Functional Materials Modulate Tumor Acidic Microenvironment For Enhanced Chemodynamic Therapy Treatment

As the rapid development of society,the mean expectancy of life extends significantly,but cancer is still one of the biggest killers that threatens people.So researching on effective treatment of cancer is still widely concerned.It is known that tumor is started from uncontrolled proliferation of cancer cells,with the environment being gradually special that is different from the normal.Based on this,there are more and more therapeutic researches targeting on tumor microenvironment,which showed great potential for effective cancer treatment.Chemodynamic Therapy(CDT),as an emerging cancer treatment technology,can kill tumor cells via introducing fenton/fenton-like reactions in tumor for in situ production of toxic·OH.It perfectly combines the specificity of tumor microenvironment and the versatility of nanomaterials,thus showing excellent development prospect.However,the slightly acid p H in environment largely limits the occurrence of the conventional fenton/fenton-like reactions,and so gives unsatisfactory efficiency of CDT.In order to improve CDT antitumor efficiency,we put efforts on regulating the tumor acidic microenvironment as well as designing functionalized nanomaterials.The specific research contents are as follows:1.Study of functional amorphous iron nanomaterials for enhanced CDT via remodeling tumor acidosis.The production of·OH during CDT depends heavily on the acidity of fenton reaction environments.However,the characteristics of tumor cell with extracellular acidity(p H_e?6.5)and intracellular alkalinity(p H_i?7.2)undoubtedly set a huge chemical barrier for effective implementation of intracellular CDT,thus severely limiting its functional activity and therapeutic effect.Here,the amorphous iron nanoparticles(AFe NPs@CAI)loaded with carbonic anhydrase CA IX inhibitor(CAI)were constructed.CAI can effectively inhibit the overexpression of CA IX in cancer cells and prevent extracellular CO₂ and H₂O to generate H⁺and HCO₃^-,further reducing the entry of HCO₃^-into cells to react with H⁺in cellular,which result in the accumulation of H⁺cell for reduced p H_i.Such,reestablished acidosis can accelerate the AFe NPs-based fenton reaction to achieve self-enhanced CDT.In addition,the continuous decrease of extracellular H⁺concentration can prevent the acid degradation process of tumor extracellular matrix,further inhibiting the invasion and metastasis of tumor.In conclusion,with this functional nanomaterial,we propose a new strategy to re-establish the tumor acidosis for optimized CDT,which provides a new paradigm for enhancing the efficacy of CDT.2.Study of H⁺nanodonor for enhanced CDT and of tumor metastasis inhibition.Since the therapeutic effect of CDT is largely limited by the weak acid of tumor microenvironment,photoacid molecules(PA)as ultraviolet visible light-control H⁺donors are chosen for tumor microenvironment adjustment and so for CDT therapeutic effect improvement.In this chapter,a novel H⁺nanodonor UCNP@MIL-88B@PA(UMP)was constructed with UCNPs as the inner core,MIL-88B as the shell layer for PA loading.In tumor site,under near-infrared(NIR)illumination,UCNPs can up-convert NIR to ultraviolet visible light,so can stimulate H⁺release form PA.The accumulation of H⁺in tumor cells will accelerate the MIL-88B induced fenton reaction,further resulting in improved production of·OH for enhanced CDT treatment to tumor.Notably,the intracellular H⁺also cause protonation of actin depolymerase protein(cofilin),further affect the polymerization of F-actin significantly reduce the invasion and metastasis of tumor cells.With the above,the functional nanoparticles regulate tumor acidic environment for improved CDT to tumor,and meanwhile,effectively reduce the exercise capacity of tumor cells via inhibiting the formation and activity of lamellipodia(that are related to cell movement ability)which significantly expand the application range and research ideas of biomedical nanomaterials.3.Study of non p H dependent heterogeneous fenton nanocatalyst for CDT.For homogeneous fenton catalyst,its reaction efficiency is dermined by the reaction environment p H,and the precipitation of iron hydroxide in during the reaction process can largely limit the efficiency of·OH generation.To break through the above limitation in tumor microenvironment,Cu₅Fe S₄ NPs were designed and synthesized as heterogeneous fenton nanocatalyst,showing non p H dependence,which can catalyze H₂O₂ into·OH in neutral and slightly acidic environments.Both cell experiments in vitro and animal experiments in vivo showed good tumor inhibition effect on tumor growth.Such p H-independent nanocatalysts overcome the strong dependence of traditional homogeneous catalysts on acidic microenvironment,and meanwhile expanding the wide application of heterogeneous catalysts in the biomedical field.