Xingxing Dai

Interaction of menthol with mixed-lipid bilayer of stratum corneum: A coarse-grained simulation study

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 menthols 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.

Interactions of Borneol with DPPC Phospholipid Membranes: A Molecular Dynamics Simulation Study

Borneol, known as a “guide” drug in traditional Chinese medicine, is widely used as a natural penetration enhancer in modern clinical applications. Despite a large number of experimental studies on borneol’s penetration enhancing effect, the molecular basis of its action on bio-membranes is still unclear. We carried out a series of coarse-grained molecular dynamics simulations with the borneol concentration ranging from 3.31% to 54.59% (v/v, lipid-free basis) to study the interactions of borneol with aDPPC(1,2-dipalmitoylsn-glycero-3-phosphatidylcholine) bilayer membrane, and the temperature effects were also considered. At concentrations below 21.89%, borneol’s presence only caused DPPC bilayer thinning and an increase in fluidity; A rise in temperature could promote the diffusing progress of borneol. When the concentration was 21.89% or above, inverted micelle-like structures were formed within the bilayer interior, which led to increased bilayer thickness, and an optimum temperature was found for the interaction of borneol with the DPPC bilayer membrane. These findings revealed that the choice of optimal concentration and temperature is critical for a given application in which borneol is used as a penetration enhancer. Our results not only clarify some molecular basis for borneol’s penetration enhancing effects, but also provide some guidance for the development and applications of new preparations containing borneol.

Dissipative particle dynamics study on self-assembled platycodin structures: the potential biocarriers for drug delivery.

Platycodin, as a kind of plant based biosurfactants, are saponins which derived from the root of Platycodon grandiflorum A. DC. It has been confirmed that platycodin have the potential to enhance the solubility of hydrophobic drugs and function as the drug carrier, which depends on their micellization over critical micelle concentration (CMC) in aqueous solutions. With the purpose of investigating the effects of influencing factors on the micellization behavior of platycodin and obtaining the phase behavior details at a mesoscopic level, dissipative particle dynamics (DPD) simulations method has been adopted in this study. The simulations reveal that a rich variety of aggregates morphologies will appear with changes of structure or the concentration of saponins, including spherical, ellipse and oblate micelles and vesicles, multilamellar vesicles (MLVs), multicompartment vesicles (MCMs), tubular and necklace-like micelle. They can be formed spontaneously from a randomly generated initial state and the result has been represented in the phase diagrams. Furthermore, deeper explorations have been done on the concentration-dependent structure variation of spherical vesicles as well as the formation mechanism of MLVs. This work provides insight into the solubilization system formed by platycodin, and may serve as guidance for further development and application in pharmaceutical field of platycodin and other saponins.

Effects of Concentrations on the Transdermal Permeation Enhancing Mechanisms of Borneol: A Coarse-Grained Molecular Dynamics Simulation on Mixed-Bilayer Membranes

Borneol is a natural permeation enhancer that is effective in drugs used in traditional clinical practices as well as in modern scientific research. However, its molecular mechanism is not fully understood. In this study, a mixed coarse-grained model of stratum corneum (SC) lipid bilayer comprised of Ceramide-N-sphingosine (CER NS) 24:0, cholesterol (CHOL) and free fatty acids (FFA) 24:0 (2:2:1) was used to examine the permeation enhancing mechanism of borneol on the model drug osthole. We found two different mechanisms that were dependent on concentrations levels of borneol. At low concentrations, the lipid system maintained a bilayer structure. The addition of borneol made the lipid bilayer loosen and improved drug permeation. The “pull” effect of borneol also improved drug permeation. However, for a strongly hydrophobic drug like osthole, the permeation enhancement of borneol was limited. When most borneol molecules permeated into bilayers and were located at the hydrophobic tail region, the spatial competition effect inhibited drug molecules from permeating deeper into the bilayer. At high concentrations, borneol led to the formation of water pores and long-lived reversed micelles. This improved the permeation of osthole and possibly other hydrophobic or hydrophilic drugs through the SC. Our simulation results were supported by Franz diffusion tests and transmission electron microscope (TEM) experiments.

A Multiscale Study on the Penetration Enhancement Mechanism of Menthol to Osthole

Menthol is a widely used penetration enhancer in clinical medicine due to its high efficiency and relative safety. However, details of the penetration enhancement mechanism of menthol on the molecular level is rarely involved in the discussion. In this work, the penetration enhancement (PE) mechanism of menthol is explored by a multiscale method containing molecular dynamics simulations, in vitro penetration experiments, and transmission electron microscopy. Osthole is chosen to be the tested drug due to its common use in external preparations and because it often accompanies menthol as a PE in the preparations. The results show that menthol in each testing concentration can impair the lipid packing of stratum corneum (SC) and promote osthole permeating into SC, and the penetration promoting effect has an optimal concentration. At a low concentration, menthol causes the bilayer to relax with a reduction in thickness and increment in the lipid headgroup area. At a high concentration, menthol destroys the bilayer structure of SC and causes lipids to form a reversed micelle structure. The penetration enhancement mechanism of menthol is characterized mainly by the disruption of the highly ordered SC lipid in low concentrations and an improvement in the partitioning of drugs into the SC in high concentrations. The results can provide some assistance for additional studies and applications of menthol as a penetration enhancer.

