Yi Xiang, Manickam Devika S, Brynskikh Anna, Kabanov Alexander V
Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Control Release. 2014 Sep 28;190:637-63. doi: 10.1016/j.jconrel.2014.06.017. Epub 2014 Jun 21.
A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics.
多种治疗性蛋白质已显示出治疗中枢神经系统（CNS）疾病的潜力。众所周知，将这些蛋白质分子输送到大脑面临挑战。通过非肠道途径给药的蛋白质往往因生物利用度差和血脑屏障（BBB）的存在而被排除在大脑之外。对于通过绕过血脑屏障的非肠道途径给药的蛋白质也存在障碍。有几种策略在将蛋白质输送到大脑方面显示出前景。本综述首先描述血脑屏障的生理学和病理学，强调每种要应用的策略的原理和需求。其次，介绍主要类别的蛋白质治疗剂以及影响其输送结果的一些关键因素。第三，讨论蛋白质给药的不同途径（非肠道、脑室内和脑实质内、鼻内和鞘内）以及与每种途径相关的中枢神经系统输送的关键障碍。最后，使用文献和我们自己工作中的例子概述当前涉及蛋白质化学修饰和基于颗粒载体使用的输送策略。虽然这些研究大多处于早期阶段，但一些研究在中枢神经系统疾病的相关模型中提供了增加蛋白质向大脑输送的机制证明，而在少数情况下，临床研究已获得概念验证。本综述将对广大学生、学者和行业专业人士有用，他们考虑蛋白质向大脑输送的关键问题，并旨在开发和研究用于蛋白质治疗剂的有效脑输送系统。
