Low frequency nanobubbles-enhanced noninvasive transcranial ultrasound for brain cancer therapy

One of the worst diagnoses in oncology is a malignant brain tumor, with survival rates that are dismal. Noninvasive surgery can be achieved using histotripsy, a local, nonthermal ultrasound (US) surgical method that uses short, high-intensity?focused US energy to mechanically ablate deep tissues through cavitation, while leaving the surrounding heathy tissues unaffected. However, brain therapy histotripsy is currently limited due to the extremely high pressures that it requires. I propose to develop a breakthrough technology for the treatment of glioblastoma (GBM) using nanobubble (NB)-mediated transcranial histotripsy combined with blood?brain barrier (BBB) opening. NBs will be coupled with low-frequency US to remotely detonate cells in a manner that was not considered feasible in the past. As a result, low-energy, NB-mediated US surgery could be performed, reducing the required energy for standard US surgery by over an order of magnitude. While US widely utilizes microbubbles (MBs) for intravascular ultrasonography, MBs are too big to extravastate into the tumor. Unlike MBs, NBs have a sufficiently small size for accumulation in tumors; however, it was assumed that there is a trade-off between the bubble size and its ability to obtain significant bioeffects as a result of cavitation. My recent research revealed that when a bubble is excited well below its resonance frequency, its oscillations are significantly enhanced. Thus, I hypothesize that upon accumulation within the GBM tumor, and coupled with low-frequency excitation, NBs can be used as mechanical therapeutic warheads to remotely detonate cells with minimal off-target effects. For GBM treatment, NBs will be innovatively used for opening the BBB to allow tumor accumulation, followed by NB-mediated transcranial histotripsy. This research will provide a foundational understanding of NB oscillations as an innovative tool for cancer therapy and has the potential to revolutionize the field of brain therapy.