A novel approach for targeted delivery to motoneurons using cholera toxin-B modified protocells.
A novel approach for targeted delivery to motoneurons using cholera toxin-B modified protocells.
复制标题
使用霍乱毒素-B修饰的原蛋白的一种新型方法，将靶向运动神经元的靶向递送。
DOI：
10.1016/j.jneumeth.2016.09.003
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发表时间：
2016-11-01
影响因子：
3
通讯作者：
Mantilla CB
中科院分区：
文献类型：
--
作者：
Gonzalez Porras MA;Durfee PN;Gregory AM;Sieck GC;Brinker CJ;Mantilla CB
神经肌肉接头（NMJ）处肌纤维和运动神经元之间的营养相互作用在整个发育、衰老、损伤或疾病中决定运动功能起着关键作用。神经肌肉疾病的治疗由于不能用药理学和遗传学干预选择性地靶向运动神经元而受到阻碍。我们描述了一种新的传递系统，运动神经元使用介孔二氧化硅纳米粒子封装在脂质双层（原细胞）和修饰的无毒亚基B的霍乱毒素（CT B），结合神经节苷脂存在于神经元膜。CTB修饰的原始细胞显示出显著更大的运动神经元摄取相比，未修饰的原始细胞处理24小时后（60%对15%，分别）。CTB-原细胞表现出运动神经元相比，肌肉细胞的特定摄取，并表现出货物释放的替代药物。原始细胞表现出缺乏细胞毒性和未受损的细胞增殖。在离体膈肌膈神经制备，优先轴突终末摄取CTB修饰的原细胞相比，在周围的肌肉组织中的摄取。与未修饰的原细胞相比，用CTB-原细胞处理后，更大比例的轴突终末显示出摄取（分别为40%对6%）。目前的运动神经元定位策略缺乏装载和递送多种货物的功能。CTB-原细胞利用脂质体和介孔二氧化硅纳米颗粒的优点，允许大的负载容量和货物释放。CTB-原始细胞在NMJ靶向运动神经元的能力赋予了比现有方法更大的优势。CTB-原细胞构成了一种可行的靶向运动神经元递送系统，用于促进神经肌肉疾病的各种治疗的药物和基因。
Trophic interactions between muscle fibers and motoneurons at the neuromuscular junction (NMJ) play a critical role in determining motor function throughout development, ageing, injury, or disease. Treatment of neuromuscular disorders is hindered by the inability to selectively target motoneurons with pharmacological and genetic interventions. We describe a novel delivery system to motoneurons using mesoporous silica nanoparticles encapsulated within a lipid bilayer (protocells) and modified with the atoxic subunit B of the cholera toxin (CTB) that binds to gangliosides present on neuronal membranes. CTB modified protocells showed significantly greater motoneuron uptake compared to unmodified protocells after 24 h of treatment (60% vs. 15%, respectively). CTB-protocells showed specific uptake by motoneurons compared to muscle cells and demonstrated cargo release of a surrogate drug. Protocells showed a lack of cytotoxicity and unimpaired cellular proliferation. In isolated diaphragm muscle-phrenic nerve preparations, preferential axon terminal uptake of CTB-modified protocells was observed compared to uptake in surrounding muscle tissue. A larger proportion of axon terminals displayed uptake following treatment with CTB-protocells compared to unmodified protocells (40% vs. 6%, respectively). Current motoneuron targeting strategies lack the functionality to load and deliver multiple cargos. CTB-protocells capitalizes on the advantages of liposomes and mesoporous silica nanoparticles allowing a large loading capacity and cargo release. The ability of CTB-protocells to target motoneurons at the NMJ confers a great advantage over existing methods. CTB-protocells constitute a viable targeted motoneuron delivery system for drugs and genes facilitating various therapies for neuromuscular diseases.
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影响因子：
17.1
作者：
Ashley CE;Carnes EC;Epler KE;Padilla DP;Phillips GK;Castillo RE;Wilkinson DC;Wilkinson BS;Burgard CA;Kalinich RM;Townson JL;Chackerian B;Willman CL;Peabody DS;Wharton W;Brinker CJ
通讯作者：
Brinker CJ
影响因子：
8
作者：
Fröhlich E
通讯作者：
Fröhlich E
影响因子：
4.2
作者：
Alvarez-Argote, Santiago;Gransee, Heather M.;Mantilla, Carlos B.
通讯作者：
Mantilla, Carlos B.
影响因子：
5.4
作者：
Edupuganti, Om P.;Ovsepian, Saak V.;Dolly, J. Oliver
通讯作者：
Dolly, J. Oliver
影响因子：
3.4
作者：
Dietrich, C;Yang, B;Jacobson, K
通讯作者：
Jacobson, K