title: Interaction of menthol with mixed-lipid bilayer of stratum corneum: A coarse-grained simulation study.
abstract: Menthol is a widely used penetration enhancer in clinical medicine due to its high efficiency and relative safety. Although there are many studies focused on the penetration-enhancing activity of menthol, the details of molecular mechanism are rarely involved in the discussion. In this study, we present a series of coarse-grained molecular dynamics simulations to investigate the interaction of menthol with a mixed-lipid bilayer model consisting of ceramides, cholesterol and free fatty acids in a 2:2:1 molar ratio. Taking both the concentration of menthol and temperature into consideration, it was found that a rise in temperature and concentration within a specific range (1-20%) could improve the penetration-enhancing property of menthol and the floppiness of the bilayer. However, at high concentrations (30% and more), menthol completely mixed with the lipids and the membrane can no longer maintain a bilayer structure. Our results elucidates some of the molecular basis for menthol's penetration enhancing effects and may provide some assistance for the development and applications of menthol as a penetration enhancer. Furthermore, we establish a method to investigate the penetration enhancement mechanism of traditional Chinese medicine using the mixed-lipid bilayer model of stratum corneum by molecular dynamics simulations.
authors.affiliation: School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China; Beijing University of Chinese Medicine, Beijing 100102, China. Electronic address: wungung91@163.com.
authors.forename: Guang
authors.initials: G
authors.lastname: Wan
authors.affiliation: Beijing University of Chinese Medicine, Beijing 100102, China; Key Laboratory of TCM-information Engineer of State Administration of TCM, Beijing 100102, China. Electronic address: jolly_1987@163.com.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Dai
authors.affiliation: School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China. Electronic address: zmnh08830@126.com.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Yin
authors.affiliation: Beijing University of Chinese Medicine, Beijing 100102, China; Key Laboratory of TCM-information Engineer of State Administration of TCM, Beijing 100102, China. Electronic address: shixinyuan01@163.com.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Shi
authors.affiliation: Beijing University of Chinese Medicine, Beijing 100102, China; Key Laboratory of TCM-information Engineer of State Administration of TCM, Beijing 100102, China. Electronic address: yjqiao@263.net.
authors.forename: Yanjiang
authors.initials: Y
authors.lastname: Qiao
mesh_terms: D002518:Ceramides; D002784:Cholesterol; D004058:Diffusion; D004337:Drug Carriers / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000493:pharmacokinetics; D004817:Epidermis / Q000737:chemistry / Q000187:drug effects*; D005079:Excipients / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified; D006801:Humans; D008051:Lipid Bilayers; D008560:Membrane Fluidity; D008610:Menthol / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D009994:Osmolar Concentration; D012869:Skin Absorption / Q000187:drug effects*; D013696:Temperature
chemical_list: D002518:Ceramides; D004337:Drug Carriers; D004365:Drugs, Chinese Herbal; D005079:Excipients; D005230:Fatty Acids, Nonesterified; D008051:Lipid Bilayers; D008610:Menthol; D002784:Cholesterol
keywords: Coarse-grained; Menthol; Mixed-lipid bilayer; Molecular dynamics simulation; Penetration enhancer