Multi-stimulation-responsive Ferrocene-based Amphiphilic Block Copolymer Self-assembled Micelles And Drug Release Studies

It is a key problem for drug delivery system(DDS)to increase the loading capacity,to reduce drug toxicity,to achieve the targeted drug release and to improve the stability in blood circulation in vivo.However,traditional DDS exhibits various defects,and thus can not well meet the needs of extensive practical treatments.Stimuli-responsive amphiphilic block copolymers show wide application potentials in the field of biomedicines as a carrier of the gene and drug controlled release because of its unique self-assembly properties.Since there exist great differences between human normal cells and lesion cell tissues,various stimuli-responsive drug carriers,for example,pH,temperature and redox responsiveness,can be designed and constructed to match different stimuli.On the other hand,a single stimuli responsive drug carrier has a certain limitation owing to complex environments in vivo.To futher achieve the targeted delivery and specific release of drug at tumour sites,to prolong drug deliverytime,to decrease dosing frequencies,and to improve the stability in blood circulation in vivo,it is necessary to engineer and construct new type of multi-stimuli responsive drug carrier materials.Considering great differences in pH and reactive oxygen species(ROS)between tumour tissues and normal tissues,two types of ferrocene-containing amphiphilic block copolymers were designed and synthesized in this work,namely,redox-responsive poly(2-acryloyloxyethyl ferrocenecarboxylate)-block-poly(2-(di-methylamino)ethyl methacrylate)(PAEFc-b-PDMAEMA)and pH-,redox-and magnetic multiple stimuli-responsive Fe3O4 graft poly(2-methacryloyloxyethyl ferrocenecarboxylate)-block-poly(acrylic acid)(Fe3O4-g-PAOEFC-b-PAA)amphiphilic block copolymers.The self-assembly behavior and biological properties of ferrocene-containing copolymers were studied.The study mainly focuses on the following two areas.1.Ferrocene-containing redox-responsive amphiphilic block copolymer self-assembly micelles and drug controlled release.2-Acryloyloxyethyl ferrocenecarboxylate was synthesized through esterification,which was then used to synthesize ferrocene-containing amphiphilic block copolymers,poly(2-acryloyloxyethyl ferrocenecarboxylate)-block-poly(2-(dimethylamino)ethyl methacrylate)(PAEFc-b-PDMAEMA)via sequential two-step ATRP routes.The effect of[initiator]/monomer]ratios on self-assembly and drug release properties were studied.The structure and molecular weights of the copolymer as well as critical micelle concentration(CMC)were characterized and determined by infrared spectrum(FT-IR),1H NMR spectrum,gel permeation chromatography(GPC)and fluorescence spectrum.Redox reversibility of the copolymer micelles was investigated by UV-vis,cyclic voltammetry(CV),transmission electron microscope(TEM)and laser particle analyzer(DLS)using H2O2,KMnO4,NaClO and FeCl3 as a model of oxidants and ascorbic acid(VC)as a model of reductants.Experimental results showed that the PAEFc-b-PDMAEMA ferrocene-containing amphiphilic block copolymers possess good redox reversibility,and can be used as an 'intelligent' on-off switch.The encapsulation and release experiments of drug hydrocamptothecine(HCPT)from the PAEFc-b-PDMAEMA amphiphilic block copolymers indicated that in simulated cancer cells of pH 5.8 having H2O2 concentrations from 0.15 to 0.60%,the drug release amount was increased from 26.5 to 60.6%,much higher than that in normal cells.2.Preparation of pH-,redox and magnetic-responsive multiple stimuli-responsive hybrid block copolymers.Fe3O4@CPADB chain transfer agents were prepared through esterification reaction between aminated Fe34a and 4-cyano-4(thiobenzoylthio)pentanioc acid(CPADB),and then Fe3O4 graft poly(2-methacryloyloxyethyl ferrocenecarboxylate)-block-poly(acrylic acid)(Fe3O4-g-PMAOEFC-b-PAA)multiple stimuli-responsive hybrid block copolymers were synthesized via sequential two-step RAFT routes by modulating[CPADB]/[monomer]ratios.The characterization was performed by FTIR,1H NMR,GPC,X-ray diffraction(XRD)and thermogravimetric analysis(TGA)techniques.The Fe3O4-g-PMAOEFC-b-PAA hybrid block copolymers can self-assemble into micelles in aqueous solution.Zeta potentials,CV,vibrating sample magnetometer(VSM),TEM and SEM findings showed that the block copolymer micellespossess good pH,magnetic and redox stimuli responsiveness.The anticancer drug paclitaxel(PTX)was entrapped in the Fe3O4-g-PMAOEFC-b-PAA block copolymer micelles and the in vitro drug release behavior was investigated.The results indicated that a pH of 5.6 and 7.4,and H2O2 concentrations of 0.20 and 0.80%,the cumulative HCPT release amount changed in the range from 26.2-72.7%.In particular,the drug release amount was remarkably increased in simulated cancer cell invironments of pH 5.3 and 6.3 and high-concentration oxygen species.This class of multiple stimuli-responsive Fe3O4-g-PAA-b-PMAOEFC copolymer materials is expected to find wide applications in the field of biomedicines.