Endonasal CNS Delivery System for Blood-Brain Barrier Impermeant Therapeutic Oligonucleotides Using Heterotopic Mucosal Engrafting.
Endonasal CNS Delivery System for Blood-Brain Barrier Impermeant Therapeutic Oligonucleotides Using Heterotopic Mucosal Engrafting.
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使用异位粘膜上的鼻鼻中枢神经系统输送系统无形治疗性寡核苷酸的递送系统。
DOI：
10.3389/fphar.2021.660841
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发表时间：
2021
影响因子：
5.6
通讯作者：
Bleier BS
中科院分区：
文献类型：
--
作者：
Pawar G;Parayath NN;Sharma AA;Coito C;Khorkova O;Hsiao J;Curry WT;Amiji MM;Bleier BS
神经系统疾病治疗中最重要的障碍是血脑屏障（BBB），它阻止了98%的潜在神经药物到达中枢神经系统（CNS）。脑源性神经营养因子（BDNF）是帕金森病（PD）中研究最多的靶点之一，因为它可以逆转疾病进展。BDNF AntagoNAT（AT）是能够上调内源性BDNF表达的合成的类BDNF化合物。尽管BDNF AT疗法对PD有重大的前景，但它们不能穿过血脑屏障（BBB）。我们的小组已经开发出一种创新的鼻内异位粘膜移植技术，提供了一种永久的方法，透化血脑屏障。该方法基于目前在常规临床实践中使用的已建立的内窥镜外科手术。本研究的总体目标是使用创新的异位粘膜移植技术，在未处理大鼠中使用颅外移植模型研究BDNF AT的分布和功效。开发了BDNF AT阳离子脂质体（理想尺寸范围200-250 nm），并表征为增强向大鼠脑的递送。在RT 4-D 6P 2 T大鼠神经鞘瘤细胞和未处理大鼠中，定性（显微镜检查）和定量（ELISA和AT杂交测定）评价了盐水和脂质体中BDNF AntagoNAT的摄取、分布和转染效率。使用蛋白质印迹和酪氨酸羟化酶免疫组织化学在PD的6-OHDA毒素模型中评价包封在脂质体中的BDNF AT的体内治疗功效。使用互补的体外和体内技术，我们的结果表明，移植物能够在整个脑中递送脂质体和盐水制剂中的治疗水平的BDNF AT，导致与PD相关的关键末端靶区域中的BDNF显著上调。与盐水对照相比，BDNF AT脂质体在大鼠脑中的分布更好。包封在脂质体中的递送的BDNF AT还在PD的大鼠6-OHDA模型中赋予神经保护作用。作为一种平台技术，这些结果进一步表明，该方法可用于递送其他BBB不渗透的基于阿糖胞苷的治疗剂，从而为CNS疾病的其他治疗选择打开大门。
The most significant obstacle in the treatment of neurological disorders is the blood-brain barrier (BBB), which prevents 98% of all potential neuropharmaceuticals from reaching the central nervous system (CNS). Brain derived neurotrophic factor (BDNF) is one of the most intensely studied targets in Parkinson’s disease (PD) as it can reverse disease progression. BDNF AntagoNAT’s (ATs) are synthetic oligonucleotide-like compounds capable of upregulating endogenous BDNF expression. Despite the significant promise of BDNF AT therapies for PD, they cannot cross the blood-brain barrier (BBB). Our group has developed an innovative endonasal heterotopic mucosal grafting technique to provide a permanent method of permeabilizing the BBB. This method is based on established endoscopic surgical procedures currently used in routine clinical practice. Our overall goal for the study was to investigate the distribution and efficacy of BDNF AT’s using an extra-cranial graft model in naïve rats using the innovative heterotopic mucosal engrafting technique. BDNF AT cationic liposomes (ideal size range 200–250 nm) were developed and characterized to enhance the delivery to rat brain. Uptake, distribution and transfection efficiency of BDNF AntagoNAT’s in saline and liposomes were evaluated qualitatively (microscopy) and quantitatively (ELISA and AT hybridization assays) in RT4-D6P2T rat schwannoma cells and in naïve rats. In vivo therapeutic efficacy of BDNF AT’s encapsulated in liposomes was evaluated in a 6-OHDA toxin model of PD using western blot and tyrosine hydroxylase immunohistochemistry. Using complimentary in vitro and in vivo techniques, our results demonstrate that grafts are capable of delivering therapeutic levels of BDNF ATs in liposomes and saline formulation throughout the brain resulting in significant BDNF upregulation in key end target regions relevant to PD. BDNF AT liposomes resulted in a better distribution in rat brain as compared to saline control. The delivered BDNF AT’s encapsulated in liposomes also conferred a neuroprotective effect in a rat 6-OHDA model of PD. As a platform technique, these results further suggest that this approach may be utilized to deliver other BBB impermeant oligonucleotide-based therapeutics thereby opening the door to additional treatment options for CNS disease.
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影响因子：
--
作者：
Ashrafuzzaman M
通讯作者：
Ashrafuzzaman M
DOI：
10.1002/ajmg.b.30109
发表时间：
2005-04-05
影响因子：
2.8
作者：
Liu, QR;Walther, D;Uhl, GR
通讯作者：
Uhl, GR
影响因子：
3.7
作者：
Bleier BS;Kohman RE;Feldman RE;Ramanlal S;Han X
通讯作者：
Han X
影响因子：
82.9
作者：
Gill, SS;Patel, NK;Heywood, P
通讯作者：
Heywood, P
影响因子：
2.6
作者：
Bleier, Benjamin S.;Wang, Eric W.;Schlosser, Rodney J.
通讯作者：
Schlosser, Rodney J.