Anchoring Microbubbles on Cerebrovascular Endothelium as a New Strategy Enabling Low‐Energy Ultrasound‐Assisted Delivery of Varisized Agents Across Blood‐Brain Barrier

Abstract

The protective blood‐brain barrier (BBB) prevents most therapeutic agents from entering the brain. Currently, focused ultrasound (FUS) is mostly employed to create microbubbles that induce a cavitation effect to open the BBB. However, microbubbles pass quickly through brain microvessels, substantially limiting the cavitation effect. Here, we constructed a novel perfluoropropane‐loaded microbubble, termed ApoER‐Pep‐MB, which possessed a siloxane bonds‐crosslinked surface to increase the microbubble stability against turbulence in blood circulation and was decorated with binding peptide for apolipoprotein E receptor (ApoER‐Pep). The microbubble with tailor‐made micron size (2 µm) and negative surface charge (−30 mV) performed ApoER‐mediated binding rather than internalization into brain capillary endothelial cells. Consequently, the microbubble accumulated on the brain microvessels, based on which even a low‐energy ultrasound with less safety risk than FUS, herein diagnostic ultrasound (DUS), could create a strong cavitation effect to open the BBB. Evans Blue and immunofluorescence staining studies demonstrated that the DUS‐triggered cavitation effect not only temporarily opened the BBB for 2 h but also caused negligible damage to the brain tissue. Therefore, various agents, ranging from small molecules to nanoscale objects, can be efficiently delivered to target regions of the brain, offering tremendous opportunities for the treatment of brain diseases.

Light on Alzheimer’s disease: from basic insights to preclinical studies

“…Finally, the blood vessel tortuosity decreased in AD mice but steadily increased in WT mice (Figure 4G). The findings from this detection align with earlier studies through in vitro electron microscopy, suggesting that Aβ plaques adhere to and accumulates on the walls of meningeal <20 mJ/cm 2 (Li B. et al, 2023;Li D. et al, 2023).…”

“…This impact is assessed using transcranial Doppler ultrasound (TCD) ( Russell and Bornstein, 2005 ; Gaudet et al, 2010 ; Gasparovic et al, 2013 ; Yan et al, 2022 ). Furthermore, the blood–brain barrier (BBB) in brain can be unfolded by exploiting the microbubble contrast agents during focused ultrasound imaging processes ( Li B. et al, 2023 ; Li D. et al, 2023 ). This mechanism allows for neuroimmune modulation and controlled drug release, presenting a promising therapeutic avenue for AD ( Silva et al, 2018 ).…”