4'-OH 作为脂质和 MRP1 的作用位点以增强类黄酮的透皮递送,ACS Applied Materials & Interfaces

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4'-OH 作为脂质和 MRP1 的作用位点以增强类黄酮的透皮递送
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2023-03-13 , DOI: 10.1021/acsami.2c18086
Zhuxian Wang ₁ , Yi Hu ₁ , Yaqi Xue ₁ , Yufan Wu ₁ , Quanfu Zeng ₁ , Hongkai Chen ₁ , Yinglin Guo ₁ , Peiyi Liang ₁ , Tao Liang ₁ , Chunyan Shen ₁ , Cuiping Jiang ₁ , Li Liu ₁ , Qun Shen ₁ , Hongxia Zhu ₁ , Qiang Liu ₁

Affiliation

迄今为止，透皮给药研究主要集中在给药系统的设计和疗效评价上。很少有研究报道药物与皮肤的结构-亲和关系，进一步揭示了药物增强渗透的作用位点。黄酮类化合物在透皮给药方面获得了相当大的兴趣。目的是开发一种系统的方法来评估有利于类黄酮递送到皮肤中的亚结构，并了解这些作用位点如何与脂质相互作用并与多药耐药蛋白 1 (MRP1) 结合以增强透皮递送。首先，我们研究了各种黄酮类化合物在猪皮肤或大鼠皮肤上的渗透特性。₃和-CH ₂ = CH ₂ -CH-(CH ₃ ) ₂不利于药物递送。4'-OH 可以将类黄酮的亲脂性降低到适当的 log  P和极化率，以实现更好的透皮给药。在角质层中，类黄酮以4′-OH为手，特异性地抓住神经酰胺NS（Cer）的C=O基团，增加了类黄酮与Cer的混溶性，进而扰乱了Cer的脂质排列，从而促进了它们的结合。渗透。随后，我们通过在野生 HaCaT 细胞中永久转染人 MRP1 cDNA 构建了过表达的 MRP1 HaCaT/MRP1 细胞。在真皮中，我们观察到 4'-OH、7-OH 和 6-OCH ₃子结构参与 MRP1 内的氢键形成，这增加了类黄酮与 MRP1 的亲和力和类黄酮外排转运。此外，黄酮类化合物处理大鼠皮肤后，MRP1 的表达显着增强。总的来说，4'-OH 作为增加脂质破坏和增强对 MRP1 亲和力的作用位点，促进类黄酮的透皮递送，为类黄酮的分子修饰和药物设计提供有价值的指导。

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

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.

更新日期：2023-03-13

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