Controlled Synthesis Of Novel Functional Heterostructures For Cancer Chemodynamic Therapy

In recent years,the incidence and mortality of cancer have been increasing year by year,and it has become the greatest threat to human life and health.How to solve the problem of tumor treatment is one of the major scientific issues in the present world that urgently need to be solved.Combining multidisciplinary concepts and technologies to develop new and efficient tumor treatment technologies is an important direction to solve the current tumor treatment dilemma.With the rapid development of nanotechnology,nanomaterials with unique physical and chemical properties and rich structural and functional designability have shown unique advantages in tumor treatment.Especially,the high catalytic activity of nanomaterials has brought dawn for tumor-specific treatment.The infinite growth of malignant tumors relies on the biochemical reactions that occurs all the time in the tumor cells,which are essentially enzyme-catalyzed reactions.On the bases of the unique chemical characters in tumor microenvironment,thereby,it will bring hope to the highly specific tumor treatment by introducing catalytic chemistry concepts into tumor treatment for developing new tumor catalytic treatment strategies,which can be realized by designing specific catalytic reactions using nano-catalysts to convert tumor endogenous molecules into anti-tumor drugs.Chemodynamic therapy(CDT)is a novel tumor treatment strategy with great clinical application development potential,which is based on the Fenton or Fenton-like reaction occurred in the acid and high H₂O₂ content tumor microenvironment.However,the low catalytic activity of traditional nanocatalysts under tumor microenvironmental conditions is a key bottleneck restricting the development of CDT.Developing novel high-efficiency nano-catalysts and catalytic strategies is the key to promoting the development of CDT,thereby improving the effect of tumor therapy.In the field of catalysis,regulating the electronic state of the active center of a catalyst is an effective way to optimize the catalytic activity.Heterostructure nanomaterials have unique advantages in electronic regulation due to their unique interface effects.Therefore,it is of important academic value and clinical significance to improve the therapeutic effect of CDT by designing new type of high-efficiency heterostructure catalysts and developing electronic state control strategy.Herein,we focuseed on the urgent need for high-performance catalysts in emerging chemodynimic therapies,puting forward the core idea of using the electronic behavior controlling properties of heterostructures to improve the catalytic activities in tumor.We have designed and developed a series of novel nano heterostructures,and systematically explored the key scientific issues of electronic regulation in achieving high catalytic activity in tumors.The main research contents are as follows:1.The built-in electric field-driven"self-repair"co-catalysis strategy based on Fe@Fe Ox-Cu2O heterostructures for high-efficiency chemodynamic therapy.One of the key bottlenecks that restrict the effect of CDT is the low conversion rate from Fe³⁺to Fe²⁺(or Cu²⁺to Cu⁺)in tumor due to the high reaction activation energy,which process needs to consume the limited H₂O₂in tumor.Aming at this problem,we have proposed an innovative self-recovering co-catalytic strategy based on the novel Janus Fe@Fe O_x-Cu₂O heterostructures,which realizing high-efficiency CDT without p H dependence.The strategy has the following characteristics:(1)Innovative material structure:amorphous Fe@Fe Ox nano spherical particles were used as seed and reducing agent,ultra-small Cu nanoparticles were grown on the surface by displacement reaction,and then through limited oxidation reaction,Fe@FeO_x-Cu₂O heterostructures were obtained.The elemental Fe core can prevent further oxidation of Cu₂O.(2)Innovation of bimetallic co-catalysis mechanism:the surface of the Fe@FeO_x-Cu₂O heterostructures has abundant Fe(II)and Cu(I)catalytic active sites,which can efficiently catalyze Fenton and Fenton-like catalytic reactions.It is worth noting that during the Fenton and Fenton-like reaction,the positively charged Fe(III)and Cu(II)generated on the surface of the heterostructures can form a built-in electric field between the zero-valent Fe core and the surface,which direction is from the Fe core to the surface of the material.Driven by the electric field force,electrons transfer from Fe to the surface and are captured by Fe(III)and Cu(II)to produce Fe(II)and Cu(I)with high catalytic activity,which endows the material has the unique recovery property in Fenton and Fenton-like reaction.