Construction Of Novel Functionalized Porous Organic Nanomaterials And Study On Tumor Enhancement Therapy

In recent years,tumor treatment has been developed rapidly,and the proposed treatment modes are diversified,such as surgery,radiotherapy,chemotherapy and so on.However,many therapies cannot specifically kill cancer cells,often leading to serious side effects,clinical efficacy is not ideal.Therefore,it is urgent to explore and develop new cancer treatment methods with high efficiency and low toxicity.Nanotechnology is a rapidly developing new technology,which is playing an increasingly important role in biomedicine.Nanoparticles and nano-drugs developed based on nanotechnology not only have the characteristics of targeting,but also have the characteristics of slow-release ability and controllable action time,providing an opportunity for strengthening anti-tumor therapy.In addition,the specificity of tumor microenvironment（TME）（hypoxic/acid-biased/redox imbalance,etc.）compared to normal tissue physiological environment also provides the basis for targeted tumor therapy.Therefore,the exploration of nano-drugs based on TME specific response has become a promising development direction in the application of tumor therapy.In this dissertation,centering on the urgent problems to be improved and solved in tumor therapy,based on the specificity of TME,a variety of porous organic nanomaterials are constructed,which are used to study the photodynamic therapy（PDT）,chemodynamic therapy（CDT）and protein therapy and their synergistic enhancement effects.In addition to achieving good therapeutic effects,it also provides new ideas for the treatment methods by regulating TME.The specific research contents are as follows:（1）Tumor treatment based on reactive oxygen species（ROS）,such as PDT,are negatively affected by hypoxia and glutathione（GSH）overexpression in TME.Based on the above theory,we developed and synthesized a novel core-shell nanostructure with cyclic catalytic properties of manganese ferrite@metal-organic framework（Mn Fe₂O₄@MOF）,which is used to simultaneously and continuously regulate tumor hypoxia and reducibility to achieve the desired therapeutic effect.The nanoplatform has both catalase-like and glutathione peroxidase activities.Most importantly,it can adjust TME to be more favorable to PDT by taking advantage of TME’s own characteristics.In addition,the nanoplatform can perform magnetic resonance imaging（MRI）simultaneously to facilitate more precise treatment.（2）At present,PDT not only faces the problems of photosensitizer inactivation/oxygen（O₂）supply shortage,but also the limited penetration depth of external light source.Here,on the basis of previous work,a nano-conjugated compound,manganese ferrite@metal-organic framework@luminol@hyaluronic acid（Mn Fe₂O₄@MOF@Luminol@HA）was designed,which can react with overexpressed hydrogen peroxide（H₂O₂）in tumor.Chemiluminiscence（CL）is used to form self-activation,eliminating the need for external light source.At the same time,Mn Fe₂O₄also has the activity of hydrogen peroxide-like and glutathione peroxidase nano-enzyme,which can further supplement the O₂content of tumor site and reduce the GSH content,and finally realize the enhancement of PDT.（3）Tumors are highly variable and complex environments,making it difficult for a single treatment strategy to produce satisfactory therapeutic effect.Based on this theory,we designed a cascading bionic nano-therapy platform,dioxalate@metal-organic framework@cancer cell membrane-glucose oxidase（C₁@M@C₂G）,integrating CL-induced PDT,Fenton reaction-based CDT and glucose oxidase catalyzed starvation therapy.In addition,H₂O₂and gluconic acid produced by GOD could further promote CPPO-H₂O₂-triggered CL-PDT,and improve the treatment effect of low p H dependent CDT based on Fenton reaction.The experimental results showed that the cascade bionic nano-therapy platform achieved remarkable therapeutic effect in the tumor bearing mouse model.（4）PDT is an anti-tumor therapy strategy based on ROS（mainly in the form of singlet oxygen,¹O₂）.However,due to the short life of¹O₂（3μs）and limited diffusion radius（20 nm）,photosensitizer can only cause light damage near the generation of¹O₂.Therefore,the efficiency of PDT is largely dependent on the accumulation and subcellular localization of photosensitizers in cells.To address this problem,an existing solution is to deliver photosensitizers to specific organelles to generate ¹O₂in situ,thereby increasing the efficiency of phototoxicity.Mitochondria,as the main intracellular power source and an important ROS source,are potential targets of PDT.Unfortunately,most photosensitizers are insoluble in water,limiting their effective biocompatibility and cellular permeability.To this end,we developed a water-soluble photosensitive small molecule（TPE-CHO）with positive charge,and designed it as a porous organic polymer（TPE-POP）.TPE-POP not only has a strong ¹O₂conversion efficiency for PDT,but also can target suborganelle-mitochondria,thereby disrupting mitochondrial function and maximizing the efficacy of PDT.Meanwhile,compared with small molecules,TPE-POP showed a longer retention time at the tumor site,which solved the problem of rapid removal of small molecule photosensitizers from tumors.（5）Emerging therapies such as PDT/CDT have greatly advanced the field of cancer treatment,but the introduction of anticancer drugs/materials inevitably distributes to certain normal tissues and damages these tissues.Therefore,the safest method is to use the intrinsic substance of TME and convert it into toxic agent in situ after reaching the tumor.Among many therapeutic approaches,protein therapy is considered the safest and most direct way to control cell function and treat human diseases.How to transport protein safely and effectively through cell membrane to intracellular target and play an effective role is still a big problem in the field of protein therapy.Based on this,we designed a biologically-mineralized metal-polyphenol nanoreactor coated with two enzymes,which integrates starvation therapy,CDT therapy and protein therapy.Manganese-tannic acid（MT）nanocomposite was used as the carrier of toxic protein（RNase A）and GOD to achieve synergistic enhancement effect between protein therapy and CDT.It was found that RNase A was effectively delivered under the protection of calcium carbonate（Ca CO₃）mineralized layer,and the high oxidation environment created by MT induced CDT could in turn enhance the activity of RNase A.The introduction of GOD not only induces starvation treatment,but also generates H₂O₂and promotes CDT of MT.In general,the three therapies interact with each other and enhance synergistically,achieving excellent tumor suppression/elimination in tumor therapy.