Early Detection and Reversal of Cell Apoptosis Induced by Focused Ultrasound-Mediated Blood–Brain Barrier Opening

Abstract

Focused ultrasound (FUS) combined with microbubbles (MBs) has recently emerged as a potential approach to open the blood-brain barrier (BBB) for delivering drugs into the brain. However, appropriate approaches are still lacking to monitor the sublethal damage during FUS-mediated BBB opening in vivo, especially the early stage cell apoptotic events. Here, we developed a kind of nanoprobe-loaded MBs (AV-ICG-NPs@MBs) which can monitor the apoptotic cells that occur during FUS-mediated BBB opening through encapsulating the annexin V-targeted nanoprobes AV-ICG-NPs into the cavity of lipid-PLGA hybrid MBs. When irradiated by FUS, AV-ICG-NPs@MBs in the cerebral blood vessels would produce cavitation, favoring the BBB opening. Meanwhile, AV-ICG-NPs@MBs would be destroyed and release their AV-ICG-NPs payload. These released AV-ICG-NPs can be further delivered into the brain via the destructed BBB and bind with the phosphatidylserine externalized on the membrane of apoptotic cells if this occurs, leading to the prolonged detention of fluorescent signals in the brain. Furthermore, we also provided an effective strategy to inhibit or reverse the possible damage to the brain from a FUS-mediated BBB opening technology, through developing AV-ICG-NPs/GAS@MBs that encapsulate the antioxidant gastrodin (GAS) into AV-ICG-NPs@MBs. Accompanied by FUS irradiation and bubble cavitation, GAS was released and delivered into the brain, where they scavenged the oxygen free radicals produced from cavitation, leading to significantly lower fluorescence signals in the brain due to the absence of externalized phosphatidylserine. In conclusion, our study provides an approach to monitor and inhibit cell apoptotic events during FUS-mediated BBB opening.