| With the development of nano-medicine synthesis technology,many functionalized nano-drugs are gradually applied in clinic.Nanomedicine brings new vitality to traditional medicine,especially in the field of tumors treatment.Compared with normal tissues,nano-drugs are more likely to accumulate at the tumor due to their size advantage(EPR effect).However,the EPR effect has poor performance in patients,during the actual tumor treatment process.The low efficiency of nano-drugs delivery has brought many obstacles to their clinical application.The irregular blood vessels and lymphatic vessels in the tumor microenvironment increase the interstitial fluid pressure and decrease the blood perfusion in the tumor which impedes the entry of the nanomedicines.More than that,the abnormally proliferated extracellular matrix became a physical barrier between nano-drugs and tumor cells.Therefore,after blood circulation,nano-medicines are mainly distributed around tumor blood vessels and tumor surface layers which leads to an unsatisfying therapeutic effects.Not only that,the transportation of oxygen and the infiltration of lymphocytes in the tumor are also limited by ECM,making many tumor treatment programs ineffective.In addition,the tumor microenvironment contains many immunosuppressive molecules and cells.The PD-L1 molecule which expresses on the tumor surface is one of the immune checkpoints.It can induce T cell apoptosis and inactivation,which directly impedes the tumor killing ability of CTL and triggered tumor immune escape.This shows that various drug delivery processes and therapeutic schedules are unavoidably affected by the tumor microenvironment.TGF-β is an over-expressed cytokine in the tumor microenvironment,which indirectly promotes the proliferation of tumor cells by regulating stromal fibroblasts,angiogenesis and ECM.At the same time,it is also an immunosuppressive molecule,which has the function of inhibiting the activity and proliferation of T cells and reducing the number of T cells at the tumor sites.Therefore,our design idea is to use TGF-β as the therapeutic target,inhibit its pathway through inhibitors,normalize the extracellular matrix at the tumor,reduce the interstitial fluid pressure of the tumor,help the drugs mor efficiently and evenly distributed at the tumor.At the same time,the degradation of ECM can improve the blood supply to the tumor,increase the oxygen content at the tumor,promote the infiltration of immune cells,and clear the obstacles for subsequent chemotherapy and immunotherapy.Based on the above design ideas,we synthesized a porous metal organic framework material ZIF-8 as the drug carrier,through the coordination effect to achieve the simultaneous loading of the chemotherapy drug DOX and TGF-β inhibitor LY364947(ZIF-8-DOX-LY).ZIF-8 as a drug carrier has the advantages of high drug loading rate and p H-responsive structural characteristics,which can improve the solubility and stability of two small molecule drugs.We have further used ultrasound to modify the red blood cell membrane on the surface of ZIF-8-DOX-LY to improve the biological safety and stability of the drug loading system,and finally obtained ZIF-8-DOX-LY-RM.Not only did we characterize the physicochemical properties of the ZIF-8-DOX-LY-RM,such as particle size,surface potential,and morphology,but we also verified the regulatory function of the ZIF-8 material loaded with two drugs on the tumor microenvironment in mice.Afterwards,we used the mouse breast cancer 4T1 subcutaneous tumor as a model.The combination of ZIF-8-DOX-LY-RM and the immune checkpoint inhibitor PD-L1 antibody significantly inhibited the growth of the tumor and prolonged the survival time of the mice.The research results show that the ZIF-8-DOX-LY-RM system can achieve the purpose of improving tumor chemotherapy and immunotherapy through effective re-modulating of the tumor microenvironment,and provide a certain idea for the related research of tumor treatment. |
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