The Preparation Of Nanometer Mixed Micelle Modified By Folic Acid For Resveratrol

ObjectiveAs a natural product present in a class of polyphenols,resveratrol has a lot of pharmacological activities such as reduce blood sugar,anti-oxidation,protect cardiovascular,anti-inflammatory and anti-tumor,but it has lower water solubility and rapid metabolism limits its application in clinical practice.This paper with folic acid modified Pluronic F127 with TPGS as carrier material for preparing a mixed micelle solution contains resveratrol,a desired effect of increasing drug circulation in vivo and enhancing tumor cells targeting.MethodsThe carrier material of pluronicF127 that modified by folic acid compounded through chemical process and the nanometer mixed micelle was prepared by these material and TPGS using film hydration method.Formulation was optimized and prepared via the central composite method.Bag filter method was used to study the release characteristics in vitro then morphology of nanometer mixed micelles was found to be near-spherical shaped with transmission electron microscope.FITC was used as fluorescence probe to study the uptake in vitro for nanometer mixed micelles modified by folic acid compared with nanometer mixed micelle without modifying and the PEG solution and compared the cytotoxicity of them through CCK-8 method.To explore resveratrol’s distribution and the long circulation in vivo,the distribution test was established in Kunming mice.The pharmacokinetic character was described by pharmacokinetic experiment in SD rat.ResultsThis topic after NMR and UV analysis confirmed the synthesis of folic acid modified Pluronic carrier material.The prescription optimization results showed that when preparing micelles contain resveratrol 2 mg / ml,the carrier materials ratio of Pluronic F127 andTPGS was 1.62,the micelles had the best characterized.The PS,EE,DL and PDI were 19.94 nm,101.21%,9.26% and 0.146,after repeated experiments showed that the results of optimization theory and actual values lower than 10%.And vitro release test results showed that resveratrol solutions reached peak release in a short time and the release rate can reach 56%,but resveratrol micelle solution reached the release peak in a long time,this may be due to sustained release micelle solution causes.By cell biology experiments show that folic acid-modified resveratrol mixed micelle solution viability of cells was significantly lower than the unmodified mixed micelle solution and suspension,which has proved a strong tumor cytotoxicity.Cellular uptake experiments show that MCF-7 cells uptake of folic acid-modified resveratrol mixed micelle solution was significantly higher than that of the micelle solution which folate closed group and unmodified group,that proved folate receptor expression MCF-7 cells uptake drugs by way of folic acid intake was mediated.Mouse tissue distribution studies have shown that the cumulative amount of the micelle solution group in the spleen and other tissues was significantly lower than homemade solutions group,a corollary of resveratrol mixed micelles have some long cycle characteristics.And pharmacokinetics in rats show resveratrol mixed micelle drug half-life has a certain extent,indicating that mixed micelles solution can significantly improve the bioavailability of resveratrol in rats.Conclusion1.For folic acid modified Pluronic carrier material can be produced through dehydrate with CDI and two-step electrophilic reaction manner,this synthetic route is a clear,and high efficiency method.2.Using the Central Composite method for the formulation optimization and this method can reduce the number of experiments and improve test accuracy,and ultimately optimize the most reasonable prescription.3.The experimental results show the small size of the micelle formulations can avoid phagocytosis and block by the liver and spleen macrophages cells and prolong the drug residence time in the body,improve the bioavailability.4.The mixed micelle solution by cell biology experiments show that folic acid can be modified into tumor cells via folate receptor-mediated effects and concentrate in the cell,that proved the drug having active tumor targeting.