Ultrasound-Activated Nanobubbles Break Down Tumor Barriers to Improve Drug Delivery

Researchers at Case Western Reserve University have discovered a way to breach one of cancer's most stubborn defenses: the impenetrable fortress that solid tumors build around themselves. By injecting nanobubbles filled with inert gas into tumors and "jiggling" them with ultrasound, the team successfully broke down tumor barriers enough for treatment-bearing molecules to get inside, according to results of a new study published in ACS Nano.

"The physical barrier is limiting delivery of cancer drugs, especially for new immunotherapies," said the vice chair and professor of biomedical engineering, a joint department of the Case School of Engineering and Case Western Reserve School of Medicine. "We developed a strategy that uses ultrasound-activated nanobubbles, which gently remodels the tumor microenvironment and effectively collapses the tumor walls, opening the door for drugs and immune cells."

The therapy could potentially be fast-tracked to clinical testing because the nanobubbles are already being commercialized for detecting prostate cancer, and the ultrasound is approved by the U.S. Food and Drug Administration (FDA) and commercially available.

As tumors grow, they create unusually stiff, dense tissue around them—made mostly from collagen, the protein that forms scar tissue. This barrier prevents modern immune therapies, particularly RNA carried in lipid nanoparticles, from reaching immune cells inside the tumor.

In a breast cancer model, the researchers injected nanobubbles filled with an inert gas, perfluoropropane, into a tumor. Then, using ultrasound, they directed sound waves at the tumor to gently "jiggle" the bubbles, breaking down the tumor's stiff structure without destroying cells.

The collaboration between the nanotechnology and immunotherapy lab and the ultrasound and nanomedicine lab of the Henry Willson Payne Professor of Radiology in the medical school and director of the CWRU Center for Imaging Research, found that the tumors became softer, more homogeneous and more penetrable by immune cells and nanoparticles.

"We drop the defenses of the cancer and give a fair chance for our therapies to actually win," said the professor of biomedical engineering. "We didn't invent a new drug, but it has the potential to make any existing or emerging therapy work much better."

Even more remarkable: The treatment activated immune cells already inside tumors without additional therapies. "They start secreting danger signals and recruiting more immune cells to the site of the tumor," researchers said. "Not only that, the killer T cells that target that cancer will also seek out other tumors—even ones that weren't treated."

The nanobubble treatment made the tumors softer for at least five days, while untreated tumors grew stiffer and more difficult to treat. When the researchers later injected lipid nanoparticles containing RNA that enhanced the tumor's T cell activity, the treatment dispersed throughout the tumor rather than remaining at the injection site.

"Any tumor that you can biopsy can potentially have nanobubbles introduced," researchers stated. "This is especially important for solid tumors that are difficult to treat, where ultrasound is already used, like liver, prostate and ovarian cancers."

The nanobubbles, developed in the lab, are being commercialized for detecting prostate cancer by Visano Theranostics, a company co-founded by the professor. An Investigational New Drug 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.

The research was funded by grants from the Case Comprehensive Cancer Center and the National Institutes of Health.