Cavitation bubbles mediated molecular delivery during sonoporation

Molecular delivery using ultrasound (US) and nano/microbubbles (NBs), i.e., sonoporation, has applications in gene therapy and anticancer drug delivery. When NBs are destructed by ultrasound, the surrounding cells are exposed to mechanical impulsive forces generated by collapse of either the NBs or the cavitation bubbles created by the collapse of NBs. In the present study, experimental, theoretical and numerical analyses were performed to investigate cavitation bubbles mediated molecular delivery during sonoporation. Experimental observation using lipid NBs indicated that increasing US pressure increased uptake of fluorescent molecules, calcein (molecular weight: 622), into 293T human, and decreased survival fraction. Confocal microscopy revealed that calcein molecules were uniformly distributed throughout the some treated cells. Next, the cavitation bubble behavior was analyzed theoretically based on a spherical gas bubble dynamics. The impulse of the shock wave (i.e., the pressure integrated over time) generated by the collapse of a cavitation bubble was a dominant factor for exogenous molecules to enter into the cell membrane rather than bubble expansion. Molecular dynamics simulation revealed that the number of exogenous molecules delivered into the cell membrane increased with increasing the shock wave impulse. We concluded that the impulse of the shock wave generated by cavitation bubbles was one of important parameters for causing exogenous molecular uptake into living cells during sonoporation.