The Construction And Antitumor Activity Research Of PH/Redox Dual-Sensitive Polymeric Nanocarrier For Drug Delivery

Recently,polymeric micelles have attracted extensive attentions as nanoscale drug delivery carriers in pharmaceutical researches due to characteristics of increased solubility,high stability,reduced side effects,intensified cell cytotoxicity,high loading capacity and ease of modification.In this study,two kinds of dual-sensitive polymer micelles drug delivery systems were designed and synthesized.The in vitro anti-tumor activity was also evaluated.(1)Targeted pH/Redox Dual-Sensitive Polymer-Drug Conjugates Drug Delivery System Self-assembled polymeric micelles from a galactose-containing DOX-conjugated methoxypolyethylene glycols-b-poly(6-O-methacryloyl-D-galactopyranose)-disulfide bond-DOX(mPEG-b-PMAGP-SS-DOX)copolymer were prepared as an antitumor carrier for doxorubicin delivery,of which the chemical modification with redox-sensitive disulfide bonds and pH-sensitive hydrazone bonds allowed micelles to release doxorubicin(DOX)selectively at acidic pH and high redox conditions.The chemical structures were characterized by 1H NMR Spectroscopy(1H NMR)and Fourier Transform Infrared Spectroscopy(FTIR).The self-assembly properties of micelles were characterized by dynamic laser light scattering instrument(DLS),transmission electron microscopy(TEM)and fluorescence spectrum.The resulting micelles exhibited coordinated pH/redox dual-sensitive and hepatoma-targeted multifunction with sustaining stability in aqueous media.The multifunctional micelles showed spherical shapes with a mean diameter of 93±2.08 nm,a low polydispersity index(PDI)of 0.21,a low CMC value of 0.095 mg/mL,a high drug grafting degree of 56.9%and a drug content of 39.0%.Remarkably,in vitro drug release studies clearly exhibited a pH and redox dual-sensitive drug release profile with significantly accelerated drug release treated with pH 5.0 and 10 mM GSH(88.4%in 72 h)without drug burst release.The tumor proliferation assays indicated that DOX-grafted micelles,along with low cytotoxicity and well biocompatibility to normal cells,inhibited the proliferation of HepG2 cells in a formulation-,time-and concentration-dependent manner in comparison with MCF-7 cells.Anticancer activity releaved that the disulfide-modified micelles possessed much higher anti-hepatoma activity with a low IC50 value of 1.1 mg/mL.Furthermore,the intracellular uptake tested by CLSM and FCM demonstrated that multifunctional polymeric micelles could be more efficiently taken up by HepG2 cells compared with MCF-7 cells,suggesting these well-defined micelles provide a potential drug delivery system for dual-responsive controlled drug release and enhanced anti-hepatoma therapy.(2)Targeted Shell-Crosslinked pH/Redox Dual-Sensitive Polymeric Nanoscaled Drug Delivery SystemBased on targeted amphiphilic block copolymer N-acetyl glucosamine-poly(styrene-alt-maleic anhydride)58-b-polystyrene130(NAG-P(St-alt-MA)58-b-PSt130),a pH/redox dual-triggered shell-crosslinked polymeric micelle system was constructed.The shell-crosslinked micelles(CLM)were prepared by post-crosslinking method to regulate drug release kinetics using cystamine as linkers between carboxy groups of the shell.The chemical structures were characterized by 1H NMR Spectroscopy(1H NMR)and Fourier Transform Infrared Spectroscopy(FTIR).The self-assembly properties of micelles were characterized by dynamic laser light scattering instrument(DLS),transmission electron microscopy(TEM)and fluorescence spectrum.Compared with non-crosslinked micelles(NCLM),CLM showed spherical shapes with little increased mean diameter of 102.40±0.54 nm,low polydispersity index(PDI)of 0.19±0.36,enlarged zeta potential value from-41.46±0.99 to-9.31±0.50 mV,indicating the successful modification of disulfide bonds in shell.In vitro drug release study clearly exhibited a pH and redox dual-sensitive drug release profile with significantly accelerated drug release under pH 5.0 and 10 mM GSH conditions(46.84%in 96 h)without burst release.Both CLM and NCLM showed quite different release profiles between physiological(pH 7.4)and tumoral microenvironment(pH 5.0),effectively avoiding the premature drug leakage and realizing on-demand drug release.The MTT assay implied that CLM presented a time-and concentration-dependent manner to inhibit proliferation of A549 and MCF-7 cells and much lower IC50 values in comparison with that of NCLM.Both FCM and CLSM results showed that CLM displayed much higher cellular uptake efficiency and anti-tumor activities than NCLM and free DOX.CLM and NCLM could be internalized by energy-dependent endocytosis and receptor-mediated endocytosis mechanisms due to similar surface properties.Overall,this dual-stimuli triggered micelle system provided a promising tumor-responsive platform for cancer therapy.