Ultrasound-Activated Bubbles Show Promise for Cancer Drug Delivery

In two new studies, researchers demonstrated techniques that use ultrasound-activated bubbles to improve cancer drug delivery. Engineers at Duke University developed a technique called SonoPIN that uses microbubbles and ultrasound to help relatively large cancer drugs enter tumor cells and cause them to self-destruct, while researchers at Case Western Reserve University used ultrasound-activated nanobubbles to break down the stiff extracellular matrix that shields solid tumors from treatment.

The Duke technique, dubbed "Sonoporation-assisted Precise Intracellular Nanodelivery," or SonoPIN for short, is designed to deliver PROTACs (proteolysis-targeting chimeras), a class of therapeutics that have shown great promise for degrading "undruggable" proteins and overcoming drug resistance in cancer therapy. PROTACs work by binding to a specific target protein and recruiting an enzyme called an E3 ubiquitin ligase, which attaches ubiquitin to the target protein, marking it for destruction by the body's natural garbage collection system. In cancer cells, PROTACs have been used to target and degrade a protein called BRD4, which breaks the cancer cells' ability to rapidly reproduce and survive. However, PROTAC molecules are too big to get into cells on their own.

To overcome this, the researchers equipped microbubbles with synthetic nucleic acid strands designed to bind to specific biochemical receptors on the cell membranes of cancer cells. When probed vigorously with ultrasound, the bubbles collapse rapidly, causing a phenomenon called sonoporation, which creates nanoscopic, temporary pores in the cell membrane large enough for PROTACs to enter. The cell membranes naturally self-heal within minutes. After a minute of ultrasound exposure, cells treated with SonoPIN glowed seven times brighter than those treated with traditional PROTAC delivery methods, indicating that they were taking in many more PROTACs. The research appears online March 13 in the journal Proceedings of the National Academy of Sciences.

In the separate study at Case Western Reserve University, researchers injected nanobubbles filled with an inert gas, perfluoropropane, into a breast cancer model and used ultrasound to "jiggle" the bubbles, breaking down the tumor's stiff structure without destroying cells. The tumors became softer, more homogeneous, and more penetrable by immune cells and nanoparticles, according to results published in ACS Nano. The nanobubble treatment also activated immune cells already present in tumors, causing them to secrete danger signals and recruit more immune cells to the tumor site. Killer T-cells that targeted the cancer also sought out other tumors, even ones that were not treated.

The nanobubble treatment kept tumors softer for at least five days, whereas untreated tumors grew stiffer and more difficult to treat. When lipid nanoparticles containing RNA that enhanced T-cell activity were later injected, the treatment spread throughout the tumor rather than remaining at the injection site. The nanobubbles are already being commercialized for detecting prostate cancer by Visano Theranostics, and the ultrasound used is FDA-approved and commercially available. An Investigational New Drug (IND) application will be submitted to the FDA within the next 18 months, and the therapeutic use could piggyback on that application, potentially enabling clinical trials within two years.