BDNF gene delivery mediated by neuron-targeted nanoparticles is neuroprotective in, peripheral nerve injury
BDNF gene delivery mediated by neuron-targeted nanoparticles is neuroprotective in, peripheral nerve injury
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DOI：
10.1016/j.biomaterials.2016.12.025
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发表时间：
2017-03-01
期刊：
影响因子：
14
通讯作者：
Pego, Ana P.
中科院分区：
文献类型：
--
作者：
Lopes, Catia D. F.;Goncalves, Nadia P.;Pego, Ana P.
神经元靶向基因递送是治疗周围神经病的一种有前途的策略。在这里，我们提出了使用聚合物纳米粒子的基础上硫醇化三甲基壳聚糖（TMCSH）介导靶向基因传递到外周神经元后，外周和微创肌内给药。将纳米颗粒与破伤风神经毒素（HC）的无毒羧基片段接枝以允许神经元靶向，并探索在外周神经损伤模型中递送编码脑源性神经营养因子（BDNF）的质粒DNA。TMCSH-HC/BDNF纳米颗粒治疗促进了BDNF在神经组织中的释放和显著表达，与对照治疗（载体和非靶向纳米颗粒）相比，这导致损伤后增强的功能恢复，这与关键促再生事件的改善有关，即损伤神经中神经丝和生长相关蛋白GAP-43的表达增加。此外，与对照组相比，靶向纳米颗粒治疗与损伤神经远端残端中有髓轴突的密度显著更高相关，并且与无髓轴突密度的保留相关，并且在损伤去神经肌肉中具有保护作用，防止它们去神经支配。这些结果突出了TMCSH-HC纳米颗粒作为非病毒基因载体将治疗基因递送到外周神经元中的潜力，从而为其用作外周神经病变的有效治疗干预铺平了道路。(C)2016爱思唯尔有限公司版权所有。
Neuron-targeted gene delivery is a promising strategy to treat peripheral neuropathies. Here we propose the use of polymeric nanoparticles based on thiolated trimethyl chitosan (TMCSH) to mediate targeted gene delivery to peripheral neurons upon a peripheral and minimally invasive intramuscular administration. Nanoparticles were grafted with the non-toxic carboxylic fragment of the tetanus neurotoxin (HC) to allow neuron targeting and were explored to deliver a plasmid DNA encoding for the brain derived neurotrophic factor (BDNF) in a peripheral nerve injury model. The TMCSH-HC/BDNF nano particle treatment promoted the release and significant expression of BDNF in neural tissues, which resulted in an enhanced functional recovery after injury as compared to control treatments (vehicle and non-targeted nanoparticles), associated with an improvement in key pro-regenerative events, namely, the increased expression of neurofilament and growth-associated protein GAP-43 in the injured nerves. Moreover, the targeted nanoparticle treatment was correlated with a significantly higher density of myelinated axons in the distal stump of injured nerves, as well as with preservation of unmyelinated axon density as compared with controls and a protective role in injury-denervated muscles, preventing them from denervation. These results highlight the potential of TMCSH-HC nanoparticles as non-viral gene carriers to deliver therapeutic genes into the peripheral neurons and thus, pave the way for their use as an effective therapeutic intervention for peripheral neuropathies. (C) 2016 Elsevier Ltd. All rights reserved.