The effects of pulsed mode HIFU, which have been observed to aid the local delivery of large molecule therapeutics without lasting detriment to the tissue, can be effectively translated from mouse models to bulk tissue models in larger animals, and eventually to humans. While pulsed HIFU drug delivery cannot be properly termed as surgery, it can be shown that the current FUS technology may be easily adapted to provide pulsed HIFU as an adjuvant or alternative therapy for those situations where FUS would be impractical. Because the pulsed HIFU power levels are much lower, on average, than normal FUS, it should be possible to pursue an efficient and effective pulsed HIFU enhanced drug delivery treatment with less concern for damage in the near and far field regions. The technique employed here, unlike other competing techniques, does not use ultrasound contrast agents or explicitly rely on cavitation. Cavitation activity is non-uniform and hard to control, ultimately leading to irreversible damage and death of some cells in the affected population, and thus may be at a disadvantage when it comes to regulatory approval. The use of ultrasound contrast agents for diagnostic echocardiography is now carrying “black box” warnings from the FDA proving that this concern is justified. Our proposed technique is designed to avoid this issue altogether. Pulsed HIFU treatment of mice without the use of contrast agents has consistently demonstrated improved local delivery of large molecular markers and has also been associated with improved therapeutic outcomes. The major hurdle to be overcome at this point is to demonstrate that the method will safely and effectively translate from the murine model to larger animal geometries. This is the main goal of the proposed research. A secondary goal is to further elucidate the mechanism behind the effect to develop a strategy for optimization of the procedure.
Use of ultrasound contrast agents for gene or drug delivery in cardiovascular medicine
