Hart, A. R. | Search bioRxiv

bioRxiv2026

Ultrasonic local anesthetic uncaging enables noninvasive, targeted, and transient knock-out of brain function

Noninvasive, spatially localized brain inhibition would enable precise neural circuit interrogation, mapping, and treatment. We previously presented SonoRopi, an acoustically activatable liposomal formulation of ropivacaine, and demonstrated its utility for targeted peripheral nerve anesthesia. Here, we extend SonoRopi to localized brain anesthesia following intravenous administration and transcranial focused ultrasound application. Ultrasonic uncaging of SonoRopi releases ropivacaine, which crosses the intact blood-brain barrier to anesthetize the sonicated region. SonoRopi uncaging in mouse primary visual cortex suppressed visually evoked cortical activity for one hour, while uncaging in rat somatosensory hindlimb cortex produced lateralized, reversible hindlimb sensory anesthesia. Off-target control sonication preserved function in both paradigms. No acute histologic injury or open-field behavioral abnormalities were detected following this intervention. SonoRopi thereby enables noninvasive, spatially targeted, reversible brain inhibition with physiologic and behavioral efficacy in two rodent species.

bioengineering↗

bioRxiv2023

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 SummaryIncorporating a few percent sucrose into a liposome transforms it into an immediately translatable vehicle for noninvasive, on-demand ultrasound-targeted drug delivery.

bioengineering↗