(3)Break through the bottleneck that conventional CDT relies on tumor acidic microenvironment:the Fe(II)-Cu(I)bimetallic co-catalysis mechanism of the heterostructures ensures that it can catalyze the production of hydroxyl radicals(·OH)in different p H regions of the tumor,thereby realizing efficient treatment of the entire tumor.The replacement mechanism of Fe@FeO_x-Cu₂O heterostructures synthesis were explored:(1)compared with crystalline Fe,the amorphous character overcomes the influence of lattice mismatch,and thus realized the nucleation and growth of Cu on the amorphous surface.(2)The replacement reaction for the synthesis of heterostructures can be realized in a wide temperature range of 180-230?.As the reaction temperature increases,the kinetics of the replacement reaction accelerated resulting in the diameters of Cu domain increased.Both in vitro and in vivo experimental results showed that compared with the simply physical mixed Fe@FeO_xand Cu₂O nanoparticles,the Fe@FeO_x-Cu₂O heterojunction exhibited significantly improved Fenton and Fenton-like catalytic efficiency,realizing the high-efficiency therapeutic effect of breast cancer tumor by CDT.In this work,we have developed a novel synthetic method for the highly monodisperse heterostructure nanoparticles based on displacement reaction,which provides a reference for the design and synthesis of new heterojunctions.In addition,we have proposed an innovative“self-recovering”co-catalysis strategy driven by the built-in electric field of the heterostructure,which will provide new ideas for the development of co-catalysts for high-efficiency CDT in a wide p H range of the entire tumor.2.Nano-galvanic cells driven highly efficient chemodynamic therapy based on Au-Fe heterostructures.In view of slow conversion rate of Fe³⁺to Fe²⁺in CDT,it is difficult to continuously provide Fe²⁺for the intratumoral Fenton reaction.Inspired by the galvanic cell reaction,we designed and synthesized a new type of eccentric core@shell structure Au@Fe heterostructure(E-Au Fe)as a nano galvanic cell that is specifically responsively activated by the acid tumor microenvironment.An innovative nano-galvanic driven Fenton reaction strategy is proposed,which realized efficient tumor CDT treatment that does not rely on Fe³⁺reduction.The strategy has the following characteristics:(1)Innovative material structure:the eccentric core@shell structure of E-Au Fe can hide the Au,just like the"packaging"to the battery,which can effectively avoid the toxicity of the galvanic reaction during the blood transport process,and losing efficiency of the nano galvanic cells before reaching the tumor.Moreover,the thinnest part of the Fe shell in the E-Au Fe is only 1?2 nm,which can enable the nano galvanic cell to be rapidly activated in the tumor acid microenvironment as the Au surface exposed with the Fe dissolved.(2)Nano galvanic reaction driven catalytic reaction mechanism innovation:according to the properties of the separation of oxidation and reduction half-reaction in the galvanic reaction,accelerated oxidation reaction occurs at the Fe negative electrode,continuously and rapidly producing Fe²⁺for catalyzing the decomposition of H₂O₂ to produce·OH.At the same time,the electrons generated in the anode reaction are transferred to the surface of the Au cathode through the interface,and then catalyze the decomposition of H₂O₂ to produce·OH,thereby realizing the rapid generation of·OH at the two electrodes of the nano galvanic battery.(3)Break through the dilemma of routin CDT therapy on Fe³⁺reduction dependence:through the anode reaction of the galvanic battery,Fe²⁺is continuously and rapidly provided for the Fenton reaction,which avoids the technical problem of reducing Fe³⁺in traditional catalysts.In this work,the effects of the surface energy of Au seed particles and interface energy on the heterogeneous nucleation of Fe are investigated through experiments and theoretical calculations,with the following findings:(1)with the decrease of the surface energy of Au seeds or interface energy,the wettability of Fe to Au increases,and the heterostructure gradually changes from the Janue structure to the central core@shell structure;(2)Fe tends to nucleate on the(200)and(220)planes of Au,rather than the Au(111)crystal plane.A series of Au-Fe heterojunctions