Novel drug-delivery approaches to the blood-brain barrier

Wang, Xiaoqing; Yu, Xiaowen; Vaughan, William P.; Liu, Mingyuan; Guan, Yangtai

doi:10.1007/s12264-014-1498-0

Cited by 9 publications

(8 citation statements)

References 73 publications

(64 reference statements)

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“…Due to the presence of blood tumor barrier (BTB), macromolecular chemotherapeutic agents are arduous to reach the tumor tissues and dramatically attenuate the chemotherapeutic effect. Accordingly, selective BTB opening is an effective method to improve chemotherapeutic efficacy of brain glioma (Black and Ningaraj, 2004 ; Wang and Liu, 2009 ; Wang et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: The Role of HOTAIR/miR-148b-3p/USF1 on Regulating the Permeability of BTB

Zhao

et al. 2017

Front. Mol. Neurosci.

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Homeobox transcript antisense intergenic RNA (HOTAIR), as a long non-coding RNA (lncRNA), has been considered to play critical roles in the biological properties of various tumors. The purposes of this study were to investigate the role and possible molecular mechanisms of HOTAIR in regulating the permeability of blood tumor barrier (BTB) in vitro. Our present study elucidated that the expressions of HOTAIR and upstream stimulatory factor 1 (USF1) was up-regulated, but miR-148b-3p was down-regulated in glioma microvascular endothelial cells (GECs). Knockdown of HOTAIR could increase the permeability of BTB as well as down-regulated the expressions of tight junction related proteins ZO-1, occludin, claudin-5, but up-regulated miR-148b-3p expressions in GECs. Meanwhile, dual-luciferase reporter assays demonstrated that HOTAIR was a target RNA of miR-148b-3p. Furthermore, overexpression of miR-148b-3p increased the permeability of BTB by down-regulating the expressions of tight junction related proteins and USF1 in GECs, and vice versa. And further result revealed USF1 was a target of miR-148b-3p. Silence of USF1 increased the permeability of BTB duo to their interaction with the promoters of ZO-1, occludin, and claudin-5 in GECs. Taken together, our finding indicated that knockdown of HOTAIR increased BTB permeability via binding to miR-148b-3p, which further reducing tight junction related proteins in GECs by targeting USF1. Thus, HOTAIR will attract more attention since it can serve as a potential target of drug delivery across BTB and may provide novel strategies for glioma treatment.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: The Role of HOTAIR/miR-148b-3p/USF1 on Regulating the Permeability of BTB

Zhao

et al. 2017

Front. Mol. Neurosci.

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“…TJ complex is composed of transmembrane proteins (occludin and claudins) and cytoplasmic proteins (zonula occludens, ZOs), which anchor to actin-based cytoskeleton proteins to form a closed structure (Wolburg et al, 2009 ). When the expressions of TJ related proteins ZO-1, occludin and claudin-5 were decreased, the TJ was opened and the permeability of BTB was increased (Drapeau and Fortin, 2015 ; Wang et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

The Role of miR-330-3p/PKC-α Signaling Pathway in Low-Dose Endothelial-Monocyte Activating Polypeptide-II Increasing the Permeability of Blood-Tumor Barrier

Liu

Chao

et al. 2017

Front. Cell. Neurosci.

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This study was performed to determine whether EMAP II increases the permeability of the blood-tumor barrier (BTB) by affecting the expression of miR-330-3p as well as its possible mechanisms. We determined the over-expression of miR-330-3p in glioma microvascular endothelial cells (GECs) by Real-time PCR. Endothelial monocyte-activating polypeptide-II (EMAP-II) significantly decreased the expression of miR-330-3p in GECs. Pre-miR-330-3p markedly decreased the permeability of BTB and increased the expression of tight junction (TJ) related proteins ZO-1, occludin and claudin-5, however, anti-miR-330-3p had the opposite effects. Anti-miR-330-3p could enhance the effect of EMAP-II on increasing the permeability of BTB, however, pre-miR-330-3p partly reversed the effect of EMAP-II on that. Similarly, anti-miR-330-3p improved the effects of EMAP-II on increasing the expression levels of PKC-α and p-PKC-α in GECs and pre-miR-330-3p partly reversed the effects. MiR-330-3p could target bind to the 3′UTR of PKC-α. The results of in vivo experiments were similar to those of in vitro experiments. These suggested that EMAP-II could increase the permeability of BTB through inhibiting miR-330-3p which target negative regulation of PKC-α. Pre-miR-330-3p and PKC-α inhibitor decreased the BTB permeability and up-regulated the expression levels of ZO-1, occludin and claudin-5 while anti-miR-330-3p and PKC-α activator brought the reverse effects. Compared with EMAP-II, anti-miR-330-3p and PKC-α activator alone, the combination of the three combinations significantly increased the BTB permeability. EMAP-II combined with anti-miR-330-3p and PKCα activator could enhance the DOX’s effects on inhibiting the cell viabilities and increasing the apoptosis of U87 glioma cells. Our studies suggest that low-dose EMAP-II up-regulates the expression of PKC-α and increases the activity of PKC-α by inhibiting the expression of miR-330-3p, reduces the expression of ZO-1, occludin and claudin-5, and thereby increasing the permeability of BTB. The results can provide a new strategy for the comprehensive treatment of glioma.

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“…We will focus eBrain to cover multiple delivery systems to allow better theoretical analysis of each delivery system. Future directions include comparing the systems effectiveness and classification of optimal delivery for treatments 31,32 . Along these lines, we have already implemented an intracerebral delivery system in which chemicals and cells are injected directly into the brain.…”

Section: Section 5: Future Ebrain Extensions and Potential Applicationsmentioning

confidence: 99%

eBrain: a Three Dimensional Simulation Tool to Study Drug Delivery in the Brain

Setty¹

2019

Sci Rep

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Neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease are severe disorders with acute symptoms that gradually progress. In the course of developing disease-modifying treatments for neurodegenerative disorders there is a need to develop novel strategies to increase efficacy of drugs and accelerate the development process. We developed a tool for simulating drug delivery in the brain by translating MRI data into an interactive 3D model. This tool, the eBrain, superimposes simulated drug diffusion and tissue uptake by inferring from the MRI data with a seamless display from any angle, magnification, or position. We discuss a representative implementation of eBrain that is inspired by clinical data in which insulin is intranasally administered to Alzheimer patients. Using extensive analysis of multiple eBrain simulations with varying parameters, we show the potential for eBrain to determine the optimal dosage to ensure drug delivery without overdosing the tissue. Specifically, we examined the efficacy of combined drug doses and potential compounds for tissue stimulation. Interestingly, our analysis uncovered that the drug efficacy is inferred from tissue intensity levels. Finally, we discuss the potential of eBrain and possible applications of eBrain to aid both inexperienced and experienced medical professionals as well as patients.

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Novel drug-delivery approaches to the blood-brain barrier

Cited by 9 publications

References 73 publications

RETRACTED: The Role of HOTAIR/miR-148b-3p/USF1 on Regulating the Permeability of BTB

RETRACTED: The Role of HOTAIR/miR-148b-3p/USF1 on Regulating the Permeability of BTB

The Role of miR-330-3p/PKC-α Signaling Pathway in Low-Dose Endothelial-Monocyte Activating Polypeptide-II Increasing the Permeability of Blood-Tumor Barrier

eBrain: a Three Dimensional Simulation Tool to Study Drug Delivery in the Brain

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