Design And Drug Release Research Of Azobenzene-based Double Stimuli-responsive Smart Polymer Nanocarriers

Health has always been a hot topic of concern,whereas cancer is one of the largest security risks to human health.A variety of novel functional smart polymer nanocarriers have been designed and developed,which can respond to different internal or external environmental stimuli.This class of smart polymers and their self-assenblies have played an important role in many fields including biomedicine,especially in the targeted and controllable treatment of cancer,and have been widely concerned.Although the existing drug delivery systems(DDSs)have been extensively reported and commercially applied,there are still some issues that have yet to be well-resolved,including the toxicity,side-effects,and targeted therapy efficiency of drugs.Consequently,it is still necessary to develop a novel,highly-efficient,controlled and targeted DDS for cancer therapy.Based on this background,this thesis has carried out the following two parts of work:(1)The host polymer,?-cyclodextrin grafted poly(2-(dimethylamino)ethyl methacrylate)(?-CD-g-PDMAEMA),and guest polymer,azobenzene modified poly(?-caprolactone)(Azo-PCL),were prepared by atom transfer radical polymerization(ATRP)and ring opening polymerization(ROP),respectively.Then,a supramolecular polymer,?-CD-g-PDMAEMA@Azo-PCL,was prepared through the host-guest inclusion complexation interactions between a host polymer?-CD-g-PDMAEMA and a guest Polymer Azo-PCL.The chemical structure and composition were determined by 1H nuclear magnetic resonance(1H NMR),13C nuclear magnetic resonance(13C NMR),Fourier transform infrared spectrometer(FT-IR)and laser light scattering gel chromatography(LLS-GC).The 2D NOESY NMR was used to show the mechanism of inclusion complexation between Azo-PCL and ?-CD-g-PDMAEMA.Furthermore,particle size,the morphology,self-assembly behavior and environmental response of polymers in aqueous solution were studied by laser particle analyzer(DLS),transmission electron microscope(TEM),fluorescence spectroscopy(FLS)and ultraviolet-visible absorption spectroscopy(UV-vis).The pH phase transition point of the supramolecular polymers is approximately 6.6,and the supramolecular micelles will reversibly self-assemble and dissociate under the alternating irradiation of ultraviolet and visible light.Doxorubicin(DOX)was encapsulated into the supramolecular polymer to form drug-loaded micelle and the effects of the external environments on drug release was explored by adjusting the light irradiation or pH values.The effects of external environment stimuli on the in vitro drug release was investigated,showing light-and pH-modulated drug release properties.The cytotoxicity assessment indicated that the blank supramolecular micelles were nontoxic,whereas the drug-loaded micelles exhibited excellent anticancer activity.(2)A novel temperature responsive lateral chain photosensitive block copolymer,poly[(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-block-propyleneacyla1ky1-4-azobenzoate](P(NIPAM-co-DMAA)-b-PAzoHPA),was designed and synthesized by two-step atom transfer radical polymerization.The chemical structure was characterized byFT-IR,1H NMR and LLS-GC.The self-assembly behavior,the morphology and sizes of micelles were investigated by FLS,TEM and DLS.Dual responsiveness to light and temperature was explored by UV-vis measuremeat.The experimental results showed that the P(NIPAM-co-DMAA)-b-PAzoHPA copolymer micelles took on apparent light and temperature dual responsiveness,and its lower critical solution temperature(LCST)was above 37? The polymer underwent a configuration transition under ultraviolet light irradiation(365 nm)and could return to its previous stable trans configuration under visible light irradiation.The developed block copolymers are expected to be potentially used as drug controlled release carriers for cellular drug release.