Focused ultrasound (FUS) with
microbubbles has been used to achieve local blood-brain barrier opening (BBB opening) and increase the penetration of therapeutic drugs into
brain tumors. However, inertial cavitation of
microbubbles during FUS-induced BBB opening causes intracerebral hemorrhaging (ICH), leading to acute and
chronic brain injury and limiting the efficiency of
drug delivery. Here we investigated whether induction of
drug (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU)-loaded bubbles (
BCNU bubbles) to oscillate at their resonant frequency would reduce inertial cavitation during BBB opening, thereby eliminating ICH and enhancing
drug delivery in a rat brain model. FUS was tested at 1 and 10 MHz, over a wide range of pressure (mechanical index ranging from 0.16 to 1.42) in the presence of
BCNU bubbles. Excitation of
BCNU bubbles by resonance frequency-matched FUS (10 MHz) resulted in predominantly stable cavitation and significantly reduced the occurrence of potential hazards of exposure to
biological tissues during the BBB opening process. In addition, the drug release process could be monitored by acoustic emission obtained from ultrasound imaging. In
tumor-bearing animals,
BCNU bubbles with FUS showed significant control of
tumor progression and improved maximum survival from 26 to 35 days. This study provides useful advancements toward the goal of successfully translating FUS
theranostic bubble-enhanced brain
drug delivery into clinical use.