Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system
Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system
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DOI：
10.3171/jns.2005.103.2.0311
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发表时间：
2005-08-01
影响因子：
4.1
通讯作者：
Oldfield, EH
中科院分区：
文献类型：
--
作者：
Chen, MY;Hoffer, A;Oldfield, EH
物体。实现基因载体的分布是基因治疗临床应用的主要障碍。由于血脑屏障的存在，基因载体向中枢神经系统(CNS)的分布比向其他组织的分布更具挑战性。直接实质内微输注是一种微创技术，它利用大块流动(对流)将大分子悬浮液广泛分布到细胞外空间(对流增强递送[CED])。虽然固体组织中的急性注射通常用于运送寡核苷酸、病毒和脂质体，而且有初步证据表明，这些大颗粒中的某些可以通过对流通过大脑间质空间传播，但使用CED在大脑中分布病毒的情况尚未得到系统的研究。这是本研究的目的。方法。研究人员使用啮齿动物模型检测了缓冲液的大小、渗透压和表面涂层对病毒大小的纳米颗粒和病毒(腺相关病毒和腺病毒)在大脑灰质中的体积分布的影响。结果表明，脑灰质细胞外空间的通道大小足以容纳病毒大小的颗粒，表面特征是病毒通过对流在脑内分布的关键决定因素。这些结果表明，对流分布可用于在中枢神经系统中分布治疗性病毒载体。
Object. Achieving distribution of gene-carrying vectors is a major barrier to the clinical application of gene therapy. Because of the blood-brain barrier, the distribution of genetic vectors to the central nervous system (CNS) is even more challenging than delivery to other tissues. Direct intraparenchymal microinfusion, a minimally invasive technique, uses bulk flow (convection) to distribute suspensions of macromolecules widely through the extracellular space (convection-enhanced delivery [CED]). Although acute injection into solid tissue is often used for delivery of oligonucleotides, viruses, and liposomes, and there is preliminary evidence that certain of these large particles can spread through the interstitial space of the brain by the use of convection, the use of CED for distribution of viruses in the brain has not been systematically examined. That is the goal of this study.Methods. Investigators used a rodent model to examine the influence of size, osmolarity of buffering solutions, and surface coating on the volumetric distribution of virus-sized nanoparticles and viruses (adeno-associated viruses and adenoviruses) in the gray matter of the brain. The results demonstrate that channels in the extracellular space of gray matter in the brain are large enough to accommodate virus-sized particles and that the surface characteristics are critical determinants for distribution of viruses in the brain by convection.Conclusions. These results indicate that convective distribution can be used to distribute therapeutic viral vectors in the CNS.