Targeting Small Molecule Delivery to the Brain and Spinal Cord via Intranasal Administration of Rabies Virus Glycoprotein (RVG29)-Modified PLGA Nanoparticles
Targeting Small Molecule Delivery to the Brain and Spinal Cord via Intranasal Administration of Rabies Virus Glycoprotein (RVG29)-Modified PLGA Nanoparticles
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DOI：
10.3390/pharmaceutics12020093
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发表时间：
2020-02-01
期刊：
影响因子：
5.4
通讯作者：
Sirianni, Rachael W.
中科院分区：
文献类型：
--
作者：
Chung, Eugene P.;Cotter, Jennifer D.;Sirianni, Rachael W.
替代给药途径是一种可用于绕过血脑屏障（BBB）以将药物有效输送至中枢神经系统（CNS）的方法。在这里，我们专注于聚合物纳米颗粒的鼻内递送。我们假设，与非靶向纳米粒子相比，用狂犬病病毒糖蛋白（RVG29）对聚（乳酸-乙醇酸）（PLGA）纳米粒子进行表面修饰会增加封装有效负载在中枢神经系统中的停留时间和暴露量。通过向健康小鼠施用负载有碳花青染料 1,1'-双十八烷基-3,3,3',3'-四甲基吲哚三碳花青碘 (DiR) 的纳米颗粒来分析递送动力学和生物分布。鼻内给药使纳米颗粒有效负载对大多数外周器官的暴露最小化，并快速、有效地递送至整个大脑。中枢神经系统内有效负载递送的区域分析显示，最接近三叉神经的组织的递送量较高，包括嗅球、纹状体、中脑、脑干和颈脊髓。 RVG29 表面修饰在给药后 2 小时对纹状体、中脑和脑干呈现适度的靶向益处，尽管在给药后 30 分钟或 6 小时没有观察到靶向作用。纳米颗粒给药后 2 小时，与对照纳米颗粒相比，靶向纳米颗粒向三叉神经的有效负载递送高出 3.5 倍。这些数据支持从鼻到脑的药物输送机制，该机制与三叉神经通过完整纳米颗粒的运输和有效负载的最终扩散来从纳米颗粒进行有效负载传递密切相关。嗅觉和脑脊液途径也被观察到发挥作用。这些数据推进了靶向纳米颗粒在亲脂性有效负载从鼻到脑药物输送中的实用性，并为设计有效的输送载体来治疗中枢神经系统疾病提供了机制见解。
Alternative routes of administration are one approach that could be used to bypass the blood-brain barrier (BBB) for effective drug delivery to the central nervous system (CNS). Here, we focused on intranasal delivery of polymer nanoparticles. We hypothesized that surface modification of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with rabies virus glycoprotein (RVG29) would increase residence time and exposure of encapsulated payload to the CNS compared to non-targeted nanoparticles. Delivery kinetics and biodistribution were analyzed by administering nanoparticles loaded with the carbocyanine dye 1,1 '-Dioctadecyl-3,3,3 ',3 '-Tetramethylindotricarbocyanine Iodide (DiR) to healthy mice. Intranasal administration yielded minimal exposure of nanoparticle payload to most peripheral organs and rapid, effective delivery to whole brain. Regional analysis of payload delivery within the CNS revealed higher delivery to tissues closest to the trigeminal nerve, including the olfactory bulb, striatum, midbrain, brainstem, and cervical spinal cord. RVG29 surface modifications presented modest targeting benefits to the striatum, midbrain, and brainstem 2 h after administration, although targeting was not observed 30 min or 6 h after administration. Payload delivery to the trigeminal nerve was 3.5x higher for targeted nanoparticles compared to control nanoparticles 2 h after nanoparticle administration. These data support a nose-to-brain mechanism of drug delivery that closely implicates the trigeminal nerve for payload delivery from nanoparticles via transport of intact nanoparticles and eventual diffusion of payload. Olfactory and CSF routes are also observed to play a role. These data advance the utility of targeted nanoparticles for nose-to-brain drug delivery of lipophilic payloads and provide mechanistic insight to engineer effective delivery vectors to treat disease in the CNS.