Covalent/metal-organic Frameworks Based Nanomedicines For Cancer Therapy

Cancer generally refers to all malignant tumors,which are formed by the mutation of proto-oncogene and tumor suppressor gene when normal cells are exposed to the action of physical,chemical,viral and other carcinogenic factors.Cancer has become one of the diseases with the highest morbidity and mortality in the world.How to effectively treat cancer remains a major problem.At present,the conventional clinical treatments of cancer are still surgery,radiotherapy,and chemotherapy.There are many problems with conventional treatment methods,such the recurrence of tumors and poor therapeutic effect.Many new cancer treatment methods have emerged,such as photodynamic therapy,chemodynamic therapy,immunotherapy,etc.However,they also have some insurmountable problems,such as the limited depth of tissue penetration during the photodynamic therapy,the low efficacy of chemodynamic therapy in the tumor microenvironment and the low response efficiency to immunotherapy.In addition,it is difficult to avoid its own defects for single cancer treatment,leading to poor treatment results.Nanomaterials are good drug carriers because of their unique nano-size,pore structure and good biocompatibility.Using nanomaterials as drug carriers combine with multiple therapeutic approaches has the potential to overcome these problems,and many nanocarriers have already shown great potential for cancer therapy.Organic framework based nanomaterials are one of the research hotspots.As an important new type of materials,covalent/metal-organic frameworks have been widely used in the biomedical field due to their porous structure,large specific surface area,safety and non-toxicity.It is a promising strategy to develop functional covalent/metal-organic nanomedicines for drug delivery and multimodal therapy of cancer.Here,three kinds of organic framework nanomedicines have been designed and synthesized for cancer therapy based on porphyrin covalent organic framework and zeolite imidazole framework.This thesis mainly includes the following three aspects of work:1.A peroxidase-like nanoscale Fe-porphyrin covalent organic framework[COF（Fe）]was designed and synthesized for reversing tumor multidrug resistance（MDR）by chemotherapy and chemodynamic therapy（CDT）.COF（Fe）has good drug loading ability,which could effectively enhance the cellular uptake of doxorubicin（DOX）and mediate its controlled release in cancer cells.Subsequently,the single catalytic sites of Fe in COF（Fe）could catalytically convert intracellular overexpressed H₂O₂ into highly reactive·OH,inducing oxidation stress and deregulating the expression of MDR protein.Therefore,this peroxidase-like COF（Fe）could reduce drug efflux and enhance the intranuclear DOX accumulation to overcome MDR.The tumor growth was greatly inhibited in two mouse models owing to the excellent anti-MDR effect.The current strategy could provide new insights for MDR tumor treatment.2.A one-step method to prepare ultrathin 2D functionalized porphyrin COF nanosheets（NSs）was developed.Tumor-targetable hyaluronic acid（HA）was employed to react with the residual amino groups on the imine-based bulk porphyrin COF.Under ultrasonication,the HA-functionalized COF nanolayers could be exfoliated thus the newly exposed residual groups could be further decorated.Therefore,HA-functionalized ultrathin COF NSs with enhanced reactive oxygen species（ROS）generation effect were prepared.Experimental results showed that the COF NSs had no side effects andcould actively target the tumor site,and enhance the effect of photodynamic therapy.Moreover,the potential of the COF NSs in inducing immunogenic death was also demonstrated.This work presented a new strategy for the preparation of COFs-based nanomedicine.3.A zeolitic imidazole framework-90（ZIF-90）based nanoplatform was explored for cancer therapy,which could initiate a series of mitochondrial cascade reactions using ATP as a molecular switch.Mitochondrial ATP can efficiently degrade ZIF-90 and release the loaded 2-methoxyestradiol（2-ME）and camptothecine（CPT）prodrug.2-ME can inhibit superoxide dismutase（SOD）activity,which induces the up-regulation of reactive oxygen species（ROS）in situ.The thioketal linkers in CPT prodrug can respond to ROS,thereby achieving subsequent release of parent CPT drug.This cascade of reactions can lead to prolonged high oxidative stress and cause continuous cancer cell apoptosis due to the increased ROS level and the liberation of CPT.In vitro and in vivo experiments indicated that the growth of cancer cells and tumor can be efficiently inhibited with the ATP-triggered strategy.