Tumor Microenvironment Responsive Nanocatalytic Tumor Therapy

The oncogenesis,biodetection,therapeutics and prophylaxis of maglinant tumors are the extensively explored research frontiers in modern nanotechnology and nanomedicine.Due to the lack of the therapuetic specificity toward malignant tumors,clinical chemotherapy and radiotherapy modalities will inevitably cause irreversible damages against healthy cells and tissues,passivating the prognosis of the cancer patients.In this dissertation,aiming at the distinct tumor microenvironment,we have elaborately designed and built functional nanomaterials for malignant tumor-specific catalytic therapeutics.First,on the basis of the tumorous exaggerated nutrient supply and lactic acidosis hallmarks,and the over-low concentration of H₂O₂ expressed in tumor for initiating Fenton reactions to produce quantitative reactive oxygen species,we established a sequential-functioning nanocatalyst delivery strategy under the“nanocatalytic medicine”concept by co-loading glucose oxidase and Fe₃O₄ nanoparticles into the dendritic silica nanoparticles?GOD-Fe₃O₄@DMSN Nanocatalysts,GFD NCs?for tumor catalytic therapeutics.The GOD functions as biocatalyst to catalyze the tumorous glucose nutrients conversion into gluconic acid and H₂O₂,elevating the localized H₂O₂concentration effectively.The abundant H₂O₂ could then serve as the reactant of Fe₃O₄nanoparticles–catalyzed Fenton reaction under the mild acidic tumor microenvironment,generating quantities of toxic hydroxyl radicals to induce tumor apoptosis.Initially,the radical production performance and corresponding kinetics are assayed through electron spin resourance spectroscopy and Michaelis-Menten enzymatic kinetics.We also tested the sequential catalytic therapeutic performance of GFD NCs againsts mice mammary 4T1 tumors and human glioma U87 tumors cells both in vitro and in vivo.Surprisingly,we found that under a low dosage of GFD NCs(12.5?g ml^-1),prominent cytotoxicities and tumor xenografts inhibition efficacies could be observed.The present design effectivley deprive the tumorous glucose nutrients,and more importantly,conquer the limited H₂O₂ concentraiton for Fenton catalysis.Furthermore,the tumor-specific acidic milieu endows the GFD NCs high therapuetic conseqeuce and biocompatibility,paving a promising paradigm for nanocatalytic medicine with high specificity.Second,aiming to elevate the catalytic activity of Fenton catalysts,we have introduced the atomically dispersed single atom Fe nanocatalysts?SAF NCs?for localized tumor Fenton therapy based on the tumorous intrinsic H₂O₂.SAF NCs were prepared by an“isolation-pyrolysis”approach and the leakage of free ferrous and ferric ions were assayed to be undetectable regardless of the acidity of the co-incubation buffer systems.However,based on the hydroxyl radical production signals detected in the ESR spectra and methylene blue bleaching experiment,heterogeneous Fenton reaction is supposed to take place on the atomically dispersed Fe single sites on SAF NCs.Through density functional theory?DFT?,we concluded that the heterogeneous Fenton reaction proceeds by a proton-mediated H₂O₂ homolytic pathway with subsequent catalytic site regeneration.This may support the evidence that under acidic microenvironment rathan then neutral,the hydroxyl radical production performance is typically enhanced.In addition,upon protein inhibitor analyses and lipidperoxide fluorescence probe detections,PEGylated SAF NCs?PSAF NCs?were confirmed to react with the intrinsic H₂O₂ to generate hydroxyl radicals to trigger both tumor apoptosis and ferroptosis effectively.Furthermore,PSAF NCs showed prominent catalytic therapeutic outcomes against mice mammary 4T1 xenografts during the therapeutic period.The present study may broaden the potential nanomedical applications of atomically dispersed catalysts to various fields including tumor therapy,antibacteria and in other pathological diseases.Third,hypoxic nature is the major obstacles for satisfactory photodynamic tumor therapy based on type-II photosensitizers during photodynamic therapy,which depends on the oxygen consumption to produce reactive oxygen species?typically ¹O₂ species?for tumor therapy.In this work,inspired by the photosynthetic character of photoautotrophic cyanobacteria?Synechococcus elongatus PCC 7942?under light,we have built a microbial hybrids,ceCyan,of the chlorin e6?ce6?-endocytosized cyanobacteria based on the homogeneity between the ce6 photosensitizer and the intracellular chlorophylls by a simple infusion method.The ceCyan cells were then endowed with simultaneous oxygen-photosynthesis and photosensitization performances upon single source laser irradiation?660 nm?.From the UV-vis spectrometry and the confocal laser microscopy,successful endocytosis of ce6photosensitizers into the cyanobacteria could be observed.Upon 660 nm laser irradiation at an extremely low power density(20 mW cm^-2),amounts of singlet oxygen species could be quantified to be 17-19 times that of the counterpart of pure ce6 with identical ce6 concentration,remarkably enhancing the photodynamic effects.In cellular therapeutics,co-incubation of ceCyan and the application of the laser irradiation leads to the bursts of intracellular reactive singlet oxygen species,damaging tumor cells effectively.The present study provides a typical paradigm to surpass the limitations in nanomedicine from nature,paving a general hybridization methodology and therapeutic modality based on microorganisms.