Synthesis Of Oxidation Responsive Polymersomes For Tumor Combinationary Therapy

Cancer has become the main cause of death in all countries in the 21st century.According to statistics,18.1 million new cancer cases and 9.6 million deaths occurred worldwild in 2018.Traditional treatments,such as chemotherapy,cause severe side effects resulted from its non-specific characteristics in vivo,while surgical resection not only has a range of indications but also a serious physical burden.Therefore,effective and safe treatments for cancer are in urgent need.Photodynamic therapy?PDT?is a promising treatment and has been approved by FDA for clinical applications.PDT requires O₂,photosensitizers and laser irradiation with specific wavelength to produce singlet oxygen,which destroys the structure and function of target organelles through oxidative damage,causing apoptosis and necrosis of target cells.Zinc phthalocyanine?ZnPc?is one of the widely used second-generation photosensitizers,with high photodynamic conversion efficiency and strong cell-killing ability,however,the insolubility of ZnPc limits its further application.In order to solve this problem,it is an effective method to encapsulate it into the oxidation-responsive nanocarriers.For example,the hydrophobic sulfide part of poly?propylene sulfide??PPS?undergoes a phase change under oxidizing environment,forming hydrophilic sulfoxide and sulfone,resulting in a sudden hydrophobic-hydrophilic transition and rapid decompose of the material.In this thesis,we designed an oxidative responsive nanosystem mediated by NIR,which could result in the combination effect of PDT and chemotherapy.The system is composed of amphiphilic polymer Poly?propylene sulfide?-b-Poly?ethylene glycol?(PPS₂₀-b-PEG₁₂).In aqueous solution,the polymer self-assembles into polymersomes with a double-layer membrane structure and a hydrophilic cavity.The shape and particle size of the polymersomes were determined by Cryo-TEM and Omini particle size analyzer,indicating a double-layer-membrane spherical structure with a diameter of130nm.The blank polymersomes showed good biocompatibility,and the ZnPc and DOX·HCl coloaded polymersomes can be oxidized by singlet oxygen generated by ZnPc,so that the PPS fragment changed from hydrophobicity to hydrophilicity,leading to the release of the encapsulated drugs and realize the combination of photodynamic therapy and chemotherapy.In vitro cytotoxicity studies,the cell viability of the co-loaded group was reduced to 10%,significantly lower than the 30%of the chemotherapy group and 28%of the photodynamic group.In animal distribution studies,polymersomes were observed to converge at the tumor site through the EPR effect and rarely aggregated in other major organs except the liver.In the anti-tumor studies,the co-loaded group showed excellent tumor growth inhibition ability,the tumor was inhibited by 70%after 14 days administration,while the photodynamic group alone with chemotherapy slightly reduced the tumor growth rate.The experimental results showed that this ROS-sensitive nanosized polymersome can be used as a multifunctional platform for combinatory cancer therapy.This platform demonstrated excellent anti-tumor effects in vivo and in vitro by encapsulating a traditional photosensitizer and chemo-therapeutic agent,therefore provide to an effective and safe method fo cancer treatment.