| Cancer treatment resistance has always been a major problem faced by clinical tumor treatment.Although scientific researchers have made great efforts on chemotherapy,radiotherapy,and new therapeutic methods such as photothermal and immunotherapy,the treatment effect for malignant tumors is still unsatisfactory.Studies have found that cancer cells can remove damaged proteins and organelles through the process of autophagy and provide energy for cancer cell biosynthesis,alleviating oxidative damage and giving them extra viability,which can significantly improve the treatment resistance and reduce the therapeutic effect of cancer.Therefore,cutting off the flow of autophagy can be used as an effective adjuvant treatment to make it sensitive to ongoing treatment.In addition,tumor associated macrophages(TAMs)in the microenvironment have a great influence on the therapeutic effect of tumor.TAMs mainly exist in the form of pro-tumor phenotype(M2),which can greatly reduce the sensitivity of tumor cells to various treatments.By polarizing M2 TAMs into anti-tumor phenotype(M1),the resistance of tumor treatment can be reduced.Therefore,the regulation of autophagy and macrophage polarization can be used as an important alternative for increasing the sensitivity of tumor cells to treatment for improving the overall therapeutic effect.This thesis designed a degradable iron-based drug loading nanoplatform for efficient tumor treatment.In this nanoplatform,the reactive oxygen species(ROS)were produced by the reaction of artemisinin(ART)peroxide bridge with ferrous ions for tumor cell killing.The constructed nanodrug can be degraded in slightly acidic microenvironment and in the presence of glutathione(GSH),releasing iron ions and ART,which solves the problem of insufficient iron ions supply and high concentration of reducing agents in cancer cells.In addition,by using autophagy inhibitor chloroquine(CQ),the autophagy process of cancer cells can be blocked and prevent them from using ROS to oxidize and inactivate proteins and organelles to provide nutrients for their continued survival;Moreover,CQ can also be used as an immunomodulator work together with ROS to re-educate TAMs into anti-tumor M1 phenotype.In vivo and in vitro experiments demonstrated that the combined therapeutic nanoplatform has significant effects in inhibiting autophagy and repolarization of TAMs.It not only improved the sensitivity of tumor cells to ROS,but also enhanced the effect of anti-tumor therapy,and inhibit the invasion and metastasis of breast cancer to a certain extent.These research results provide a reference for reducing treatment resistance in tumor treatment,and provide ideas for innovative approaches to maximize the effectiveness of cancer treatment in the future. |
