Construction And Application Of Several Tumor Microenvironment-Responsive Multifunctional Nanocomposite Systems

Compared with normal tissues,tumors have developed unique microenvironments during evolution.The tumor microenvironment(TME)is the soil in which cancer cells are cultured.It profoundly affects tumor initiation and growth.Since tumors proliferate and metabolize faster than normal tissues,TME typically exhibit more acidic,high expression of hydrogen peroxide(H2O2),high levels of enzymes and glutathione(GSH),and severe hypoxia.The unique physiological characteristics of TME can promote tumor angiogenesis and metastasis,and cause drug resistance,but at the same time,it can also act as a stimulus for specific tumor killing.Therefore,it is of great significance to design TME-response intelligent nanosystems for efficient and specific cancer therapy.To this end,this paper has carried out the following work:(1)A pH/H2O2 dual stimulus-responsive anti-tumor nanocomposite system ZIF8@Mn-PDA(ZMP)is constructed for near-infrared(NIR)excited photothermal therapy(PTT)/chemodynamic therapy(CDT)/ion interference therapy(IIT).First,ZIF8 with uniform morphology is synthesized.ZIF-8 is then coated with Mn-doped polydopamine(PDA).The synthesized ZMP has good photothermal properties,which can generate high temperature under 808 nm laser irradiation to kill cancer cells and realize PTT.In an acidic environment,ZMP can release Zn2+and Mn2+.Zn2+can damage the function of mitochondria,which can stimulate the production of reactive oxygen species to induce cancer cell death for IIT.Meanwhile,the released Mn2+can catalyze the overexpressed H2O2 in TME to generate hydroxyl radicals(·OH)for CDT.In addition,the ZMP nanocomposite system has good biocompatibility and low toxicity to the organs and tissues.In vitro and in vivo anti-tumor experiments show that under the excitation of NIR,ZMP can realize the combined treatment of PTT/CDT/IIT,which effectively inhibit the growth of tumor.(2)A pH/H2O2-responsive anti-tumor nanocomposite system Co/ZIF-8/ICG/Pt(CZIP)is designed to alleviate tumor hypoxia and realize the combined CDT/enhanced photodynamic therapy(PDT).Irradiated under 808 nm laser irradiation,the photosensitizer indocyanine green(ICG)can generate singlet oxygen(1O2)to induce the apoptosis of cancer cells for PDT.Meanwhile,the loaded Pt can catalyze the overexpressed H2O2 in TME to generate O2,which alleviate tumor hypoxia and promote PDT-induced 1O2 production.In addition,the nanocomposites can be degraded in TME to release Co2+.The released Co2+ can react with H2O2 to generate ·OH for CDT.CZIP nanocomposite system has high biosafety and can effectively inhibit the tumor growth,which provide a new way for cancer treatment.(3)A pH/H2O2/GSH-responsive multifunctional nanocomposite system MnSiO3Pt@BSA-Ce6(MPBC)is constructed to alleviate tumor hypoxia and achieve MRIguided enhanced sonodynamic therapy(SDT)/CDT.Under ultrasound irradiation,Ce6 can induce cancer cell apoptosis by generating 1O2 through SDT.The loaded Pt has catalase-like activity,which can react with overexpressed H2O2 in TME to generate O2.The generated O2 can promote 1O2 production to enhance the SDT effect and alleviate tumor hypoxia.Meanwhile,MnSiO3 nanospheres are degradable in acidity and GSH environment.The released Mn2+ can not only catalyze H2O2 to generate ·OH for CDT,but also for MR imaging.In vitro and in vivo data show that the MPBC-based combination therapy can kill tumors safely and effectively,which has great potential for clinical application.