Betting on Bubble Technology: From Alzheimer’s Treatment to Enhanced Cancer Drug Delivery
Ultrasound-based therapies hold immense potential for improving patient care and advancing precision medicine — but it’s the bubble, not the beam, doing the real work.
By Clayton Larsen, President and CEO — Vesselon
Recent advancements in medical technology have hit the consumer news, highlighting the multifaceted applications of ultrasound in addressing various health challenges. Pioneering research led by Dr. Ali Rezai at the Rockefeller Neuroscience Institute at West Virginia University has demonstrated the potential of ultrasound therapy in treating Alzheimer’s disease and addiction.
First reported in The New England Journal of Medicine just last month, Dr. Rezai and his team “applied focused ultrasound with each of six monthly aducanumab (Aduhelm®) infusions to temporarily open the blood-brain barrier to enhance amyloid [plaque] removal in selected brain regions in three participants [with mild Alzheimer’s] over 6 months.” When the barrier was opened, researchers discovered that 50% more plaque was dissolved than areas treated by IV drug infusion alone.
But you would be hard-pressed to scour that NEJM article and find any mention of microbubbles, the enabling drug that allows the whole procedure. You have to go to a 2020 reference by Dr. Rezai for details of the Materials and Methods, and even in that 2020 PNAS paper, you have to dig to find microbubbles even being mentioned.
Fortunately, the New York Times summarized this exciting research and reported that this approach involves injecting patients with small microbubbles of perfluorocarbon gas, which “…have a twenty-year track record of being safe,” according to Dr. Alexandra Golby, a professor of neurology and radiology at Harvard Medical School. Subsequently, ultrasound pulses are targeted at the specific brain area. These pulses induce waves in the fluid within blood vessels, causing the microbubbles to expand and contract rapidly. This wave energy translates into biophysical energy via the microbubbles, and it is that process that safely opens the vessels, allowing temporary access to the brain for therapeutic drugs without causing harm.
These human studies were preceded by several notable preclinical studies including Leinenga and Götz (2015) and Burgess et al. (2014) which established the efficacy of ultrasound in clearing amyloid-beta plaques associated with Alzheimer’s disease. But even back then all the focus (no pun intended) was on the ultrasound beam and not the bubbles. Both the article titles and abstracts make no mention of what is arguably the most important link in the technology — gas-filled micron-sized bubbles safely coursing through the bloodstream. This lack of attribution to the microbubbles (also known as microspheres) is understandable, as many of the clinical initiatives are being funded by the company Insightec which manufactures the multi-million dollar machines used to generate the ultrasound.
Beyond neurological disorders, where researchers are mum about microbubbles, ultrasound technology empowered by microbubbles is also being leveraged to enhance brain cancer treatment strategies. As reported last summer in The Wall Street Journal’s “Future of Everything” column, recent early human trials using ultrasound and microbubble technology are yielding promising results. The study they referred to, published in The Lancet, involved patients with glioblastoma, a type of brain cancer. Researchers were up front in explaining “low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood–brain barrier.” They observed that combining ultrasound and microbubbles with powerful chemotherapeutic drugs carboplatin (Paraplatin®) and nab-paclitaxel (ABRAXANE®) achieved 5.9 and 3.7 times more drug into the tumor. Adam Sonabend, an associate professor of neurological surgery at Northwestern University and lead author of the trial, noted that both drugs are typically not used for brain cancer due to their limited ability to penetrate the blood-brain barrier. Hence microbubbles are making existing medicines far more effective.
Beyond the brain, microbubbles hold even more potential for making a tectonic shift in how cancer drugs are delivered. One of the first clinical applications in humans was published by Dimcevski (2016) where they treated dreaded pancreatic cancer with the standard-of-care drug gemcitabine but augmented it with microbubbles and ultrasound. Patients doubled their median overall survival from 8.9 months to 17.6 months, an extraordinary improvement without using any new, expensive drugs.
In Vesselon’s groundbreaking preclinical study, Xu (2021) we demonstrated that sonoporation, using our FDA-approved drug Imagent® and commercial ultrasound, can enable the systemic administration of the STING agonist, MSA-1 to enter tumors in far higher concentrations than its normal PK/PD characteristics provide. It is important to note that, unlike many of the previous preclinical studies in the field employing customized and difficult-to-standardize ultrasound equipment, as well as microbubbles that are made in-house, Vesselon’s study used FDA-approved microbubbles and a commercially available diagnostic ultrasound system to foster faster and broader clinical translation.
Vesselon’s data showed that a 5-minute procedure “substantially elevated” cytokine production and induced immunomodulatory benefits by sustaining STING-mediated immune activation while reversing its impact on immune suppression. These immune-engaging aspects of the Vesselon drug/STING combination resulted in the complete regression of both primary and distant tumors in 44% of subjects, an effect that even an intratumoral dose could not provide.
The integration of ultrasound technology into neurology and oncology holds great promise for optimizing treatment outcomes and overcoming challenges associated with drug delivery — IF accompanied by microbubbles — the cellular enablers to opening the blood-brain barrier and tumors to drug therapies. Vesselon’s ongoing research efforts aim to further translate these findings into clinical applications for the benefit of patients worldwide.
References:
Leinenga, G., & Götz, J. (2015). Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model. Science Translational Medicine, 7(278), 278ra33. DOI: 10.1126/scitranslmed.aaa2512
Burgess, A., Dubey, S., Yeung, S., Hough, O., Eterman, N., Aubert, I., & Hynynen, K. (2014). Alzheimer disease in a mouse model: MR imaging–guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior. Radiology, 273(3), 736–745. DOI: 10.1148/radiol.14140207
Sonabend, Adam M. et al., Repeated blood–brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial. Lancet Oncol 2023; 24: 509–22
Dimcevski, G et al., A human clinical trial using ultrasound and microspheres to enhance gemcitabine treatment of inoperable pancreatic cancer G. Dimcevski et al. Journal of Controlled Release 243 (2016) 172–181
Jun Xu, Nicolas Solban, Yun Wang, Heidi Ferguson, Samanthi Perera, Ken Lin, Mingmei Cai, Miller Paul, Ernest G. Schutt, Clayton T. Larsen, Rhodemann Li, Robert Saklatvala, Brian J. Long, Sheila Ranganath, Adam T. Procopio, Sachin Mittal, Allen C. Templeton. Sonoporation-Enhanced Delivery of STING Agonist Induced Robust Immune Modulation and Tumor Regression. Advanced Therapeutics. Volume 4, Issue 10 October 2021 2100154
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Vesselon develops patentable drug co-formulations using an FDA-approved, biophysically activated lipid microsphere and self-assembling liposomes. These co-formulations safely make targeted tissues more receptive to therapeutic drugs, producing unprecedented levels of efficacy. Watch the company’s digital town hall event to learn more at www.vesselon.com/townhall.
