4′-OH as the Action Site of Lipids and MRP1 for Enhanced Transdermal Delivery of Flavonoids

透皮 哈卡特 角质层 渗透 类黄酮 亲脂性 药理学 药物输送 化学 立体化学 生物化学 有机化学 医学 抗氧化剂 体外 病理
作者
Zhuxian Wang,Yi Hu,Yaqi Xue,Yufan Wu,Quanfu Zeng,Hongkai Chen,Yinglin Guo,Peiyi Liang,Liang Tao,Chunyan Shen,Cuiping Jiang,Li Liu,Qun Shen,Hongxia Zhu,Qiang Liu
出处
期刊:ACS Applied Materials & Interfaces [American Chemical Society]
被引量:6
标识
DOI:10.1021/acsami.2c18086
摘要

To date, the transdermal delivery study mainly focused on the drug delivery systems' design and efficacy evaluation. Few studies reported the structure-affinity relationship of the drug with the skin, further revealing the action sites of the drugs for enhanced permeation. Flavonoids attained a considerable interest in transdermal administration. The aim is to develop a systematic approach to evaluate the substructures that were favorable for flavonoid delivery into the skin and understand how these action sites interacted with lipids and bound to multidrug resistance protein 1 (MRP1) for enhanced transdermal delivery. First, we investigated the permeation properties of various flavonoids on the porcine skin or rat skin. We found that 4'-OH (hydroxyl group on the carbon 4' position) rather than 7-OH on the flavonoids was the key group for flavonoid permeation and retention, while 4'-OCH3 and -CH2═CH2-CH-(CH3)2 were unfavorable for drug delivery. 4'-OH could decrease flavonoids' lipophilicity to an appropriate log P and polarizability for better transdermal drug delivery. In the stratum corneum, flavonoids used 4'-OH as a hand to specifically grab the C═O group of the ceramide NS (Cer), which increased the miscibility of flavonoids and Cer and then disturbed the lipid arrangement of Cer, thereby facilitating their penetration. Subsequently, we constructed overexpressed MRP1 HaCaT/MRP1 cells by permanent transfection of human MRP1 cDNA in wild HaCaT cells. In the dermis, we observed that 4'-OH, 7-OH, and 6-OCH3 substructures were involved in H-bond formation within MRP1, which increased the flavonoid affinity with MRP1 and flavonoid efflux transport. Moreover, the expression of MRP1 was significantly enhanced after the treatment of flavonoids on the rat skin. Collectively, 4'-OH served as the action site for increased lipid disruption and enhanced affinity for MRP1, which facilitate the transdermal delivery of flavonoids, providing valuable guidelines for molecular modification and drug design of flavonoids.
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