Duke Engineers Develop SonoPIN Technology to Enhance Delivery of Large Cancer Therapeutics
核心洞察
Duke University (搜索) engineers have developed SonoPIN technology that uses microbubbles and ultrasound to deliver large cancer drugs like PROTACs (搜索) directly into tumor cells.
The technology achieved 50% cancer cell destruction while maintaining 99% viability of healthy cells in benchtop experiments, demonstrating precise targeting capabilities.
SonoPIN overcomes the size limitation of PROTAC molecules by creating temporary nanoscopic pores in cell membranes through controlled sonoporation.
Duke University (搜索) engineers have developed a breakthrough technology called SonoPIN (Sonoporation-assisted Precise Intracellular Nanodelivery) that uses microbubbles and ultrasound to deliver large cancer therapeutics directly into tumor cells. The research, published March 13 in the Proceedings of the National Academy of Sciences, demonstrates significant potential for precisely targeting cancer cells while minimizing damage to healthy tissue.
Addressing PROTAC Delivery Challenges
The technology specifically addresses limitations of proteolysis-targeting chimeras (PROTACs (搜索)), an emerging class of cancer therapeutics that show promise for degrading "undruggable" proteins and overcoming drug resistance. PROTACs work by binding to specific target proteins and recruiting an enzyme called E3 ubiquitin ligase (搜索), which marks proteins for destruction by the body's natural cellular garbage collection system.
In cancer applications, PROTACs (搜索) target and degrade BRD4, a protein essential for cancer cell reproduction and survival. Once destroyed, cancer cells lose their ability to rapidly reproduce and are forced to self-destruct. However, PROTACs face significant delivery challenges due to their large molecular size.
"PROTAC molecules are too big to get into cells in the first place," said Yuqi Wu, a doctoral student in the laboratory of Tony Jun Huang, the William Bevan Distinguished Professor of Mechanical Engineering and Materials Science at Duke. "But with our SonoPIN platform, the PROTACs (搜索) can enter into targeted cancer cells while almost completely ignoring non-targeted cells."
Mechanism of Action
SonoPIN utilizes prefabricated microbubbles commonly used in ultrasound imaging for contrast enhancement. The researchers equipped these microbubbles with synthetic nucleic acid strands designed to bind specifically with biochemical receptors present on cancer cell membranes but absent on healthy cells.
When exposed to vigorous ultrasound waves, the microbubbles collapse rapidly, creating a phenomenon called sonoporation in nearby cells. According to current hypotheses, the bubble collapse forms high-velocity microjets and emits shock waves that create nanoscopic, temporary pores in cell membranes large enough for PROTACs (搜索) to enter.
"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."
Experimental Results
The research team optimized ultrasound frequencies and intensities to achieve maximum therapeutic delivery efficiency. To validate their platform, they attached fluorescent molecules to PROTACs (搜索) and conducted comparative experiments on both cancer cells and healthy cells.
After one minute of ultrasound exposure, cells treated with SonoPIN glowed seven times brighter than those treated with traditional PROTAC delivery methods, indicating significantly enhanced drug uptake. This improved delivery resulted in 50% of targeted cancer cells self-destructing while maintaining 99% viability of non-targeted healthy cells.
Future Applications and Development
The researchers have applied for a patent covering their work and plan to advance testing to mouse models. Their approach involves injecting PROTACs (搜索) and cancer-seeking microbubbles intravenously, then focusing ultrasound waves on tumor locations to create a highly targeted cancer treatment with minimal side effects.
The mechanical nature of SonoPIN's delivery approach offers broader therapeutic potential beyond PROTACs (搜索). "Because SonoPIN relies on a mechanical delivery approach rather than biological engulfment, it could theoretically deliver therapeutics of almost any size," Huang noted. "We would also be excited to see how it performs with therapeutics such as large gene-editing complexes."
The research was supported by multiple National Institutes of Health grants (R01AG084098, R01CA282939, R01GM141055, R44GM154514, and R44GM154515) and the National Science Foundation (CMMI-2104295).