Acoustomechanically activatable liposomes for ultrasonic drug uncaging

Ultrasound-activatable drug-loaded nanocarriers enable noninvasive and spatiotemporally-precise on-demand drug delivery throughout the body. However, most systems for ultrasonic drug uncaging utilize cavitation or heating as the drug release mechanism and often incorporate relatively exotic excipients into the formulation that together limit the drug-loading potential, stability, and clinical translatability and applicability of these systems. Here we describe an alternate strategy for the design of such systems in which the acoustic impedance and osmolarity of the internal liquid phase of a drug-loaded particle is tuned to maximize ultrasound-induced drug release. No gas phase, cavitation, or medium heating is necessary for the drug release mechanism. Instead, a non-cavitation-based mechanical response to ultrasound mediates the drug release. Importantly, this strategy can be implemented with relatively common pharmaceutical excipients, as we demonstrate here by implementing this mechanism with the inclusion of a few percent sucrose into the internal buffer of a liposome. Further, the ultrasound protocols sufficient for in vivo drug uncaging with this system are achievable with current clinical therapeutic ultrasound systems and with intensities that are within FDA and society guidelines for safe transcranial ultrasound application. Finally, this current implementation of this mechanism should be versatile and effective for the loading and uncaging of any therapeutic that may be loaded into a liposome, as we demonstrate for four different drugs in vitro, and two in vivo. These acoustomechanically activatable liposomes formulated with common pharmaceutical excipients promise a system with high clinical translational potential for ultrasonic drug uncaging of myriad drugs of clinical interest. One Sentence Summary Incorporating a few percent sucrose into a liposome transforms it into an immediately translatable vehicle for noninvasive, on-demand ultrasound-targeted drug delivery. ### Competing Interest Statement RDA has equity and has received consulting fees from Cordance Medical and Lumos Labs and grant funding from AbbVie Inc. All other authors declare no conflicts of interest.