Abstract
Microbubbles (MBs) serve as a critical catalyst to amplify local cavitation in CNS capillary lumen to facilitate focused ultrasound (FUS) to transiently open the blood-brain barrier (BBB). However, limited understanding is available regarding the effect of different microbubbles to induce BBB opening. The aim of this study is to characterize different MBs on their effect in FUS-induced BBB opening. Three MBs, SonoVue, Definity, and USphere, were tested, with 0.4-MHz FUS exposure at 0.62–1.38 of mechanical index (MI) on rats. Evans blue, dynamic contrast-enhanced (DCE) MRI and small-animal ultrasound imaging were used as surrogates to allow molecule-penetrated quantification, BBB-opened observation, and MBs circulation/persistence. Cavitation activity was measured via the passive cavitation detection (PCD) setup to correlate with the exposure level and the histological effect. Under given and identical MB concentrations, the three MBs induced similar and equivalent BBB-opening effects and persistence. In addition, a treatment paradigm by adapting exposure time is proposed to compensate MB decay to retain the persistence of BBB-opening efficiency in multiple FUS exposures. The results potentially improve understanding of the equivalence among MBs in focused ultrasound CNS drug delivery, and provide an effective strategy for securing persistence in this treatment modality.
Highlights
Low-pressure burst mode focused ultrasound (FUS) exposure in conjunction with the administration of microbubbles (MBs) has been found to produce transient alteration of blood-brain barrier (BBB) permeability[2]
The SonoVue-group generated more apparent subharmonic/ultraharmonic emissions at low (0.62 mechanical index (MI)) exposure level (2–3 dB higher than the Definity- and USphere-group), indicating that stable cavitation activity in SonoVue can be triggered at this exposure level
Wideband emissions were not apparent in 0.62-MI exposure for three MBs, but were all significantly elevated at 0.85-MI exposure level, implying the inertial cavitation did not present at 0.62-MI but were significantly involved at high (1.38-MI) exposure
Summary
Low-pressure burst mode focused ultrasound (FUS) exposure in conjunction with the administration of microbubbles (MBs) has been found to produce transient alteration of BBB permeability[2]. This technology has the potential to enhance delivery of various kinds of therapeutic agents into the brain and has potential to benefit treatment of CNS diseases. Commercial bubbles are generally larger than 2 μmand their applicable time window is about 5–10 min These commercialized MBs have been shown to effectively assist with the opening of the BBB under FUS exposure[5,13,14,15]. Cavitation activity was measured via passive cavitation detection (PCD) to correlate with the exposure levels and the histological effects
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