Construction And Properties Of PH/reduction Responsive Polymer Cross-linked Micelles

Polymer drug-loaded micelles play an important role in the research of drug delivery systems because of their advantages of drug solubilization,improving drug treatment effects and reducing toxic side effects.However,they still have the problems of low stability and poor controlled drug release properties.In view of the above problems,this thesis intends to construct a p H/reduction dual-responsive amphiphilic polymer cross-linked micelle PPEGMA-SS-P(CL-co-DCL)and apply it to the delivery of the hydrophobic drug paclitaxel.It improves the stability of micelles and realizes the controlled release of drugs at tumor targets.In this thesis,three amphiphilic polymer molecules,PPEGMA₈-SS-P(CL₄₇-co-ACL₁₅),PPEGMA₁₂-SS-P(CL₄₇-co-ACL₁₅)and PPEGMA₂₃-SS-P(CL₄₇-co-ACL₁₅),were designed and synthesized as expected.And their basic structural characteristics were characterized by~1H NMR,FT-IR and GPC.Then,the self-assembly behavior of the above three polymers in water was investigated using DPD simulation method,and their CMC were determined by fluorescence spectrophotometry.The CMC values were 1.26 mg/L,1.41 mg/L and 1.66 mg/L,respectively.The results showed that they could form micelles in aqueous solution.Blank micelles particle size changes at different p H values and reducing conditions were measured by DLS.It was found that all three blank micelles exhibited good p H/reduction responsive behaviors with swelling due to protonation and gradually increasing particle size.Using paclitaxel as a model drug,drug-loaded micelles were prepared and their drug-loading capacity and encapsulation efficiency were studied by UV-Vis spectrophotometer.The LC and EE were P8(19.88%,59.63%),P12(19.39%,58.16%)and P23(16.67%,49.99%),respectively.Finally,the controlled release properties of the above three drug-loaded micelles were studied in vitro.The results showed that in the p H 7.4/0 m M DTT environment,the three drug-loaded micelles released slowly,and the cumulative release within 120 h were less than 20%.In the p H 5.0/10m M DTT environment,the cumulative release of drug-loaded micelle P8 reached 67%within120 h,which was slightly better than the other two drug-loaded micelles,showing good p H/reduction responsiveness.Subsequently,cross-linked micelles PPEGMA-SS-P(CL-co-DCL)were prepared using DMMA as a cross-linking agent.The size changes of blank micelles before and after cross-linking were tested by DLS,and it was found that the particle size of blank micelles after cross-linking was smaller than that of uncross-linked blank micelles.By comparing the drug-loading properties of cross-linked drug-loaded micelles prepared by different preparation methods,combined with the drug-loaded micelle structure and drug distribution structure displayed by DPD simulation,it could be seen that the cross-linked drug-loaded micelles prepared by the method of drug loading first and then cross-linking,better than prepared by cross-linking first,then drug-loading and drug-loading cross-linking at the same time.The cross-linked drug-loaded micelles were more stable at p H 7.4/0 m M DTT.Under the condition of p H 5.0/10 m M DTT,the cumulative release of cross-linked drug-loaded micelles reached71%within 120 h,showing a good p H/reduction-responsive drug release effect.Finally,from CCK-8,it could be seen that the toxicity of cross-linked blank micelles was low,and cell viability was about 80%when the concentration was 200 mg/L.The cross-linked drug-loaded micelles had good apoptosis and inhibitory effects on Hep G2 cells.In conclusion,the stability of the amphiphilic polymer-crosslinked micelles PPEGMA-SS-P(CL-co-DCL)were improved compared to the uncross-linked micelles.Moreover,it also has good anti-tumor effect,and it has potential application prospects as a drug delivery carrier.