Influence of Temperature on Transdermal Penetration Enhancing Mechanism of Borneol: A Multi-Scale Study

The influence of temperature on the transdermal permeation enhancing mechanism of borneol (BO) was investigated using a multi-scale method, containing a coarse-grained molecular dynamic (CG-MD) simulation, an in vitro permeation experiment, and a transmission electron microscope (TEM) study. The results showed that BO has the potential to be used as a transdermal penetration enhancer to help osthole (OST) penetrate into the bilayer. With the increasing temperature, the stratum corneum (SC) becomes more flexible, proving to be synergistic with the permeation enhancement of BO, and the lag time (TLag) of BO and OST are shortened. However, when the temperature increased too much, with the effect of BO, the structure of SC was destroyed; for example, a water pore was formed and the micelle reversed. Though there were a number of drugs coming into the SC, the normal bilayer structure was absent. In addition, through comparing the simulation, in vitro experiment, and TEM study, we concluded that the computer simulation provided some visually detailed information, and the method plays an important role in related studies of permeation.

Solubilization of menthol by platycodin D in aqueous solution: An integrated study of classical experiments and dissipative particle dynamics simulation

Menthol (M) and platycodin D (PD) are the main active ingredients in Mentha haplocalyx and Platycodon grandiflorum A. DC., respectively. They are commonly used in combination in traditional Chinese medicine. In this study, laboratory experiments and computer simulations were used to investigate the solubilization of M by PD, which was believed to be one of the main causes of the synergistic effect of M. haplocalyx and P. grandiflorum A. DC. Results showed that both the method by which M was added and the concentration of PD had significant effects on the solubilization efficiency of M, and these influences were closely associated with each other. Temperature, an important environmental condition, was also found to have a significant effect on the solubilization effect of PD. These findings not only clarify the molecular basis of the solubilization effect, including amount solubilized at the macroscale and the structures of the micelles, and the drug loading mechanisms and processing at the mesoscale. This work may provide some guidance for the further development of saponins and fundamental research in the drug delivery system.

Permeation-enhancing effects and mechanisms of borneol and menthol on ligustrazine: A multiscale study using in vitro and coarse-grained molecular dynamics simulation methods

Borneol (BO) and menthol (MEN) are two widely used natural permeation enhancers in the transdermal drug delivery system. In previous studies, their permeation enhancement effects and mechanisms of action on the hydrophobic drug osthole (logP = 3.8) and hydrophilic drug 5‐fluorouracil (logP = −0.9) have been studied. In this study, ligustrazine (LTZ), whose logP is 1.3, was used as a model drug to provide a comprehensive understanding of the influence of its logP on the permeation‐enhancing effects of BO and MEN. Both BO and MEN enhanced the permeation of LTZ through the skin stratum corneum, as determined using the modified Franz diffusion cell experiment. The enhancement mechanisms were illustrated by coarse‐grained molecular dynamics simulations as follows: at low concentrations, the enhancing ratio of MEN was higher than that of BO because of the stronger perturbation effects of MEN on the lipid bilayer, making it looser and facilitating LTZ diffusion. However, at high concentrations, in addition to the diffusion mechanism, BO induced the formation of water channels to improve the permeation of LTZ; however, MEN had no significant effects through this mechanism. Their results were different from those found with osthole and 5‐fluorouracil and have been discussed in this study.

Dealing with heterogeneous classification problem in the framework of multi-instance learning

To deal with heterogeneous classification problem efficiently, each heterogeneous object was represented by a set of measurements obtained on different part of it, and the heterogeneous classification problem was reformulated in the framework of multi-instance learning (MIL). Based on a variant of count-based MIL assumption, a maximum count least squares support vector machine (maxc-LS-SVM) learning algorithm was developed. The algorithm was tested on a set of toy datasets. It was found that maxc-LS-SVM inherits all the sound characters of both LS-SVM and MIL framework. A comparison study between the proposed approach and the other two MIL approaches (i.e., mi-SVM and MI-SVM) was performed on a real wolfberry fruit spectral dataset. The results demonstrate that by formulating the heterogeneous classification problem as a MIL one, the heterogeneous classification problem can be solved by the proposed maxc-LS-SVM algorithm effectively.