School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
ACS Chem Neurosci. 2020 Dec 16;11(24):4301-4315. doi: 10.1021/acschemneuro.0c00564. Epub 2020 Nov 23.
Membrane transporters have long been utilized to improve the oral, hepatic, and renal (re)absorption. In the brain, however, the transporter-mediated drug delivery has not yet been fully achieved due to the complexity of the blood-brain barrier (BBB). Because L-type amino acid transporter 1 (LAT1) is a good candidate to improve the brain delivery, we developed here four novel LAT1-utilizing prodrugs of four nonsteroidal anti-inflammatory drugs. As a result, all the prodrugs were able to cross the BBB and localize into the brain cells. The brain uptake of salicylic acid (SA) was improved five times, not only across the mouse BBB but also into the cultured mouse and human brain cells. The naproxen prodrug was also transported efficiently into the mouse brain achieving less peripheral exposure, but the brain release of naproxen from the prodrug was not improved. Contrarily, the high plasma protein binding of the flurbiprofen prodrug and the premature bioconversion of the ibuprofen prodrug in the mouse blood hindered the efficient brain delivery. Thus, the structure of the parent drug affects the successful brain delivery of the LAT1-utilizing prodrugs, and the small-sized LAT1-utilizing prodrug of SA constituted a successful model to specifically deliver its parent drug across the mouse BBB and into the cultured mouse and human brain cells.
膜转运体长期以来一直被用于提高药物的口服、肝肠和肾（再）吸收。然而，由于血脑屏障（BBB）的复杂性，脑内的转运体介导的药物递送尚未完全实现。由于 L 型氨基酸转运体 1（LAT1）是提高脑内递送的良好候选物，我们在此开发了四种新型的 LAT1 利用型前药，它们是四种非甾体抗炎药。结果，所有前药都能够穿过血脑屏障并定位于脑细胞内。水杨酸（SA）的脑摄取增加了五倍，不仅穿过了小鼠血脑屏障，而且还进入了培养的小鼠和人脑细胞内。萘普生前药也能有效地转运到小鼠脑中，外周暴露减少，但前药中萘普生的脑释放没有改善。相反，氟比洛芬前药的高血浆蛋白结合和布洛芬前药在小鼠血液中的过早生物转化阻碍了有效的脑内递送。因此，母体药物的结构影响 LAT1 利用型前药的成功脑内递送，而 SA 的小尺寸 LAT1 利用型前药构成了一个成功的模型，可以特异性地将其母体药物穿过小鼠血脑屏障并进入培养的小鼠和人脑细胞内。
