Ultrasound and Microbubble Mediated Delivery of Virus-Sensitizing Drugs Improves In Vitro Oncolytic Virotherapy...

Oncolytic virotherapy is an emerging form of cancer treatment that uses replication-competent viruses to kill cancer cells. However, as for other cancer therapies, oncolytic viruses are not effective against all cancers and there is a need to further improve treatment efficacy while maintaining low toxicity. Viral sensitizers are drugs that potentiate viral replication in tumor cells. While various studies have shown their synergy with oncolytic virotherapy, the risks associated with systemic toxicities that vary according to the drug used limit the clinical translation of the approach. In this study, we used an ultrasound and image-guided approach in which we loaded viral-sensitizing drugs onto microbubbles which are then cavitated by ultrasound to deliver the encapsulated drugs to tumor cells, which improves in vitro oncolytic virotherapy efficacy in the 4T1 breast cancer model.

In this study, we loaded two viral sensitizers, paclitaxel and volasertib, onto lipid microbubbles and comprehensively characterized their effect on the infection of 4T1 murine mammary carcinoma cells by oncolytic Vesicular stomatitis virus in vitro.

We synthesized lipid microbubbles with high and moderate encapsulation efficiency for paclitaxel (83.7%) and volasertib (28.6%), respectively. Stability assessments demonstrated excellent retention in various conditions, highlighting their potential for in vivo use. In vitro studies confirmed their acoustic responsiveness essential for controlled drug release at targeted sites. Paclitaxel and volasertib release from viral sensitizer-loaded microbubbles following ultrasound-triggered cavitation significantly increased viral replication (57-fold, p < 0.0001 and 27-fold, p < 0.01, respectively), as well as tumor cell killing compared to virus-infected untreated cells.

Altogether, our data show that drug-loaded microbubble cavitation and free drugs both sensitize cancer cells to oncolytic viruses to equivalent levels. These findings provide a proof of concept for the use of ultrasound-guided microbubble drug delivery in combination with oncolytic virotherapy.