Preparation Of Dual Stimuli-responsive Polymeric Vesicles For Application In Drug Delivery

Traditional drug treatment is generally on the basis of direct oral or injection drug with low drug utilization rate.The great physical harm and high price of treatment bring physical,mental,economic and other pressures to patients.The emergence and development of intelligent polymer carriers（stimulus-responsive polymer nanocarriers）provide a new platform for drug delivery.Polymer drug carriers have many advantages such as multiple kinds of loading drugs,wide application of drug carriers,enhancing drug stability,enhancing the accuracy and pertinence of drug release,less damage to normal organs or tissues,effectively prolonging the action time of drugs and improving the bioavailability of drugs.Considering of the complex physiological environment in organisms and the advantages of polymer vesicles,we designed three different dual responsivet polymer vesicles for controlled drug release.Polymer vesicles with different responses were prepared by integrating functional groups into the polymer.The specific work contents are as follows:1.In this experiment,a diblock copolymer poly（caprolactone-b-dimethylamino ethyl methacrylate）was synthesized by ring-opening polymerization and atom transfer radical polymerization（ATRP）.The azobenzene moiety was then modified to the hydrophilic segment of the polymer by quaternization reaction.The“compound vesicles”were prepared by self-assembly from a host-guest interaction between a diblock copolymer and a water-soluble pillar[6]arene.The composition of block polymer was characterized by nuclear magnetic（¹H NMR）andthe morphology and particle size of the nanocarriers were characterized by transmission electron microscopy（TEM）and dynamic light scattering（DLS）.Results showed that the prepared“compound vesicles”could undergo morphological transformation under external stimulation of light and pH,respectively.Moreover,the drug-loaded“compound vesicles”were prepared by the loading of the anticancer drug doxorubicin hydrochloride.The in vitro release experiments showed that“compound vesicles”could release doxorubicin hydrochloride upon different stimuli.The in vitro cytotoxicity of drug-loading compound vesicles showed that the cytotoxicity of the vesicles was very low.And the cell uptake experiment showed that the“compound vesicles”could be uptaken by the tumor cells and further released drugs in cell.The experment proves indicated that this vehicle can be used as a drug carrier for drug delivery.2.In this study,a macroinitiator was prepared by esterification between polyethylene glycol and a reversible addition-fragmentation chain transfer reagent（RAFT reagent,PEG-RAFT）.An amphiphilic block polymer with dual response of glucose and hydrogen peroxide was then prepared by using the PEG-RAFT macronitiator.The polymer vesicles were prepared by self-assembly method utilizing the molecular recognition between pinacol ester unit andα-cyclodextrin.Then the stimulu-responsiveness of the polymeric vesicles was studied under different conditions（glucose,hydrogen peroxide）.The prepared polymer vesicles have a glucose and hydrogen peroxide response.The UV-vis spectrophotometer was used to study the drug release rate under different stimulation conditions,and the quantitative relationship between drug release rate and regulation means was established.CCK-8cytotoxicity test was used to determine the in vitro cytotoxicity of doxorubicin hydrochloride-loaded polymer vesicles by using human breast cancer cells（MCF-7）.Polymeric vesicles were localized by cell staining experiments,and the phagocytosis of polymer vesicles by cancer cells was studied.It proved that tumor cells had good phagocytic effect on polymer vesicles,and this vector can be used as a potential drug carrier for the treatment of cancer.3.In this experiment,polyethylene glycol-trithioester（PEG-DDMAT）was used as a macroinitiator to synthesis glucose and hydrogen peroxide-sensitive amphiphilic triblock polymers by reversible addition-fragmentation chain transfer polymerization（RAFT）.Dual-responsive polymer vesicles of glucose and hydrogen peroxide were prepared by self-assembly process.The composition of block polymer was characterized by nuclear magnetic（¹H NMR）andthe morphology and particle size of the nanocarriers were characterized by transmission electron microscopy（TEM）and dynamic light scattering（DLS）.A dual-responsive insulin delivery device by integrating glucose-and H₂O₂-responsive polymeric vesicles（PVs）with transcutaneous microneedles（MNs）has been designed.After loading with insulin and glucose oxidase（GOx）,the drug-loaded PVs display a basal insulin release as well as a promoted insulin release in response to hyperglycemic states.Finally,the transdermal delivery of insulin to the diabetic rats（（Insulin+GOx）-loaded MNs）presents an effective hypoglycemic effect compared to that of subcutaneous injection or only insulin-loaded MNs,which indicates the as-prepared MNs insulin delivery system could be of great importance for the applications in the therapy of diabetes.