Construction Of ZIF-8 Smart Nano Drug Delivery System And Its Antitumor Application

Cancer has become a serious threat to human health.Existing treatments,such as operative resection,chemotherapies and radiotherapy,are not only effective in treating cancer,but also affected and restricted by drug toxicity,drug resistance and postoperative tumor metastasis.Therefore,it is particularly important to seek new strategies for cancer treatment.Studies have shown that chemotherapy,radiotherapy,photothermal/kinetic therapy,and immunotherapy can activate the protective autophagy of cancer cells and reduce the therapeutic effect.Regulating the autophagy has become a new strategy in cancer treatment.Chloroquine(CQ)is a classical autophagy inhibitor.Its introduction into the smart nanodelivery system can inhibit the protective autophagy of cancer cells and destroy the cell defense system,and that effectively reducing the therapeutic resistance of cancer cells and enhancing the efficacy of chemotherapy and photothermal/kinetic therapy.Zeolitic Imidazolate Framement-8(ZIF-8)is a porous material connected by zinc ions and 2-methylimidazole through coordination,with the advantages of simple synthesis,large specific surface area,wonderful stability and biocompatibility.At the same time,ZIF-8 is easy to modify.Its can be achieve that drug loading efficiency highly.In addition,the degradation of ZIF-8 in the slightly acidic environment of tumors is also conducive to the construction of tumor-targeted acid-sensitive vectors.Thinking about the deficiency of current monotherapy(starvation therapy and photothermal therapy can activate autophagy)and the important role of autophagy in the tumor,autophagy inhibitors such as CQ,GOx and photothermal materials were introduced into ZIF-8 nano drug carrier to build an intelligent nano drug delivery system and improve the antitumor effect of drugs.This paper is divided into four chapters:Chapter 1: Current cancer treatment methods,the important role of autophagy in cancer and nanomodicine carrier are introduced in detail.Chapter 2: In this chapter,FA-CQ/GOx@ZIF-8(FA@CGZ)smart nanodelivery system was successfully constructed,in which CQ was used to inhibit autophagy activated by GOx consumption of nutrients in tumor cells and increase the sensitivity of tumor cells to starvation therapy.First of all,synthesis of composite nanoparticles CQ/GOx@ZIF-8(CGZ)by one-pot method and tumor-targeted modification with folic acid to acquire FA@CGZ.The materials were characterized by transmission electron microscopy,X-ray diffraction analysis,dynamic light scattering,infrared spectrum and UV-vis absorption spectrum.The loading rates and encapsulation rates were calculated.The encapsulation rate and drug loading rate of CQ were 91.94% and32.95%,respectively.The encapsulation rate and drug loading rate of GOx were91.74% and 13.52%,respectively.The results showed that CGZ had good p H response and the composite nanoparticles had obvious cytotoxicity.Moreover,western blotting showed that FA@CGZ could release CQ to inhibit autophagy and induce Hela cell apoptosis and decreased membrane potential,further enhancing the efficacy of the combination therapy.To sum up,FA@CGZ prepared in this chapter integrates starvation therapy and tumor targeting,which can achieve controlled release of drugs and enhance therapeutic effect.Chapter 3: In this chapter,FA-CQ/Au NSs@ZIF-8(FA@CAZ)smart nanodelivery system was successfully constructed,in which CQ was used to inhibit autophagy activated by Au NSs photothermal therapy and increase the sensitivity of tumor cells to photothermal therapy.First of all,preparation of Au NSs with excellent photothermal properties,and then using ZIF-8 as the carrier to encapsulate CQ and Au NSs simultaneously to obtain the compound CQ/Au NSs@ZIF-8(CAZ);The tumor targeting ligand(FA)was modified onto its surface to obtain FA-CQ/Au NSs@ZIF-8(FA@CAZ).The materials were characterized by transmission electron microscopy,scanning electron microscopy,UV-Vis absorption spectrum,infrared spectrum and dynamic light scattering.The results showed that FA@CAZ was successfully prepared.The encapsulation and drug loading rates of CQ were 41.95% and 2.01%,respectively.The results of in vitro heating experiments show that the prepared Au NSs and Au NSs@ZIF-8 have wonderful photothermal properties.In vitro release test show that CAZ has good p H response and can achieve controlled release of drugs.Cytotoxicity experiments showed that FA@CAZ had obvious phototoxicity and good antitumor effect.Chapter 4: Summary and prospect.