Construction Of Nanoreaction Systems Targeting Tumor Microenvironment For Cancer Therapy

Malignant tumors are one of the leading causes of human death worldwide.In recent years,a variety of methods have been developed for the treatment of tumors.Tumor microenvironment is the cellular environment in which tumors exist and plays a key role in tumor progression,metastasis and immune escape.In addition to malignant cells,it also includes extracellular matrix,blood vessels and different types of stromal cells.Moreover,the metabolism of cancer cells differs from that of normal cells,and the tumor microenvironment is typically characterized by hypoxia,angiogenesis,acidosis,hypermetabolism and elevated redox status.A better understanding the characteristics of tumor microenvironment and its role in tumor development is crucial for customizing nanomaterials that target the tumor microenvironment.Although many nanotherapeutic systems targeting tumor microenvironment have been reported,there are still some problems,such as the high oxygen dependence of reactive oxygen species(ROS)based therapies,the limited action range of ROS,and the insufficient accumulation of drugs in tumors.In this paper,a series of intelligent nanoreaction systems,which targeted the tumor microenvironment,have been designed to avoid the inactivation of free radicals and reduce the off-target effects of drugs,thus providing more active molecules for tumor therapy.In addition,other problems in tumor treatment are also addressed,such as immune escape,drug resistance and resistance to apoptosis.Based on this,new prospects for therapeutic approaches targeting tumor microenvironment are proposed,such as the regulation of immunosuppressive tumor microenvironment,reducing autophagy of tumor and so on.The results we have done so far are summarized as follows:1.Tumor hypoxia significantly diminishes the efficacy of ROS-based therapy.Although researchers have made significant efforts in recent years,these strategies still could not get rid of the dependence on oxygen well and might accompany with some severe side effects.Furthermore,overexpressed glutathione(GSH)in cancer cells would potently scavenge the free radicals.Here,a system generating oxygen-independent free radicals and depletion intracellular GSH with a benign manner simultaneously for enhanced free radical-based cancer therapy were designed.Firstly,we used PEG-MoS2 nanoflowers as a carrier and heat source,loaded with the thermally unstable azo initiator AIBI,and then encapsulated with phase change materials to construct the final MoS2@AIBI-PCM nanosystem.Under near-infrared light,the photothermal effect of PEG-MoS2 leaded to the melting of the phase change material,which resulted in the rapid release and decomposition of AIBI and the generation of alkyl radicals.In addition,PEG-MoS2 could accelerate the oxidation of GSH under the 808 nm irradiation induced hyperthermia.,avoiding the introduction of toxic metal ions.The depletion of GSH reduced the consumption of the generated alkyl radicals and greatly improved the therapeutic efficiency.2.The acidic pH of the tumor microenvironment,due to its prevalence in most solid tumors,is the most widespread trigger used to stimulate responsive drug delivery systems.Herein,we designed an intelligent all-in-on nanoplatform responsive to acidic tumor microenvironment,combining the prodrug and catalyst to increase the amount of bioorthogonal catalyst activated drugs at the tumor site.Usually,bioorthogonal chemistry-based drugs activation require additional injection of small molecule,while the intravenously injected small molecule with short half-life and poor water solubility are difficult to accumulate in tumors.Therefore,an all-in-one platform combined prodrug and catalyst was constructed.Palladium nanoparticles were grown in situ on metal-organic framework material MIL-101(Fe).Then,the nanoparticles were mineralized with a CaCO3 mineral layer.Finally,the precursor 5-fluoro-1-propargyl-uracil(Pro-5FU)and hyaluronic acid(HA)were integrated into MIL-101-Pd@CaCO3.Before reaching the tumor site,the prodrug and catalyst were isolated by CaCO3 shells to avoid premature drug release.Having arrived at the desired site,the prodrug would be exposed to bioorthogonal catalyst following the collapse of CaCO3 in the acidic tumor microenvironment,inducing the drug synthesis in situ.Compared to the stepwise delivery approach,the synchronous release of bioorthogonal catalysts and prodrugs greatly simplifies the delivery system without imposing an additional burden.3.Elevated levels of ROS in tumors are a typical feature of cancer cells and are widely used as targets for tumor therapy to reduce adverse side effects on normal tissues.Among that,H2O2 as the main component of ROS,can be converted to ·OH,which is more toxic than O2·-and H2O2,mediating intracellular cytotoxicity and inducing apoptosis of tumor cells.However,·OH originated from fenton and fenton-like reactions has the problems of short lifetime and limited range of action.Notably,the redox homeostasis of mitochondria plays a key role in many biological processes,and about 90%of intracellular ROS in cancer cells are produced in mitochondria,which are therefore more vulnerable to elevated oxidative stress.Based on this,we constructed a mitochondria-mediated self-cycling system to achieve high dose of ·OH production through continuous H2O2 supply.The Cu(Ⅱ)MOF was loaded with a small molecule of cinnamaldehyde(CA)and further modified with triphenylphosphorus(TPP)and polyethylene glycol(PEG).CA could induce elevated ROS in mitochondria;therefore,after active targeting of mitochondria,the intrinsic high level of H2O2 in mitochondria of cancer cells could induce degradation of Cu(Ⅱ)MOF,releasing the initially free CA.The CA released in situ further triggered the upregulation of endogenous H2O2,resulting in the subsequent adequate release of CA and the final burst growth of H2O2,which greatly promoted the fenton-like reaction between Cu2+and H2O2 and induced long-term high oxidative stress.In summary,we have designed a series of nanoreaction systems targeted to tumor microenvironment for enhanced free radical generation or drug accumulation at the tumor site,with improved treatment of hypoxic tumors and in situ drug synthesis by bioorthogonal catalyst.In addition,we also discussed some other problems still existed in cancer treatment,and provided new ideas for future tumor therapy.