Study On Drug Loading Mechanisms Of Lipids Film Based On Self-Assembled Supramolecular

In this study,molecular interactions between the hydrophobic compound 20（R）-25-methoxyl-dammarane-3 β,1 2β,20-triol（AD-1）and different phospholipids were investigated using the Langmuir film balance technique.And then,the thermodynamic characteristics of mixed monolayers were used to predicted the loading efficiency and physical stability of the corresponding drug delivery systems.An HPLC-ELSD method was established for the analysis of AD-1 in vitro.The solubility of AD-1 in various solutions was investigated and showed that AD-1 was insoluble both in oil（<1 mg/g）and water（<10.2 μg/mL）.The IogP of AD-1 between octanol/distilled water was 0.436.These results revealed that the solubility and distribution coefficient of AD-1 is not dependent on the pH value.The monolayer of AD-1 with a limiting area of about 272 （?）2/molecule and the lift-off area is 334.1 （?）2/molecule.Based on the calculated values of （?）Gex,we found that the AD-1/DSPC binary mixed monolayers exhibited the best stability when XAD-1=0.8.In the region of a lower AD-1 content（XAD-1≤ 0.2）the interactions between AD-1 and SOPC（DOPC）molecules is attractive and stable.However,further addition of AD-1（XAD-1≥0.4）may additionally change the interactions to repulsive.The results showed that the influence of AD-1 depends on not only the monolayer composition（AD-1 molar fraction）but also due to the Intermolecular distance（surface pressure）.Thus,the presence of additional mono-unsaturated carbon chain for DOPC has only a very weak action on the intermolecular interaction induced by AD-1.The predicted results of binary Langmuir monolayers were verified by the molecular docking calculations.The hydrophobic interactions between AD-1 and lipid are clearly evident,and the trend in binding affinities is consistent with the stability enhancement.These states are characterized by a significant tilt of the AD-1 plane to the radial axis of the channel and by strong hydrophobic interaction between the side hydrocarbon tails of lipids.It appears that this variation is influenced by AD-1/lipid steric interactions as well as by the AD-1/lipid mole ratio.The above experiments results indicated the close relationship between the 2D membrane insertion ability and the 3D hydrophobic bound conformation of AD-1.The interface phase behaviors of ternary mixed systems（AD-1/DSPC/DSPE and AD-1/SOPC/Chol）were also investigated.At a lower DSPE content(X_DSPE≤0.15),the presence of DSPE enhanced the interface stability of AD-1/DSPC mixed system.The monolayer composition and Intermolecular distance were the most important factors which influence the interaction behaviors.The presence of Cholesterol(X_Chol<0.4)enhanced the interface stability of AD-1/SOPC mixed system significantly.However,further addition of Cholesterol(X_Chol>0.6)may additionally decrease the stability of AD-1/SOPC mixed system.To clarify this,a series of AD-1/lipid-based carrier systems were prepared according to the predicted and experimental results.Thus,there is an excellent agreement between these stability results and the predicted trends from drug/lipids mixed monolayers.Aqueous solutions of lipid-based carrier systems load AD-1 increasing its water solubility up to 500 fold from below 10 μg/mL to around 5 mg/mL allowing to attain therapeutically required concentrations.Mixed drug delivery systems are stable in aqueous solution for at least 3 months when kept at room temperature.Upon incubation with blood components the drug delivery systems do not induce hemolysis.Altogether,the physico-chemical properties and the good biocompatibility of the system open the possibility to use this platform for the design of novel nanocarriers for hydrophobic or amphipathic active pharmaceutical ingredients.