School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211Kuopio, Finland.
Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151Lodz, Poland.
Mol Pharm. 2022 Nov 7;19(11):3806-3819. doi: 10.1021/acs.molpharmaceut.2c00328. Epub 2022 Aug 26.
Oxidative stress and pathological changes of Alzheimer's disease (AD) overlap with metabolic diseases, such as diabetes mellitus (DM). Therefore, tackling oxidative stress with antioxidants is a compelling drug target against multiple chronic diseases simultaneously. Ferulic acid (FA), a natural antioxidant, has previously been studied as a therapeutic agent against both AD and DM. However, FA suffers from poor bioavailability and delivery. As a solution, we have previously reported about L-type amino acid transporter 1 (LAT1)-utilizing derivatives with increased brain delivery and efficacy. In the present study, we evaluated the pharmacokinetics and antioxidative efficacy of the two derivatives in peripheral mouse tissues. Furthermore, we quantified the LAT1 expression in studied tissues with a targeted proteomics method to verify the transporter expression in mouse tissues. Additionally, the safety of the derivatives was assessed by exploring their effects on hemostasis in human plasma, erythrocytes, and endothelial cells. We found that both derivatives accumulated substantially in the pancreas, with over a 100-times higher area under curve compared to the FA. Supporting the pharmacokinetics, the LAT1 was highly expressed in the mouse pancreas. Treating mice with the LAT1-utilizing derivative of FA lowered malondialdehyde and prostaglandin E production in the pancreas, highlighting its antioxidative efficacy. Additionally, the LAT1-utilizing derivatives were found to be hemocompatible in human plasma and endothelial cells. Since antioxidative derivative 1 was substantially delivered into the pancreas along the previously studied brain, the derivative can be considered as a safe dual-targeting drug candidate in both the pancreas and the brain.
氧化应激和阿尔茨海默病（AD）的病变与代谢疾病重叠，如糖尿病（DM）。因此，用抗氧化剂来对抗氧化应激是同时针对多种慢性疾病的一个有吸引力的药物靶点。阿魏酸（FA）是一种天然抗氧化剂，之前已被研究作为治疗 AD 和 DM 的药物。然而，FA 的生物利用度和递送效果较差。作为一种解决方案，我们之前曾报道过利用 L 型氨基酸转运蛋白 1（LAT1）的衍生物，这些衍生物具有更高的脑内递送和疗效。在本研究中，我们评估了这两种衍生物在周围小鼠组织中的药代动力学和抗氧化功效。此外，我们使用靶向蛋白质组学方法来量化研究组织中的 LAT1 表达，以验证其在小鼠组织中的转运蛋白表达。此外，通过研究衍生物对人血浆、红细胞和内皮细胞止血作用的影响来评估其安全性。我们发现，两种衍生物在胰腺中的积累量都很大，与 FA 相比，曲线下面积（AUC）高出 100 多倍。支持药代动力学的结果，LAT1 在小鼠胰腺中高度表达。用 FA 的 LAT1 利用衍生物治疗小鼠可降低胰腺中的丙二醛和前列腺素 E 的产生，突出了其抗氧化功效。此外，发现 LAT1 利用衍生物在人血浆和内皮细胞中具有良好的血液相容性。由于抗氧化衍生物 1 沿着之前研究过的脑大量递送到胰腺，因此该衍生物可以被认为是一种安全的双重靶向药物候选物，可同时在胰腺和大脑中发挥作用。
