Rare Disease Research Unit, Pfizer Worldwide Research, Development and Medicine, Cambridge, MA, USA.
Handb Exp Pharmacol. 2022;273:83-95. doi: 10.1007/164_2021_453.
Efficient therapeutic transport across the neurovasculature remains a challenge for developing medicine to treat central nervous system (CNS) disorders (Bell and Ehlers, Neuron 81:1-3, 2014). This chapter is meant to provide some insight and key considerations for developing and evaluating various technologies and approaches to CNS drug delivery. First, a brief review of various biological barriers, including the immune system, cellular and protein components of the blood-brain barrier (BBB), and clearance mechanisms in peripheral organs is provided. Next, a few examples and learnings from existing BBB-crossing modalities will be reviewed. Insight from "BBBomic" databases and thoughts on basic requirements for successful in vivo validation studies are discussed. Finally, an additional engineering barrier, namely manufacturing and product scalability, is highlighted as it relates to clinical translation and feasibility for developing BBB-crossing delivery technologies. A goal of this chapter is to provide an overview of the many barriers to the successful delivery of medicines into the brain. An emphasis will be placed on biotherapeutic and gene therapy applications for the treatment of neurological and neurodegenerative disorders.
高效的神经血管治疗仍然是开发治疗中枢神经系统（CNS）疾病的药物的一个挑战（Bell 和 Ehlers，Neuron 81：1-3，2014）。本章旨在为开发和评估各种 CNS 药物输送技术和方法提供一些见解和关键考虑因素。首先，简要回顾了各种生物屏障，包括免疫系统、血脑屏障（BBB）的细胞和蛋白质成分以及外周器官的清除机制。接下来，将回顾一些现有的 BBB 穿越模式的例子和经验教训。讨论了“BBBomic”数据库的见解以及对成功体内验证研究的基本要求的思考。最后，突出了另一个工程屏障，即制造和产品可扩展性，因为它与开发 BBB 穿越输送技术的临床转化和可行性有关。本章的目的是概述将药物成功递送到大脑中所面临的许多障碍。重点将放在生物治疗和基因治疗应用于治疗神经和神经退行性疾病上。
