Preparation Of Stimuli-responsive Polymer Nanocarriers And Their Applications In Anti-tumor Drug Delivery System

The application of stimuli-responsive nanopolymers in the anti-tumor drug delivery system can provide unprecedented control of drug delivery to achieve "on-demand" drug release,and produce excellent anti-tumor effects,which is a promising new drug delivery system.The study designed a kind of polymer micelles with pH responsive.It found that the micelles have the problems of high drug release under normal physiological conditions such as blood and incomplete release in tumor sites.Therefore,we further optimized the polymer to build more stability structure and achieve simultaneously dual or multi-stimuli responsive of polymer nano-cross-linked micelles and nanohydrogels for realizing the target delivery of anticancer drugs.In this paper,the relationships between polymer structure,nano-carrier structure and performance and drug delivery system performance were studied in detail,which provided theoretical support and technical basis for anti-tumor drug delivery system in the material selection,structure construction,performance regulation and application of anti-tumor drug delivery system.The specific contents are as follows:Based on the weak acidic of tumor environment,we designed and synthesized a six-arm star-shaped amphiphilic copolymer with poly(caprolactone)-b-poly(acrylic acid)-b-poly(poly(ethylene glycol)methyl ether methacrylate)(6AS-PCL-PAA-PPEGMA).PCL is a hydrophobic block,while PPEGMA is a hydrophilic block and PAA is a functional block.GPC and 1H NMR were used to characterize the molecular weight and structure of the copolymer,while DLS were used to characterize the structure and properties of the self-assembled micelles,and the pH responsive drug release performance of the micelles was studied.The copolymer self-assembled into polymer micelles with pH responsive.With the change of pH,the micelles changed from the swelling state in bloodstream and normal tissues(pH 7.4)to the shrinking structure in the tumor acidic environment(pH 5.0).However,the micelles had high drug release(46.5%)under normal physiological condition and incomplete release(62.1%)in tumor site.With disulfide bond was introduced,a four-arm star-shaped copolymer 4 AS-PMAA-(PHEMA-SS～)-PPEGMA was designed and synthesized,and then self-assembled into disulfide-cross-linked polymer micelles with pH/Reduction dual-stimuli-responsive.After loading the anti-tumor drug doxorubicin(DOX),the DOX-loaded cross-linked micelles have strong resistance to dilution of solution under the normal physiological condition(pH 7.4).However,in the weak acidic and high glutathione(GSH)concentration of tumor environment(pH 5.0,10 mM GSH),the shrinkage of micellar stucture was to squeeze the entrapped DOX released from polymer micelles,and the disulfide bonds in the backbone of the cross-linked polymer micelles were broken down and the micellar architecture was disassembled,which led to a fast and controllable DOX release.The interaction between the DOX and polymer micelles in the DOX release process was analyzed via thermodynamic analysis.Moreover,the cytotoxicity assay showed well cytotoxicity of DOX-loaded cross-linked micelles.On this basis,the block ratio of the polymer was further adjusted,and the copolymers of 4AS-PMAAx-(PHEMA-SS～)y-PPEGMAz with four different block ratios were designed and synthesized.The effect of the ratio of hydrophobic and hydrophilic blocks on the structure of drug-loaded cross-linked micelles(stability,particle size,morphology,zeta potential,drug loading,encapsulation rate,pH response behavior)and release performance were discussed.The results show that the structural stability of the cross-linked micelles can be effectively improved by optimizing the ratio of the hydrophilic and hydrophobic blocks of the copolymer,and the loading and controlled release properties of the drug-loaded cross-linked micelles can be regulatedNew pH/redox/UV irradiation multi-stimuli responsive nanohydrogels,based on polymer micelles self-assembled by six-arm star copolymer of 6AS-PCL-PAA-PPEGMA,were prepared by the complexation of ferric ions(Fe3+)and the carboxyl groups in the polymer micelles.The formation and morphology of the nanohydrogel system,the entrapment and release of DOX,cytotoxicity and intracellular distribution were studied.The result showed that DOX-loaded nanohydrogels were degraded with a gel to sol transition after UV irradiation,suggesting the property of UV degradation.The release of DOX was slow in the normal physiological condition.However,under the exposure to UV and the weak acidic and high glutathione(GSH)concentration of tumor environment,the release of DOX was fast,and the DOX cumulative release was up to 82.1%after 116 h.In addition,DOX-loaded nanohydrogels could be endocytosed by HepG2 cells quickly,and inhibited the proliferation of HepG2 cells effectively.