Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the Brain
Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the Brain
复制标题
DOI：
10.1016/j.biomaterials.2013.07.081
复制
发表时间：
2013-12-01
期刊：
影响因子：
14
通讯作者：
Hart, Stephen L.
中科院分区：
文献类型：
--
作者：
Kenny, Gavin D.;Bienemann, Alison S.;Hart, Stephen L.
对流增强给药(CED)是一种直接注射到大脑的方法，可以实现治疗药物的广泛分散，包括基因治疗，从一次剂量。非病毒的纳米复合体作为大脑基因治疗的载体是有意义的，但至关重要的是，给药应该实现最大限度的分散，以最大限度地减少所需的注射次数。我们假设，由CED管理的阴离子纳米络合物应该比类似大小的阳离子在大鼠大脑中分散得更广泛，阳离子通过静电结合到细胞表面的阴离子部分，如蛋白多糖，限制了它们的扩散。用质粒DNA制备了含有神经降压素靶向多肽的阴离子、受体靶向纳米复合体(RTN)，并与阳离子RTN的分散性和转染率进行了比较。这两个RTN都用Gd标记，以便通过MRI在大脑中定位，并通过LA-ICP-MS在脑切片中进行标记，以及用罗丹明荧光团进行荧光显微镜检测。MRI分布研究证实，阴离子rtns的分布比阳离子rtns分布更广泛，尤其是在胼胝体。阴离子制剂的基因表达水平与阳离子RTN相似。因此，阴离子RTN制剂在CED单剂量给药后，可以在大脑中实现广泛的分散和有效的基因表达。(C)2013年提交人。爱思唯尔有限公司出版。保留所有权利。
Convection enhanced delivery (CED) is a method of direct injection to the brain that can achieve widespread dispersal of therapeutics, including gene therapies, from a single dose. Non-viral, nanocomplexes are of interest as vectors for gene therapy in the brain, but it is essential that administration should achieve maximal dispersal to minimise the number of injections required. We hypothesised that anionic nanocomplexes administered by CED should disperse more widely in rat brains than cationics of similar size, which bind electrostatically to cell-surface anionic moieties such as proteoglycans, limiting their spread. Anionic, receptor-targeted nanocomplexes (RTN) containing a neurotensin-targeting peptide were prepared with plasmid DNA and compared with cationic RTNs for dispersal and transfection efficiency. Both RTNs were labelled with gadolinium for localisation in the brain by MRI and in brain sections by LA-ICP-MS, as well as with rhodamine fluorophore for detection by fluorescence microscopy. MRI distribution studies confirmed that the anionic RTNs dispersed more widely than cationic RTNs, particularly in the corpus callosum. Gene expression levels from anionic formulations were similar to those of cationic RTNs. Thus, anionic RTN formulations can achieve both widespread dispersal and effective gene expression in brains after administration of a single dose by CED. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.