Abstract
The use of focused ultrasound (FUS) with microbubbles has been proven to induce transient blood–brain barrier opening (BBB-opening). However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB-opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1–4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz) can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg) by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.
Highlights
The blood–brain barrier (BBB) presents a major obstacle to the entry of therapeutic molecules into the central nervous system (CNS) [1]
The results of Group 2 demonstrated that stable cavitation activity could be induced with mismatched the frequency of focused ultrasound (FUS), and BBB-opening occurred at pressure of 2.0 MPa (Figure 3A and 3B)
Thereby improve the safety of novel low frequency FUS induced BBB-opening process in the future. The roles of both cavitation activities within FUSinduced BBB-opening process and the feasibility of enhancing local drug release to brain tissue have been confirmed by our designed submicron bubbles and matched the frequency FUS sonication
Summary
The blood–brain barrier (BBB) presents a major obstacle to the entry of therapeutic molecules into the central nervous system (CNS) [1]. The interaction between microbubbles and FUS temporarily deforms endothelial cells and changes the integration of tight junctions [6,7]. This procedure leads to temporarily disruption of the BBB and thereby increases the efficiency of drug delivery locally in the CNS. This technology is ideally suited for the transcranial delivery of water-soluble drugs, and has the potential to deliver macromolecules (e.g. monoclonal antibodies) with up to tens of kilodaltons in size. FUS-induced BBB opening is reversible within several hours, providing a window of opportunity for local delivery of therapeutic agents into the brain [10,11,12,13,14,15]
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