Engineers at Duke University announced on March 13 a new technique called Sonoporation-assisted Precise Intracellular Nanodelivery, or SonoPIN, which uses microbubbles and ultrasound to help large cancer drugs enter tumor cells and trigger their self-destruction.
The development of SonoPIN is significant because it could allow for more precise delivery of large-molecule therapeutics, such as proteolysis-targeting chimeras (PROTACs), with fewer side effects on healthy cells. In laboratory experiments, the technology caused half of the targeted cancer cells to self-destruct while leaving nearly all non-targeted cells unharmed.
PROTACs are a class of drugs that degrade proteins considered "undruggable" and can overcome resistance in cancer therapy. However, these molecules are typically too large to enter cells efficiently. "PROTAC molecules are too big to get into cells in the first place," said Yuqi Wu, a doctoral student in Tony Jun Huang's laboratory at Duke. "But with our SonoPIN platform, the PROTACs can enter into targeted cancer cells while almost completely ignoring non-targeted cells."
SonoPIN works by attaching prefabricated microbubbles—commonly used for ultrasound imaging—to cell membranes. When exposed to strong ultrasound waves, these bubbles collapse and create temporary pores in nearby cell membranes through a process called sonoporation. This allows large therapeutic molecules like PROTACs to pass into the cell. "This process is less like an explosion and more like a temporary, controlled mechanical opening," explained Huang. "While it involves physical force, because cell membranes are fluid and dynamic, they naturally self-heal and close these pores within minutes if not seconds."
In experiments using fluorescently labeled PROTACs, researchers found that cancer cells treated with SonoPIN absorbed significantly more of the drug than those treated with traditional methods—glowing seven times brighter under observation—and about half of these cancer cells self-destructed while 99% of healthy cells remained viable.
Looking ahead, the research team plans to test this approach in mouse models and has applied for a patent on their work. Huang said: "And because SonoPIN relies on a mechanical delivery approach rather than biological engulfment, it could theoretically deliver therapeutics of almost any size. We would also be excited to see how it performs with therapeutics such as large gene-editing complexes." The project received support from the National Institutes of Health and the National Science Foundation.
