Multimodal evaluation of blood-brain barrier opening in mice in response to low-intensity ultrasound and a claudin-5 binder

Chen, Liyu; Song, Jae; Richter-Stretton, Gina; Lee, Wendy; Padmanabhan, Pranesh; Götz, Jürgen

doi:10.7150/ntno.95146

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Nanotheranostics 2024; 8(4):427-441. doi:10.7150/ntno.95146 This issue Cite

Research Paper

Multimodal evaluation of blood-brain barrier opening in mice in response to low-intensity ultrasound and a claudin-5 binder

Liyu Chen, Jae Song, Gina Richter-Stretton, Wendy Lee, Pranesh Padmanabhan, Jürgen Götz^✉

Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, Brisbane QLD 4072, Australia.

Citation:

Chen L, Song J, Richter-Stretton G, Lee W, Padmanabhan P, Götz J. Multimodal evaluation of blood-brain barrier opening in mice in response to low-intensity ultrasound and a claudin-5 binder. Nanotheranostics 2024; 8(4):427-441. doi:10.7150/ntno.95146. https://www.ntno.org/v08p0427.htm

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Abstract

Background: The blood-brain barrier (BBB) is a major bottleneck in delivering therapeutics to the brain. Treatment strategies to transiently open this barrier include focused ultrasound combined with intravenously injected microbubbles (FUS^+MB) and targeting of molecules that regulate BBB permeability.

Methods: Here, we investigated BBB opening mediated by the claudin-5 binder cCPEm (a microorganismal toxin in a truncated form) and FUS^+MB at a centre frequency of 1 MHz, assessing dextran uptake, broadband emission, and endogenous immunoglobulin G (IgG) extravasation.

Results: FUS^+MB-induced BBB opening was detectable at a pressure ≥0.35 MPa when assessed for leakage of 10 and 70 kDa dextran, and at ≥0.2 MPa for uptake of endogenous IgG. Treating mice with 20 mg/kg cCPEm failed to open the BBB, and pre-treatment with cCPEm followed by FUS^+MB at 0.2 and 0.3 MPa did not overtly increase BBB opening compared to FUS^+MB alone. Using passive cavitation detection (PCD), we found that broadband emission correlated with the peak negative pressure (PNP) and dextran leakage, indicating the possibility of using broadband emission for developing a feedback controller to monitor BBB opening.

Conclusions: Together, our study highlights the challenges in developing combinatorial approaches to open the BBB and presents an additional IgG-based histological detection method for BBB opening.

Keywords: blood-brain barrier, broadband emission, claudin-5, focused ultrasound, immunoglobulins

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APA

Chen, L., Song, J., Richter-Stretton, G., Lee, W., Padmanabhan, P., Götz, J. (2024). Multimodal evaluation of blood-brain barrier opening in mice in response to low-intensity ultrasound and a claudin-5 binder. Nanotheranostics, 8(4), 427-441. https://doi.org/10.7150/ntno.95146.

ACS

Chen, L.; Song, J.; Richter-Stretton, G.; Lee, W.; Padmanabhan, P.; Götz, J. Multimodal evaluation of blood-brain barrier opening in mice in response to low-intensity ultrasound and a claudin-5 binder. Nanotheranostics 2024, 8 (4), 427-441. DOI: 10.7150/ntno.95146.

NLM

CSE

Chen L, Song J, Richter-Stretton G, Lee W, Padmanabhan P, Götz J. 2024. Multimodal evaluation of blood-brain barrier opening in mice in response to low-intensity ultrasound and a claudin-5 binder. Nanotheranostics. 8(4):427-441.

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