with various structures were successfully prepared,including E-Au Fe.In aqueous solution that simulates the tumor microenvironment,it is proved that E-AuFe exposed the Au surface in about 10 hours and then activated the galvanic reaction.Both in vitro and in vivo experimental results show that,compared with the central core@shell structured C-Au Fe,E-AuFe and J-AuFe both show significantly improved catalytic efficiency in Fenton and Fenton-like reactions,thereby realizing highly effective CDT treatment for breast cancer.In this work,we have developed an effective synthesis method for hybrid nanoparticles with different structures based on the regulation of seed surface energy and interface energy,which will provide theoretical and methodological references for structural control in heterogeneous formation.Moreover,an innovative strategy based on galvanic cells driven high-efficiency catalysis is proposed,which will provide reference ideas for the design and development of new-type high-efficiency CDT catalysts,and will also provide inspiration for the application and development of nano-scale galvanic cells in other application fields.3.The magnetic field-driven electronic eddy current effect of FePt-FeC heterostructures for magneto-electric enhancement chemodynamic therapy.Aiming at the key problem that the rapid immortal proliferation of malignant tumor cells is resistant to·OH,which leads to the reduction of the therapeutic effect of CDT,we proposed an innovative magnetic-electric enhanced catalytic strategy based on the novel Janus FePt-FeC heterostructures,according to the principle of the electric eddy current effect induced by the alternating magnetic field.The efficacy of CDT is significantly improved by inducing malignant tumor cell senescence.This strategy has the following characteristics:(1)Innovative material synthesis methods:FePt cubic nanoparticles were used as seeds,through selective heterogeneous nucleation and oriented growth at the high-energy sites of cubic seed,Janus FePt-Fe₃O₄heterostructures was synthesized.After carbonization reaction in liquid phase,Janus FePt-FeC heterostructures were successfully prepared.(2)Innovative composition and structure of materials:the heterostructure composed of FePt magnetic alloy and FeC magnetic intermetallic compound has good magnetic and electrical conductivity,which is helpful for the generation of eddy current under alternating magnetic field.It is worth mentioning that because the work function of FePt is higher than that of Fe C,which can drive the eddy current electrons to shift to FePt.(3)Mechanism innovation of electron eddy current driven catalytic reaction:under the alternating magnetic field,eddy current is generated in the heterostructures with an obvious charge accumulation at the interface of the heterojunction,especially on the Fe Pt side.The significant increase charge density around catalytically active centers of Pt and Fe increases the activity for NAD⁺catalytic hydrogenation reactions by about 3.5 times,and the Fenton-like reaction·OH yield by about 1.6 times.(4)The innovation of combined treatment of aging and CDT:the serious imbalance of the ratio of NAD⁺/NADH in tumor cells induces the gradual senescence of tumor cells and reduces the resistance to·OH,which significantly improves the therapeutic effect of CDT on breast cancer.The finite element simulation and powder magneto-thermal experiments proved that the Fe Pt-Fe C heterostructure generated the eddy current under the alternating magnetic field.Both in vitro and in vivo experimental results show that,compared with the case of no altering magnetic field,the FePt-FeC heterostructure has significant increase in the catalytic efficiency of the NAD⁺catalytic hydrogenation reaction and Fenton-like reaction under an alternating magnetic field.High-efficiency breast cancer tumor treatment was achieved by combining cell senescence and CDT.This work created a synthetic method for the carbonization of Fe₃O₄ as well as its containing heterostructures in the liquid phase,providing theoretical and methodological support for the synthesis of iron carbide and its heterostructures.We have proposed the design principles and feasibility schemes of heterostructures for magneto-electrically enhanced catalytic reactions,which opening up a new path for the application of biosafety alternating magnetic fields in biomedicine.This strategy will also provide methods and ideas for the realization of high catalytic activity in other fields catalysis.