Synthesis And Characterization Of Stimuli Sensitive Core Cross-linked Drug Carrier Based On Polyphosphoester

During the process of delivery,drug carrier would first be accumulated in tumor tissue via the enhanced permeability and retention(EPR)effect,then internalized by cells via cell uptake.Finally,under the influence of the intracellular environment,drug carrier would be broken up and released the anticancer drug.In this process,several unique abilities of carrier such as good stability,drug controlled release and fine biocompatibility were necessary.And those require strict requirements for the structure,morphology,particle size or other physical and chemical properties of the carrier.In this paper,we designed the cross-linkage to enhance the stability and introduced the acid/reductive sensitive bonds to control drug release.In addition,we also tried to conjugate target molecules on the micelles to enhance the effect of cell uptake,design prodrug to further improve stability.The specific contents are as follows:1.Folate-Conjugated Polyphosphoester with Reversible Cross-Linkage and Reduction Sensitivity for Drug Delivery.To improve the therapeutic efficacy and circulation stability in vivo,we synthesized a new kind of drug delivery carrier based on folic acid conjugated polyphosphoester via the combined reactions of Michael addition polymerization and esterification.The produced amphiphilic polymer,abbreviated as P(EAEP-AP)-LA-FA,could self-assemble into nanoparticles(NPs)with core-shell structure in water and reversible core cross-linked by lipoyl groups.To verify the stability,target ability,drug controlled release ability and antitumor activity,we synthesized and prepared five kinds of NPs:CCL-FA NPs,UCL-FA NPs,DOX-loaded CCL-FA NPs,DOX-loaded UCL-FA NPs and DOX-loaded CCL NPs.Based on the five kinds of NPs mentioned above,we designed the test of size changes and drug released in vitro under the different reductive with or without PDE I conditions.In addition,we designed the experiment that cells treated with different NPs and monitored by MTT assay,confocal microscopy or confocal microscopy.Those results all indicate that the CCL-FA NPs have unique stability and target ability.2.Dual-Responsive Core Corss-linked Prodrug Based on Polyphosphoester:Synthesis,Characterization and Drug Delivery.To improve the circulation stability in vivo and drug controlled release ability,we synthesized a new kind of produrg based on polyphosphoester via the reactions of addition polymerization and esterification.The prodrug could be self-assembled into nanoparticles(NPs)in aqueous solution and cross-linked by adding additional DTT.In this study,1H NMR,UV-Vis and GPC were used to verity the structure of Polymer 3 and its intermediate products.DLS and TEM were used to monitor and observe the particles size,size PDIs and morphologies of those NPs.In addition,several experiments were designed and carried on,for example,the particle size changes of CCL NPs or drug released from the CCL NPs in different acid/reductive conditions were used to prove the CCL NPs based on Polymer 3 had good acid/reductive sensitive ability.Several kinds of cells treated with CCL NPs based on Polymer 3 or Polymer 2 were used to prove the good biocompatibility of Polymer 2 or anticancer activity of DOX.Cells uptake against CCL NPs to prove CCL NPs could be effectively internalized by HeLa cells or HepG2 cells.