Synthesis Of Cyclodextrin-based Stimuli-responsive Block Copolymer And Its Application For Controlling DOX Release

Malignant tumor has become a danger to human life and health of the most serious diseases that have antitumor drugs exist mostly poor solubility,side effects.?-cyclodextrin??-CD?has the outer ring of the hydrophilic and hydrophobic cavity,the cavity can carry hydrophobic drugs,and increase the drug solubility,stability and bioavailability.The stimulus responsive cyclodextrin polymers were functionalization of cyclodextrin modified and give its responsiveness.?-CD as the core,this paper use the atom transfer radical polymerization?ATRP?,reversible addition fragmentation chain transfer?RAFT?,Click chemistry and ring opening polymerization?ROP?method of the preparation of a series of ?-CD as nuclear star amphiphilic polymers.Observe the self-assembly behavior of polymer in aqueous solution,and as a drug carrier is evaluated.The main research work is as follows:?1?Well-defined amphiphilic ?-cyclodextrin??-CD?star-shaped copolymers with poly??-caprolactone?-poly?2-?2-methoxyethoxy?ethylmethacrylate?-co-poly?ethyleneglycol?metha crylate)(?-CD-?PCL-P?MEO2MA-co-PEGMA??₂₁ were synthesized via ROP and ATRP.Which were confirmed by fourier transforms infrared spectroscopy?FTIR?,nuclear magnetic resonance?¹H NMR?and gel permeation chromatography?GPC?.The star-shaped copolymers could self-assemble into micelles in aqueous solution,which was investigated by ultraviolet-visible spectroscopy?UV-vis?,dynamic light scattering?DLS?and transmission electron microscopy?TEM?.The lower critical solution temperature?LCST?could be controlled by changing the ratio of monomers.Doxorubicin?DOX?,as the model drug,the in vitro DOX release studies showed that DOX released from drug-loaded micelles in different temperature?37oC and 50oC?,pH 7.4 buffer solution.CCK-8 assays demonstrated that these star shaped copolymers could possess low cytotoxicity against HeLa cells,and the DOX-loaded micelles exhibited a higher inhibition of the proliferation of HeLa cells in comparison with free DOX.Moreover,the results from confocal laser scanning microscopy?CLSM?revealed that these different concentrations of polymer micelle make HeLa cells survival rate reached about 90% and drug micelle has cytotoxicity,with a laser confocal microscope?CLSM?showed that the drug DOX different times the distribution of cells and polymeric micelles could efficiently deliver and release DOX into the nuclei of HeLa cells.?2?Well-defined dual pH and temperature responsive triblock star-shaped amphiphilic copolymers of ?-cyclodextrin-g-poly?2-hydroxyethylmethacrylate?-b-poly?N-Isopropylacrylamide?-b-poly?2-?dimethylamino?-ethylmethacrylate???-CD-g-?PHEMA-b-PNIPAM-b-PDMAEMA??,were synthesized by the ?-cyclodextrin xanthic acid ester??-CD-?xanthate?₃?as reversible addition-fragmentation chain transfer?RAFT?chain transfer agent.The chemical structures and compositions of these copolymers were characterized by FTIR,¹H NMR,and GPC measurements.Subsequently,the obtained triblock copolymers could self-assemble into micelles in aqueous solution owing to their amphiphilic property resulting from the hydrophobic ?-CD core and the hydrophilic PHEMA,PNIPAM,and PDMAEMA segments,which were investigated by UV-vis,DLS and TEM.The stimuli-responsive self-assembly behavior of these triblock copolymers in aqueous solutions were investigated the DOX loaded micelles in drug controlled release ability at different temperature and pH.CCK-8 assays research the toxicity HeLa cells and biocompatibility on the polymer micelles and the DOX loaded micelles;which the DOX loaded micelles were found to be taken up by the nuclei of the cells via the endocytosis process using CLSM,which could kill HeLa cells.?3?Star polymers poly??-caprolactone?-graft-?-cyclodextrin-graft-poly?2-?dimethylamino?ethylmethacrylate?-co-poly?ethyleneglycol?methacrylate)?PCL-g-?-CD-g-P?DMAEMA-coPEGMA??through the ROP and click reaction on the synthetic reaction,the structure of the polymer showed by FTIR,¹H-NMR and GPC.Star polymers self-assemble into micelles in aqueous solution,after DLS and TEM observation its size is about 60 nm,polymer micelles can effective load hydrophobic drug doxorubicin.In vitro release results show that polymer micelle under the pH value of the response,could to effective drug release under acid environment.Through the CCK-8 poisonous to the cells of the biocompatibility of the polymer micelle and study,the drug micelle on HeLa cells has good biological compatibility.By CLSM observation found that micelle into the nucleus and drug release.?4?A star-shaped amphiphilic block copolymers with dual stimulus response,?-cyclodextrin-poly?Nisopropylacrylamide?-block-poly[2-?dimethylamino?ethylmethacrylate]-(?-CD-?PNIPAM-b-PDMAEMA?₂₁)was successfully synthesized through the combination of ATRP.Afterwards,the polymers were coupled via click chemistry with propinyloxy coumarin and azido-polymers in order to prepare fluorescent copolymers.The chemical structures of the copolymers were well characterized,which the ?-CD-?PNIPAM-b-PDMAEMA?₂₁-g-PC could self-assemble in aqueous solution at room temperature to form core-shell micelles and the particle size of the polymer micelle,Zeta potential,drug loading content and loading efficiency,while studying polymer micelles control release behavior in vitro environment.DOX,as the model drug,and their using of CCK-8 assay,CLSM images and flow cytometry instrument testing HeLa and Colorectal cancer?C26?cells on drug uptake conditions,polymer micelles toxicity of kinds of tumor cells and cell apoptosis.Using C26 bearing mice as animal model and research the antitumor activity in vivo bearing mice of the polymeric micelles.In addition,the hematoxylin and eosin?HE?staining images of tumor tissues and major organs showed and analysed.