Study On The Strategy And Mechanism Of Synergistic Cancer Therapy Mediated By Multifunctional Co/Fe-MOFs Derivatives

Metal-organic frameworks（MOFs）,also known as porous crystalline materials,are formed by bridging metal-ligand coordination bonds between inorganic metal nodes or metal groups and organic ligands.Nano-sized MOFs have been widely used in biomedical applications,because of mild synthesis conditions,diverse structure and physicochemical properties,strong loading capacity,easy functionalization and their inherent biodegradability,etc.MOFs with different compositions,structures and morphologies can be prepared by design,and nanomaterials of MOFs can also be synthesized with other materials or molecules.Novel therapies based on nano-MOFs materials have been developed,such as photothermal therapy（PTT）,photodynamic therapy（PDT）,starvation therapy,chemodynamic therapy（CDT）,etc.Although the researchers have conducted a series of studies on these treatments,there are considerable limitations exist including:（1）low achievable drug concentrations at tumor sites;（2）low efficacy of single treatment;（3）some characteristics of tumor microenvironment（TME）,such as acidity,hypoxia,redox and other characteristics,are not amplified to achieve the therapeutic effect of intracellular oxidative stress;（4）the poor biosafety.Therefore,it is urgent to develop MOFs nanocomposite drugs with TME responsiveness to improve treatment efficiency by amplifying intracellular oxidative stress and integrating multiple therapeutic approaches.In this paper,combining the structural characteristics and prospects for biomedical applications of MOFs and its derivatives,several cobalt/iron based MOFs nanocomposites were innovatively synthesized,the potential of its application in cancer treatment was evaluated by in vitro cell assay and in vivo tumor suppressor assay.The main achievements are summarized as follows:1.Near-infrared light-triggered synergistic antitumor therapy based on hollow ZIF-67-derived Co3S4-indocyanine green nanocomplexIn order to overcome the problems of low therapeutic efficiency and instability of photosensitizers,we designed hollow structure cobaltosic sulfide（Co₃S₄）derived from zeolitic imidazole framework-67（ZIF-67）nanoparticles.We subsequently loaded photosensitizer indocyanine green（ICG）to obtain a multifunctional nanocomplex Co₃S₄-ICG（Scheme 1）.The Co₃S₄-ICG as a superior reactive oxygen species（ROS）generator possesses the following features:（1）Co₃S₄ is more conducive to drug loading and delivery due to its hollow structure;（2）the obtained Co₃S₄-ICG is a good photothermal therapy（PTT）reagent because of its excellent photothermal conversion efficiency for near-infrared（NIR）lasers;（3）Co₃S₄-ICG would be degraded in tumor acidic microenvironment and realized responsive release of Co²⁺and ICG,which locally triggers a Fenton-like reaction to generate cytotoxic·OH for CDT,and laser-induced ¹O₂to realize PDT;（4）the converted heat energy by Co₃S₄-ICG can enhance CDT performance under NIR laser excitation.As a result,Co₃S₄-ICG can act as a trimodal synergistic cancer treatment agent by PTT,PDT,and photothermal-enhanced CDT,which may provide a“kill three birds with one stone”strategy for achieving enhanced therapeutic efficacy.2.ZIF-67-derived Co3-x Cux S4 for glutathione depleting and hyperthermia dual-augmented Fenton-like reaction for CDT/PTT synergistic cancer therapyTo protect the generated ROS from being cleared by glutathione,we used ZIF-67 as a template to synthesize Co₃S₄,and then mixed copper ions(Cu²⁺)into Co₃S₄ through cation exchange to synthesize bimetallic sulfide Co_3-xCu_xS₄.By ingeniously designing the doping of copper ions into Co₃S₄ with the properties of MOFs,the possibility of its leakage in normal tissues is reduced.Co_3-xCu_xS₄ is coarse-surfaced hollow dodecahedron,which retains the frame structure of MOFs.At the same time,it also has the acid responsiveness of MOFs,realizing the controllable release of Co²⁺and Cu²⁺under the p H and GSH response.Then,the release of Co²⁺triggers a Fenton-like reaction that converts endogenous H₂O₂ to highly toxic·OH.In addition,the redox reaction between the released Cu²⁺ions and