Design And Synthesis Of Several Multifunctional Nanocomposites For Synergistic Tumor Therapy

Cancer is the deadliest disease around the world,and millions of people die due to cancer every year.Although traditional chemotherapy,radiotherapy,and surgical treatment have been used in clinical,they will cause serious toxic effects to the body.Phototherapy(including photothermal therapy and photodynamic therapy)has received extensive research due to its advantages of accurate treatment in tumor sites without causing invasive damage to healthy tissues.However,lasers exhibit finite penetration depth in tissue,which limits the application of phototherapy in depth solid tumors.In addition,the hypoxic state of the tumor microenvironment also greatly limits the generation of reactive oxygen species from photodynamic therapy,resulting in poor therapeutic effects.In contrast,sonodynamic therapy is a non-invasive treatment with deep penetration,and also reduces the damage to normal tissue.However,the therapeutic effect of sonodynamics is also limited by the hypoxic state of the tumor and the low quantum efficiency of sonosensitizers.Immunotherapy can modulate the autoimmune system and reduce immune response.However,the acti vation of tumor-immune system is inefficient,which limits the application in clinical.At the same time,a series of factors such as patient-specific immune status,genetics,tumor type and environmental exposure also reduce the efficacy of tumor immunotherapy.Gas therapy is a "green therapy" developed in recent decades.However,gas therapy has little inhibitory effect to cancer cells.Therefore it needs to be combined with other treatments to meet the requirements of clinical treatment.With the development of nanoscience,researchers have integrated multiple nanomaterials into multifunctional nanoplatforms.The multifunctional nanoplatforms ingeniously realize synergistic treatment,avoiding the respective limitations of monotherapy and improving treatment efficiency.In response to the above problems,we mainly carried out the following research work:(1)ZIF-90 nanoparticles have been widely reported as anticancer drugs.However,chemotherapy often faces the risk of premature drug leakage,which reduces the anticancer efficiency and exhibits toxicity to normal issues.To solve this problem,we designed a core-shell nanomaterial 5-FU@ZIF-90@ZnO(FZZ).In this nanoplatform,the premature release of chemotherapeutic drugs is avoided by two routes.First,zinc oxide acts as a shell in the nanosystem,delaying drug release during blood circulation.Secondly,ZIF-90 and zinc oxide can degrade and release chemotherapeutic drugs only in the acidic tumor microenvironment,achieving the pH-controlled drug release and avoiding the toxic effects of chemotherapy drugs to normal cells.In addition,the nanocomposite realizes the integration of therapy and nano-carrier.This FZZ nanoparticle can be degraded in the acidic tumor microenvironment to generate zinc ions,which can not only overcome the resistance of tumor cells to chemotherapeutic drugs but also acts as a therapeutic agent to regulate a series of physiological responses.In this study,we synthesize multifunctional nanocomposites combined with chemotherapy and ion therapy with significant tumor inhibition both in vivo and in vitro cancer treatment,demonstrating that synergistic therapy has extremely high treatment efficiency.(2)The therapeutic efficacy of immunotherapy,especially immune checkpoint blockade(ICB),is limited by the immunosuppressive tumor microenvironment(TME).Therefore,it is an urgent need to reverse the immunosuppressive TME in clinical treatment.Immunogenic cell death(ICD)can activate antitumor immunity.In this work.we synthesized a carbon monoxide gas generator,CO2-g-C3N4-Au@ZIF-8@F127(CCAZF),which successfully induced immunogenicity by carbon monoxide gas and stimulated the generation of a large amount of reactive oxygen species.The generation of ROS induces immunogenic cell death and enhances the immune response of tumor cells.Cell death enhances the immune response of tumor cells and improves treatment efficiency.In addition,traditional gas therapy is toxic to normal tissue cells due to the uncontrollability of gas release,and the treatment efficiency is limited.The synthesized CCAZF nanoparticles achieve light-pH-responsible gas release by integrating gas therapy with immunotherapy,which not only overcome the uncontrollable defects of single gas therapy but also activate innate and adaptive immunity.Crucially,this study also uses the immune checkpoint blocker PD-L1 antibody in combination with CCAZF,which effectively inhibits the growth of primary tumors and substantially prevents lung metastasis.This paper innovatively combines gas therapy with immunotherapy,breaking the limitation of single therapy and providing a new way for CO gas therapy in cancer treatment.(3)Nanozymes with the advantages of both nanomaterials and natural enzymes have been extensively studied over the past few decades.However,most nanozyme treatments are based on the limited endogenous stimuli of TME,which reduce their therapeutic efficiency.To solve these problems,we synthesized a multifunctional 2D nanosheet B-OH@Cy5-PEG-NH2(BOP)by a liquid exfoliation technique.The BOP nanosheets have narrower band gaps than other nanosonosensitizers,increasing the production of reactive oxygen species.More importantly,the degradability of boronbased nanosheets is investigated for the first time in this paper,which avoids the toxic effects caused by long-term retention in the body of traditional inorganic nanomaterials.BOP nanosheets exhibit anti-tumor inhibition efficiency both in vitro and vivo experiments,as a result of the synergistic treatment of SDT and nanozymes.