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dc.contributor.authorJablonska, A.
dc.contributor.authorLan, X.
dc.contributor.authorJanowski, M.
dc.contributor.authorWalczak, P.
dc.date.accessioned2020-01-08T15:05:30Z
dc.date.available2020-01-08T15:05:30Z
dc.date.issued2020
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85075973955&doi=10.1016%2fj.jconrel.2019.11.019&partnerID=40&md5=1f95ed33cc5d42ea54c1661044d0d2f9
dc.identifier.urihttp://hdl.handle.net/10713/11576
dc.description.abstractIntra-arterial (IA) infusion of mannitol induces osmotic blood-brain barrier opening (OBBBO) and that method has been used for decades to improve drug delivery to the brain. However, high variability of outcomes prevented vast clinical adoption. Studies on dynamic multi-scale imaging of OBBBO as well as extravasation of IA injected therapeutic agents are essential to develop strategies assuring precision and reproducibility of drug delivery. Intravital microscopy is increasingly used to capture the dynamics of biological processes at the molecular level in convenient mouse models. However, until now OBBBO has been achieved safely in subcortical structures, which prevented direct insight into the process of extravasation through the skull window. Here, we used our previously developed real-time MRI to adjust the procedure to achieve robust cortical OBBBO. We found that catheter-mediated delivery to the cortex from the ipsilateral carotid artery can be improved by temporarily occluding the contralateral carotid artery. The reproducibility and safety of the method were validated by MRI and histology. This experimental platform was further exploited for studying with intravital microscopy the extravasation of 0.58 kDa rhodamine and 153 kDa anti-VEGF monoclonal antibody (bevacizumab) upon IA injection. Dynamic imaging during IA infusion captured the spatiotemporal dynamic of infiltration for each molecule into the brain parenchyma upon OBBBO. Small-sized rhodamine exhibited faster and higher penetration than the antibody. Histological analysis showed some uptake of the monoclonal antibody after IA delivery, and OBBBO significantly amplified the extent of its uptake. For quantitative assessment of cortical uptake, bevacizumab was radiolabeled with zirconium-89 and infused intraarterially. As expected, OBBBO potentiated brain accumulation, providing 33.90 ± 9.06% of injected dose per gram of brain tissue (%ID/g) in the cortex and 17.09 ± 7.22%ID/g in subcortical structures. In contrast IA infusion with an intact BBB resulted in 3.56 ± 1.06%ID/g and 3.57 ± 0.59%ID/g in the same brain regions, respectively. This study established reproducible cortical OBBBO in mice, which enabled multi-photon microscopy studies on OBBBO and drug targeting. This approach helped demonstrate in a dynamic fashion extravasation of fluorescently-tagged antibodies and their effective delivery into the brain across an osmotically opened BBB.en_US
dc.description.sponsorshipThis study was supported by 2017-MSCRFD-3942, 2019-MSCRFD-5031, NIH R01NS091110 , R01NS102675 R21NS091599 .en_US
dc.description.urihttps://doi.org/10.1016/j.jconrel.2019.11.019en_US
dc.language.isoen_USen_US
dc.publisherElsevier B.V.en_US
dc.relation.ispartofJournal of Controlled Release
dc.subjectBlood-brain barrieren_US
dc.subjectCortexen_US
dc.subjectIntra-arterialen_US
dc.subjectMannitolen_US
dc.subjectTwo-photon microscopyen_US
dc.titleOptimization of osmotic blood-brain barrier opening to enable intravital microscopy studies on drug delivery in mouse cortexen_US
dc.typeArticleen_US
dc.identifier.doi10.1016/j.jconrel.2019.11.019
dc.identifier.pmid31751635


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