Hypoxia Tumor Microenvironment Responsive Covalent Organic Frameworks: Synthesis And Their Application In Tumor Thersnostics

In recent years,phototherapy techniques with photocontrolled and noninvasive killing of tumor cells have been widely studied and become increasingly mature.Phototherapy methods can be divided into photothermal therapy（PTT）and photodynamic therapy（PDT）.PTT refers to the use of specific light to irradiate photothermal agents to generate a large amount of heat so as to rapidly heat up and kill tumor cells.PDT means that photosensitizers consume oxygen to produce toxic reactive oxygen species（ROS）under light of a specific wavelength,which can effectively cause apoptosis and necrosis of cancer cells,thus avoiding surgery.And because laser,photothermal agents,photosensitizers and oxygen itself are harmless,so phototherapy for normal tissues and cells have very low toxic side effects.However,phototherapy still has some limitations,such as low penetration depth,low killing efficiency,poor water solubility of photosensitizer,poor tumor enrichment effect and other problems.In the field of biomedicine,there are great differences between tumor and normal cell microenvironments in essence,such as hypoxia,low p H,high concentration of H₂O₂,GSH overexpression,vascular hyperpermeability,inflammatory reaction and other characteristics of tumor microenvironment,among which hypoxia is the most obvious difference.Tumor hypoxia results from the rapid spread of cancer cells and incomplete vascular system in the tumor,which greatly affects tumor metabolism and immunity,and indirectly leads to acidic environment and inflammatory reaction.Meanwhile,in recent years,fluorescent probes with emission wavelength in the near infrared（NIR）range have attracted more and more attention because of their higher spatial and temporal resolution,deeper penetration depth,better image quality and higher signal-to-noise ratio.Based on the above research,this paper continues to explore.The topic uses covalent organic framework（COFs）with large specific surface area,adjustable function and good stability as the skeleton of nanomaterials.Through chemical modification,the problems of water solubility and targeting of nanomaterials are solved,and two kinds of PDT tumor drugs with tumor microenvironment response are designed.The specific research of this paper is as follows:1.Preparation of COF nanoparticles containing AZO bonds（AZO）that can be sensitive to the tumor microenvironment:in the anoxic tumor microenvironment,azo reductase and nitroreductase will be overexpressed.The azo bond is responsive to both enzymes,so we designed and developed a hypoxic responsive porphyrin COF containing azo bond.Firstly,we selected tetracarboxyporphyrin（TCPP）as the skeleton material of COF,and modified folic acid（FA）on its outer surface to obtain nanomaterials that can accurately target tumor sites.We then used the porosity and structural stability of COF to load doxorubicin（DOX）chemotherapy drugs,resulting in nanomaterials DOX@AT-FA NPs that are sensitive to the tumor microenvironment and achieve therapeutic effects.TCPP can consume oxygen and produce reactive oxygen species（ROS）under laser irradiation,which exacerbates the hypoxia in tumor environment,and also accelerates the cracking of COF nanoparticles.The cracking of COF releases the nanomaterial loaded DOX drugs and activates the fluorescence of TCPP so that it can be used for fluorescence imaging.Experimental results show that DOX@AT-FA NPs can accurately target tumors,effectively inhibit tumor growth,and achieve fluorescence image-guided chemotherapy and PDT combined therapy.2.Construction of COFs loaded with near-infrared region Ⅱ fluorescence molecules with anoxic characteristics of tumor microenvironment:First,we used FD1080 loaded with near-infrared region Ⅱ fluorescence molecules by COF to make it have deeper optical penetration.Then the targeting group hyaluronic acid（HA）was modified on the outer layer of COF,and the nanomaterial F@TA-COF-HA NPs was obtained.The nanoparticle actively binds to the overexpressed CD44 on the outer surface of the tumor through HA,accurately targets the tumor site,and achieves the fluorescence image-guided PDT therapy of IR-Ⅱ.After relevant tests,F@TA-COF-HA NPs has a fluorescence emission peak near 1000 nm wavelength,which has been successfully applied to IR-Ⅱ fluorescence imaging（FL）.At the same time,it can effectively kill cancer cells and has no obvious toxic and side effects on normal cells.It is a highly effective,tumor anoxic microenvironment responsive,IR-Ⅱ FL-guided PDT treatment strategy.