Construction And Anticancer Properties Of Drug-Loading System Targeting Tumor Microenvironment

Tumor microenvironment is composed of tumor cells and the surrounding environment,and mainly includes tumor cells,tumor blood vessels,extracellular matrix and related enzymes,growth factors,immune factors and so on.Tumor cells and tumor microenvironment interact and restrict each other,breaking the balance between tumor cells and microenvironment would become a new breakthrough in the treatment of tumor diseases.With the tumor microenvironment as the target of cancer treatment,we have constructed a series of drug-loading platforms based on different nanocomposites for anti-tumor and anti-metastasis research.Detailed contents are as follows:In chapter one,we described the main characteristics of the tumor microenvironment,namely the acidic microenvironment and the hypoxic microenvironment and discussed the regulation of lactate accumulation,tumor hypoxia and extracellular matrix in tumor proliferation and metastasis.Subsequently,the construction and application of drug nanocarriers are reviewed,including porous nanomaterials,two-dimensional nanomaterials and other multifunctional composites nanomaterials.In chapter two,a drug delivery system based on porphyrinic MOFs which carry MCT1 inhibitor for non-invasive photodynamic therapy(PDT)of tumors.In this study,?-cyano-4-hydroxycinnamate(CHC)was incorporated into a porous Zr(IV)-based porphyrinic metal-organic framework(PZM)nanoparticle,to reduce the lactate uptake by inhibiting the expression of lactate-proton symporter,monocarboxylate transporter 1(MCT1)in tumor cells,thus transformed lactate-fueled aerobic respiration to anaerobic glycolysis.The alteration in energy supply could also decrease the oxygen consumption in tumor cells,which would facilitate the photodynamic therapy(PDT)in cancer treatment.Moreover,hyaluronic acid(HA)was coated on the surface of PZM nanoparticles for CD44-targeting and hyaluronidase-induced intracellular drug releasing.Both in vitro and in vivo studies confirmed good biocompatibility and enhanced PDT efficacy of the HA-coated PZM nanoparticles(CHC-PZM@HA)in tumor cells.In chapter three,a double drugs delivery system based on mesoporous silicon nanoparticles(MSNs)for targeted tumor therapy and anti-metastatic was developed.Metformin(Me)and fluvastatin sodium(Flu)were loaded into the porous structure of MSNs and potassium permanganate(KMn O₄)reacted with the sulfhydryl group on the silicon sphere to form a dense Mn O₂ shell in situ,which could be degraded by intracellular glutathione(GSH)by oxidation reduction reaction and induced Me and Flu release in the acidic tumor microenvironment.Subsequently,the copolymer PEG-FA was modified on the surface of MSN@Mn O₂ to improve the biocompatibility of the nanoparticles,and the drug delivery system Flu&Me@MSN@Mn O₂@PEG-FA was obtained.In vivo experiments,paramagnetic Mn²⁺was introduced in the nanoplatform for MR imaging,proved that Flu&Me@MSN@Mn O₂@PEG-FA could be enriched in the tumor region with high expression of folate receptor.Once the drugs was released in tumor cells,the aerobic respiration of pyruvate was blocked by Me,thus more anaerobic respiratory metabolites lactate was produced.Simultaneously,MCT4 protein,which mediates lactate efflux would be suppressed by Flu,further aggravated the accumulation of lactate in cells and triggered intracellular acidosis.As a result of the reduced extracellular lactate concentration,the ability of cancer cells to migrate was weakened.Thus,this is an ingenious strategy based on Flu&Me@MSN@Mn O₂@PEG-FA,which showed the obvious inhibitory effect on tumor and resistant to metastasis.In chapter four,a new strategy based on the down-regulation of extracellular matrix(ECM)level was designed for enhanced tumor photodynamic therapy.Antifibrotic drug pirfenidone(PFD)was loaded in a covalent organic framework(COF_DHTA-TTA)and followed by the coating of PLGA-PEG on the surface to fabricate PLGA-PEG@COF_DHTA-TTA@PFD(PCPP).After being intravenously injected,the PFD in PCPP gradually released in the acidic tumor microenvironment and lead to the down-regulation of HA and collagen I,which are major components of ECM in tumor,thus significant enhance the tumor uptake of the PDT reagent(PPIX-NM).Additionally,the distintegrate of tumor stroma also resulted in the increasing efficience vescular area and the improveming oxygen supplement in tumor area,which greatly improved the in vivo antitumor efficacy of PDT.Further,blood routine analysis and H&E staining of the major organs after the treatment both indicated a good biological security of the nanomaterials.Of special note,long-term observation demonstrated the outstanding anti-metastasis effect after the treatment of combined PCPP and PPIX.Thus,the strategy of degrading ECM enhanced the efficiency of PDT treatment and also plays a role in anti-metastasis of tumor.