Gene and drug delivery using ultrasound-targeted microbubble cavitation

Abstract

Therapeutic delivery of oligonucleotides, such as RNAs, has the potential to treat heretofore “undruggable” targets in diseases such as cancer. However, systemic intravascular delivery of RNAs to tumor tissue is limited by the vascular endothelium, which provides a barrier to transendothelial passage of large, charged molecules. To address RNA delivery challenges, we and others have developed an approach employing ultrasound targeted microbubble cavitation (UTMC), which utilizes 2–4 μm diameter gas-filled microbubbles that carry RNA on the shell and also serve as an ultrasound imaging agent. As intravenously injected microbubbles travel through the microcirculation, localized ultrasound induces microbubble cavitation, causing localized payload release from the microbubble. In addition to delivering the RNA payload, UTMC increases endothelial permeability, thus increasing local extravasation of the payload, while sparing non-insonified tissue (reduced off-target effects). Microbubbles are non-immunogenic and protect loaded RNA against nuclease digestion. Because UTMC concentrates the RNA at the tumor site, lower systemic RNA doses can be used, resulting in fewer off-target effects. A unique feature is that the microbubble that carries and releases the RNA also permits simultaneous US imaging of microbubble location. This lecture will review these unique features of UTMC for drug delivery and current work in this area.