intracellular GSH will induce GSH depletion and reduce Cu²⁺to Fenton agent Cu⁺ions,and then trigger the hydrogen peroxide（H₂O₂）to generate·OH by a Cu⁺-mediated Fenton-like reaction,resulting in enhanced CDT efficacy.Moreover,Co_3-xCu_xS₄ has high absorption in the NIR region,which can achieve a synergistic effect based on the combined performance of PTT and CDT.Subsequently,the ROS-mediated therapeutic efficiency is significantly improved.Therefore,this study provides a proof of concept of hyperthermia-augmented Fenton-like activity of bimetallic sulfide for tumor ablation.3.GSH/H2O2 triggered cascade reaction for chemodynamic therapy base on smart MIL-53@Mn O2In order to overcome the problem of abnormal tumor development caused by hypoxia in tumor microenvironment,we designed MIL-53（Fe）-NH₂ composed of Fe³⁺and NH₂-H₂BDC,coated with Mn O₂ on the surface of MOFs by solvothermal method and modified with polyethylene glycol（PEG）to obtain MIL-53@Mn O₂-PEG（FMP）.We developed a cyclic catalysis based on MIL-53@Mn O₂ core-shell nanostructures that utilize the endogenous H₂O₂ of the TME to generate continuous oxygen to achieve O₂self-sufficiency and reduce GSH,and the Mn O₂ shell can undergo redox reactions with GSH generate Mn²⁺and glutathione disulfide（GSSG）.In the presence of abundant physiological buffers HCO₃^-/CO₂,Mn²⁺activates the Fenton-like response and triggers oxidative death of cancer cells.More importantly,Fe³⁺in MIL-53（Fe）reacts with excess GSH in cancer cells to form Fenton agent Fe²⁺,which then generates·OH.Besides,consumption of intracellular antioxidant GSH and prevention of its scavenging·OH,which can enhance the anti-tumor effect of CDT.Because GSH depletion induces damage to the cellular antioxidant defense system,cancer cells are more susceptible to Fe²⁺/Mn²⁺-induced oxidative stress,The obtained nanocatalysis reactor can achieve the efficient CDT treatment effect of Fe-Mo Fs by introducing bimetal and consuming GSH.4.TME-responsive MIL-53@ZIF-67/S-DOX/GOx for cascade reaction-enhanced antitumor therapyIn order to overcome the p H dependence of traditional chemodynamic agents and the insufficient concentration of H₂O₂ in tumors,we designed the in-situ growth of ZIF-67 shell using iron-based MOFs（MIL-53（Fe）-NH₂）as template,and then vulcanized by solvothermal method to obtain MIL-53@ZIF-67/S（FCS）.Finally,DOX and GOx were loaded by electrostatic interaction to obtain FCSDG.When the nanoparticles were ingested by tumor cells,the structure collapse of MOFs was induced in the environment of acidic and excessive GSH,and the loaded DOX was released for chemotherapy.Importantly,excessive GSH at the tumor site reduced Fe³⁺to Fe²⁺in MIL-53（Fe）,resulting in a complete collapse of the FCS framework and a more complete release of iron.Besides,FCSDG can effectively oxidize reducing GSH to GSSG,which greatly protects the generated reactive oxygen species from being consumed by oxidative stress.Gox-driven oxidation can effectively remove glucose in tumors for starvation therapy,The resulting H₂O₂ acts as a substrate and is converted into highly toxic·OH through Co²⁺/Fe²⁺-mediated Fenton-like reactions to trigger CDT.In addition,the increased acidity produced by gluconic acid can speeds up the degradation of nanomaterials.Under the condition of low p H,the synergistic effect between CDT and starvation therapy is enhanced by promoting the reaction of Co²⁺/Fe²⁺and H₂O₂ to produce a large amount of·OH,which causes oxidative damage to tumor cells and leads to tumor cell death.FCSDG,a cascade of nanodrugs,was designed to achieve the synergistic anti-tumor treatment of chemotherapy/starvation therapy/enhanced CDT.In summary,this paper developed a variety of tumor treatment schemes based on Co/Fe-MOFs composites by designing and constructing MOFs nanocomposite derivatives with good tumor microenvironment response and biocompatibility.Under exogenous or endogenous stimulation,the intracellular redox state was up-regulated to achieve the therapeutic effect,triggering the multi-way collaborative treatment of tumors.These results provide basic research data for the development of MOFs nanocomposites with combined or synergistic therapeutic functions.