Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, Im Neuenheimer Feld 329, 69120, Heidelberg, Germany.
Pharm Res. 2022 Jul;39(7):1415-1455. doi: 10.1007/s11095-022-03241-x. Epub 2022 Mar 31.
Limited drug delivery to the brain is one of the major reasons for high failure rates of central nervous system (CNS) drug candidates. The blood-brain barrier (BBB) with its tight junctions, membrane transporters, receptors and metabolizing enzymes is a main player in drug delivery to the brain, restricting the entrance of the drugs and other xenobiotics. Current knowledge about the uptake transporters expressed at the BBB and brain parenchymal cells has been used for delivery of CNS drugs to the brain via targeting transporters. Although many transporter-utilizing (pro)drugs and nanocarriers have been developed to improve the uptake of drugs to the brain, their success rate of translation from preclinical development to humans is negligible. In the present review, we provide a systematic summary of the current progress in development of transporter-utilizing (pro)drugs and nanocarriers for delivery of drugs to the brain. In addition, we applied CNS pharmacokinetic concepts for evaluation of the limitations and gaps in investigation of the developed transporter-utilizing (pro)drugs and nanocarriers. Finally, we give recommendations for a rational development of transporter-utilizing drug delivery systems targeting the brain based on CNS pharmacokinetic principles.
向大脑的药物递送有限是中枢神经系统 (CNS) 候选药物高失败率的主要原因之一。血脑屏障 (BBB) 及其紧密连接、膜转运蛋白、受体和代谢酶是向大脑递药的主要参与者，限制了药物和其他外源性物质的进入。目前关于 BBB 和脑实质细胞表达的摄取转运蛋白的知识已被用于通过靶向转运蛋白将 CNS 药物递送至大脑。尽管已经开发了许多利用转运体的（前）药物和纳米载体来提高药物向大脑的摄取，但它们从临床前开发到人类的转化成功率可以忽略不计。在本综述中，我们系统总结了利用转运体的（前）药物和纳米载体开发用于向大脑递药的最新进展。此外，我们应用 CNS 药代动力学概念来评估所开发的利用转运体的（前）药物和纳米载体的研究中的局限性和差距。最后，我们根据 CNS 药代动力学原则，就基于转运体的脑靶向药物递送系统的合理开发提出了建议。
