Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Bioneer-Farma, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Handb Exp Pharmacol. 2022;273:151-183. doi: 10.1007/164_2020_403.
The brain capillary endothelium serves both as an exchange site for gases and solutes between blood and brain and as a protective fence against neurotoxic compounds from the blood. While this "blood-brain barrier" (BBB) function protects the fragile environment in the brain, it also poses a tremendous challenge for the delivery of drug compounds to the brain parenchyma. Paracellular brain uptake of drug compounds is limited by the physical tightness of the endothelium, which is tightly sealed with junction complexes. Transcellular uptake of lipophilic drug compounds is limited by the activity of active efflux pumps in the luminal membrane. As a result, the majority of registered CNS drug compounds are small lipophilic compounds which are not efflux transporter substrates. Small molecule CNS drug development therefore focuses on identifying compounds with CNS target affinity and modifies these in order to optimize lipophilicity and decrease efflux pump interactions. Since efflux pump activity is limiting drug uptake, it has been investigated whether coadministration of drug compounds with efflux pump inhibitors could increase drug uptake. While the concept works to some extent, a lot of challenges have been encountered in terms of obtaining efficient inhibition while avoiding adverse effects.Some CNS drug compounds enter the brain via nutrient transport proteins, an example is the levodopa, a prodrug of Dopamine, which crosses the BBB via the large neutral amino acid transporter LAT1. While carrier-mediated transport of drug compounds may seem attractive, the development of drugs targeting transporters is very challenging, since the compounds should have a good fit to the binding site, while still maintaining their CNS target affinity.Receptor-mediated transport of drug compounds, especially biotherapeutics, conjugated to a receptor-binding ligand has shown some promise, although the amounts transported are rather low. This also holds true for drug-conjugation to cell-penetrating peptides. Due to the low uptake of biotherapeutics, barrier-breaching approaches such as mannitol injections and focused ultrasound have been employed with some success to patient groups with no other treatment options.
脑毛细血管内皮细胞既是血液和大脑之间气体和溶质交换的场所，也是防止血液中神经毒性化合物进入大脑的保护屏障。虽然这种“血脑屏障”（BBB）功能保护了大脑中脆弱的环境，但它也给药物化合物向脑实质的输送带来了巨大的挑战。药物化合物的细胞旁脑摄取受到内皮细胞物理紧密性的限制，内皮细胞通过连接复合物紧密密封。亲脂性药物化合物的细胞内摄取受到腔膜中主动外排泵活性的限制。因此，大多数已注册的中枢神经系统药物化合物都是小亲脂性化合物，不是外排转运体的底物。小分子中枢神经系统药物开发因此侧重于确定具有中枢神经系统靶标亲和力的化合物，并对其进行修饰以优化亲脂性并减少外排泵相互作用。由于外排泵活性限制了药物摄取，因此研究了是否可以将药物化合物与外排泵抑制剂共同给药以增加药物摄取。虽然这一概念在一定程度上是可行的，但在获得有效抑制的同时避免不良反应方面遇到了很多挑战。一些中枢神经系统药物化合物通过营养转运蛋白进入大脑，左旋多巴就是一个例子，它是多巴胺的前体药物，通过大中性氨基酸转运蛋白 LAT1 穿过 BBB。虽然药物化合物的载体介导转运似乎很有吸引力，但针对转运蛋白的药物开发非常具有挑战性，因为化合物应该与结合位点很好地匹配，同时仍然保持其中枢神经系统靶标亲和力。药物化合物的受体介导转运，特别是与受体结合配体偶联的生物治疗剂，已经显示出一些希望，尽管转运量相当低。将药物与细胞穿透肽偶联也是如此。由于生物治疗剂的摄取量低，因此采用了甘露醇注射和聚焦超声等突破屏障的方法，对没有其他治疗选择的患者群体取得了一些成功。
