The Construction Of Multifunctional Polymer Vesicles Of Bubble Generation And Its Anti-tumor Research

Cancer is a very complex disease and faces various challenges in the course of treatment.The current research trend is gradually shifted from a single treatment to a combination treatment to improve the therapeutic effect.As a multifunctional drug carrier,polymersomes formed by self-assembly of amphiphilic block copolymers are widely used as drug delivery systems due to their good stability,easy modification and excellent drug-loading ability.According to the changes of the tumor microenvironment,two smart polymersomes which can respond to internal or external stimuli of the tumors were constructed for the combination cancer treatment.The specific research contents are as follows:First,bubble-generating polymersomes with dual pH/temperature responsiveness was constructed for chemo-photothermal combination therapy of tumor.In this study,the bubble-generating polymersomes(BG-DIPS)was prepared by membrane hydration ultrasonic dispersion method and ammonium bicarbonate gradient active drug loading method,which contained chemotherapeutic drug doxorubicin(DOX)and photosensitizer indocyanine green(ICG).BG-DIPS has dual pH/temperature responsiveness.Laser irradiation or acidic environment can trigger the decomposition of ammonium bicarbonate(NH4HCO3),which was entrapped in the vesicle internal cavity,thus generating carbon dioxide(CO2)bubbles and destroying the vesicle structure to promote drug release.The formation of bubbles inside the vesicles was observed by transmission electron microscopy.The in vitro characterization showed that BG-DIPS had good stability,drug loading capacity and strong photothermal conversion efficiency.The cell experiments showed that laser can promote the uptake of BG-DIPS by cells,and BG-DIPS with laser irradiation can effectively reduce tumor cell survival.Animal experiments showed that chemo-photothermal combination therapy mediated by BG-DIPS had a good anti-tumor effect and significantly reduced the side effects of DOX.Second,oxygen and bubble generating polymersomes with pH/temperature/reduction responsiveness was constructed for alleviating tumor hypoxia as well as targeted and enhanced cancer photothermal-photodynamic combination therapy.In this study,the oxygen and bubble generating polymersomes(FIMPs)was prepared by membrane hydration ultrasonic dispersion method,which contained manganese dioxide(MnO2)nanoparticles and photosensitizer indocyanine green(ICG).FIMPs have pH/temperature/reduction multiple responsiveness.Laser irradiation or acidic environment can trigger the decomposition of ammonium bicarbonate(NH4HCO3),which was entrapped in the internal cavity of the vesicles,thus generating carbon dioxide(CO2)bubbles and destroying the vesicle structure to promote drug release.In the reducing environment,the disulfide bond of the amphiphilic block copolymer would break and promote drug release.In addition,MnO2 can react with endogenous H2O2 to produce oxygen.In vitro characterization studies showed that FIMPs can produce more singlet oxygen.The results of cell experiments showed that FIMPs can produce oxygen in tumor cells,and the ROS production in the cells increased significantly after laser irradiation.Animal experimental studies showed that photothermal-photodynamic combination therapy mediated by FIMPs can significantly inhibit tumor growth with good biocompatibility.The immunohistochemical results of tumors showed that FIMPs can effectively improve the hypoxic environment in tumor cells and enhance the photodynamic therapy effect.