicable of these strategies. Indeed, some in vitro studies have shown that combining OV stealthiness and ultrasound can provide a powerful stimulus to propel Ads deep into tumor-mimicking material to overcome poor pharmacokinetics and limited extravasation and penetration into the tumor. Microbubbles can effectively enclose and protect Ads from inactivation allowing targeted non-invasive systemic delivery. An important aspect of using Ads with ultrasound and microbubbles technique is that high levels of transgene activity are obtained in a target tissue without expression in other organs and toxicity. It results that the use of ultrasound and microbubbles as delivery vehicles can improve the specific Ads gene transduction and both the number of Ads entering tumors and its intratumoral penetration/distribution. Therefore, the use of ultrasound-mediated microbubble destruction for enhanced delivery of OV offers a potential solution to the reported limited tumor extravasation and viral spread.
The formation and subsequent interaction between microbubbles and ultrasound are the keys to their exploitation in diagnostic and therapeutic applications. Creative Biolabs employs the most advanced OncoVirapy™ platform to provide comprehensive oncolytic virus engineering services for the delivery research and therapeutic market. If you are interested in learning more about the delivery of OVs, please do not hesitate to contact us.
Reference
- Nande, R.; et al. Ultrasound-mediated oncolytic virus delivery and uptake for increased therapeutic efficacy: state of art. Oncolytic virotherapy. 2015, 4, 193.