Preparation And Structure-Property Relationship Study Of Stimulus Response Reversible Cross-linked Micelles

As a kind of drug carrier,polymeric micelles are widely used in improving drug solubility and bioavailability.However,how to maintain the structural stability of micelles in vivo and control drug release is an important challenge.In this paper,reversible cross-linked micelles were synthesized,and their stability,drug loading properties and drug release in different environments were investigated.Finally,the structure property relationship of reversible crosslinked micelles with different topologies was studied by dissipative particle dynamics（DPD）.Based on the characteristics of weak acidity and high redox potential of human tumor tissues,an amphiphilic copolymer（dimethylaminoethyl methacrylate-co-phenylboronic acid）-b-polylactic acid-SS-polylactic acid-（dimethylaminoethyl methacrylate-co-phenylboronic acid）[（PBA-co-PDMAEMA）-b-PLA-SS-PLA-b-（PDMAEMA-co-PBA）]responding to triple stimulation of p H/reduction/H₂O₂ was synthesized.The polymer self-assembled in water to form micelles with core-shell structure,which can be used for DOX loading.In order to enhance the stability of micelles and avoid the sudden release of micelles due to dilution and disintegration in blood circulation,the phenylboronic acid（PBA）on the hydrophilic branched chain reacts with the crosslinking agent polyvinyl alcohol（PVA）to form borate ester,which can form reversible crosslinked micelles.The results showed that the non-crosslinked micelles aggregated after dilution,but the reversible crosslinked micelles remained stable after dilution.At pH 7.4,the cumulative release was 24.56%（108 h）,and the continuous cumulative release of cross-linked drug-loaded micelles under simulated normal environment and tumor cell microenvironment was 77.11%.When the concentration of drug-loaded cross-linked micelles was 12.5μg/m L,the survival rates of HepG2 and Caco-2 cells were both lower than 20%,indicating that drug-loaded cross-linked micelles can effectively inhibit tumor cell proliferation.The DPD method was used to simulate the effect of cross-linked micelle structure based on polymer（PBA-co-PDMAEMA）-b-PLA-SS-PLA-b-（PDMAEMA-co-PBA）on self-assembly and drug release behavior,and the structure property relationship was discussed from the mesoscopic level of computer simulation.After establishing the coarse-grained model of reversibly cross-linked micelles,a Perl language script that can be recognized by the MS software was written to simulate the cross-linked micelles.According to the formation-fracture process of crosslinked structure under different conditions,the effects of crosslinking process on micelle self-assembly behavior,drug loading and release were discussed.The results showed that the micelles have two distribution forms:bending and stretching,and the density of the micelle core increases significantly after cross-linking（183.28>128.79）.When the ratio of drug to polymer increases to 15:30,the drug loading capacity of micelles after crosslinking decreases.The intelligent response of reversible cross-linking structure to different simulated conditions endows micelles with controlled drug release performance in different environments.Taking crosslinked micelles as the research object,based on the mesoscopic model of DPD coarse-grained simulation of crosslinked micelles,the effects of block ratio,topological structure,crosslinking degree and other factors on the structure of crosslinked micelles were explored,and then the effects of various factors on the self-assembly behavior and drug loading of crosslinked micelles were analyzed and summarized.Furthermore,the universal mathematical model of crosslinking degree was established by using the kinetic equation of dynamic chemical bond formation fracture in reversible crosslinking structure,and the effects of polymer concentration and self-assembled p H environment on crosslinking degree were systematically discussed.Through the results of computer simulation and kinetic model to guide and optimize the experiment,it is expected to shorten the experimental period and reduce the experimental cost to a great extent.At the same time,the phenomena and rules that cannot be observed by the experimental means can be found in the mesoscopic scale,which has a good theoretical value and significance for the study of drug loaded cross-linked micelles as drug delivery system.