Role for caveolin-mediated transcytosis in facilitating transport of large cargoes into the brain via ultrasound

Pandit, Rucha; Sullivan, Rodney N.; Palliyaguru, Tishila; Parton, Robert G.; Götz, Jürgen

doi:10.1016/j.jconrel.2020.09.015

Cited by 50 publications

(57 citation statements)

References 43 publications

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“…Interestingly, we also observed correlations between CE and expression of Cav1 24 hours later. Upregulation of caveolin-1 expression after FUS BBBD mediates transcellular transport across the BBB 41 , 42 , representing an alternative to the paracellular mechanism for how FUS enhances BBB permeability. Our data support both phenomena.…”

Section: Discussionmentioning

confidence: 99%

Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption

2021

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Background: Focused ultrasound (FUS) blood brain barrier disruption (BBBD) permits the noninvasive, targeted, and repeatable delivery of drugs to the brain. FUS BBBD also elicits secondary responses capable of augmenting immunotherapies, clearing amyloid-β and hyperphosphorylated tau, and driving neurogenesis. Leveraging these secondary effects will benefit from an understanding of how they correlate to the magnitude of FUS BBBD and are differentially affected by the mechanical and biochemical stimuli imparted during FUS BBBD. Methods: We aggregated 75 murine transcriptomes in a multiple regression framework to identify genes expressed in proportion to biochemical (i.e. contrast MR image enhancement (CE)) or mechanical (i.e. harmonic acoustic emissions from MB-activation (MBA)) stimuli associated with FUS BBBD. Models were constructed to control for potential confounders, such as sex, anesthesia, and sequencing batch. Results: MBA and CE differentially predicted expression of 1,124 genes 6 h or 24 h later. While there existed overlap in the transcripts correlated with MBA vs CE, MBA was principally predictive of expression of genes associated with endothelial reactivity while CE chiefly predicted sterile inflammation gene sets. Over-representation analysis identified transcripts not previously linked to BBBD, including actin filament organization, which is likely important for BBB recovery. Transcripts and pathways associated with neurogenesis, microglial activation, and amyloid-β clearance were significantly correlated to BBBD metrics. Conclusions: The secondary effects of BBBD may have the potential to be tuned by modulating FUS parameters during BBBD, and MBA and CE may serve as independent predictors of transcriptional reactions in the brain.

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Section: Discussionmentioning

confidence: 99%

Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption

2021

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“…When the pressure is too low, there is no functional BBB opening and no cargoes are taken up, and as the pressure increases, cargoes can be taken up increases, until due to the interaction with microbubbles a pressure threshold is reached that causes inertial cavitation of the microbubbles with ensuing damage [43]. Agents which have been safely delivered into the brain parenchyma by FUS include dextrans of various sizes [44,45], chemotherapeutic drugs such as doxorubicin or methotrexate [46,47], antibodies in various formats [48][49][50][51], and as viral vectors for gene therapy [52]. Here we asked whether it would be possible to increase permeability at a given FUS pressure when combined with compounds targeting TJ proteins such as claudin-5.…”

Section: Discussionmentioning

confidence: 99%

Claudin-5 binder enhances focused ultrasound-mediated opening in anin vitroblood-brain barrier model

Chen

Sutharsan

Lee

et al. 2021

Preprint

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Rationale: The blood-brain barrier (BBB) while functioning as a gatekeeper of the brain, impedes cerebral drug delivery. An emerging technology to overcome this limitation is focused ultrasound (FUS). When FUS interacts with intravenously injected microbubbles (FUS+MB), the BBB opens, transiently allowing the access of therapeutic agents into the brain. However, the ultrasound parameters need to be tightly tuned: when the acoustic pressure is too low there is no opening, and when it is too high, bleeds can occur. We therefore asked whether BBB permeability can be increased by combining FUS+MB with a second modality such that in a clinical setting lower acoustic pressures could be potentially used. Methods: Given that FUS achieves BBB opening by the disruption of tight junction (TJ) proteins such as claudin-5 of brain endothelial cells, we generated a stable MDCK II cell line (eGFP-hCldn5-MDCK II) that expresses fluorescently tagged human claudin-5. Two claudin-5 binders, mC5C2 (a peptide) and cCPEm (a truncated form of an enterotoxin), that have been reported previously to weaken the barrier, were synthesized and assessed for their abilities to enhance the permeability of cellular monolayers. We then performed a comparative analysis of single and combination treatments. Results: We successfully generated a novel cell line that formed functional monolayers as validated by an increased transendothelial electrical resistance (TEER) reading and a low (< 0.2%) permeability to sodium fluorescein (376 Da). We found that the binders exerted a time- and concentration-dependent effect on BBB opening when incubated over an extended period, whereas FUS+MB caused a rapid barrier opening followed by recovery after 12 hours within the tested pressure range. Importantly, preincubation with cCPEm prior to FUS+MB treatment resulted in greater barrier opening compared to either FUS+MB or cCPEm alone as measured by reduced TEER values and an increased permeability to fluorescently labelled 40 kDa dextran (FD40). Conclusion: The data suggest that pre-incubation with clinically suitable binders to TJ proteins may be a general strategy to facilitate safer and more effective ultrasound-mediated BBB opening in cellular and animal systems and potentially also for the treatment of human diseases of the brain.

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“…Pandit et al compared the leakage of substances of different molecular weights in Cav-1-deficient and WT mice exposed to ultrasound. Results showed that the two strains showed a significant difference in the BBB leakage of large molecular substances (500 kDa), but no difference in the leakage of small molecular substances (3 kDa and 70 kDa) was detected, suggesting that Cav-1-related transcytosis induced by therapeutic ultrasound may play a key role in the transport of macromolecules [61]. To date, no original research has reported on the application of ultrasound in the treatment of IS, but these studies have shed light on the mechanism of a transient, targeted, and reversible opening of the BBB for drug delivery.…”

Section: Transcytosis-targeted Drug Delivery Strategymentioning

confidence: 92%

Caveolae-Mediated Endothelial Transcytosis across the Blood-Brain Barrier in Acute Ischemic Stroke

Min

Shi

Liu

et al. 2021

JCM

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Blood-brain barrier (BBB) disruption following ischemic stroke (IS) contributes to hemorrhagic transformation, brain edema, increased neural dysfunction, secondary injury, and mortality. Brain endothelial cells form a para and transcellular barrier to most blood-borne solutes via tight junctions (TJs) and rare transcytotic vesicles. The prevailing view attributes the destruction of TJs to the resulting BBB damage following IS. Recent studies define a stepwise impairment of the transcellular barrier followed by the paracellular barrier which accounts for the BBB leakage in IS. The increased endothelial transcytosis that has been proven to be caveolae-mediated, precedes and is independent of TJs disintegration. Thus, our understanding of post stroke BBB deficits needs to be revised. These recent findings could provide a conceptual basis for the development of alternative treatment strategies. Presently, our concept of how BBB endothelial transcytosis develops is incomplete, and treatment options remain limited. This review summarizes the cellular structure and biological classification of endothelial transcytosis at the BBB and reviews related molecular mechanisms. Meanwhile, relevant transcytosis-targeted therapeutic strategies for IS and research entry points are prospected.

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Role for caveolin-mediated transcytosis in facilitating transport of large cargoes into the brain via ultrasound

Cited by 50 publications

References 43 publications

Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption

Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption

Claudin-5 binder enhances focused ultrasound-mediated opening in anin vitroblood-brain barrier model

Caveolae-Mediated Endothelial Transcytosis across the Blood-Brain Barrier in Acute Ischemic Stroke

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