Construction Of Nanoscale Covalent Organic Frameworks For Cancer Therapeutics

Cancer is a serious disease that threatens human health.In the continuous search for cancer diagnosis and treatment,nanomedicine has flourished.Numerous novel therapeutic approaches,such as phototherapy,targeted therapy,immunotherapy,and catalytic therapy,have achieved success to a certain extent in the laboratory and preclinical stages.Covalent organic frameworks（COFs）,among various nanomaterials,have become a member of the candidate library of nanomedicine materials due to their high crystallinity,highly ordered structure,inherent porosity,versatility,and favorable biocompatibility.However,many COFs are synthesized by solvothermal processes,which are difficult to produce on a large scale.More importantly,their particle size is usually in the micrometer range and thus their dispersibility is poor,which cannot fully meet the requirements of biomedical applications.In fact,mass producing nanoscale COFs under mild conditions remains challenging.In addition,the ease of functionalization of COF makes it a potential platform for combination therapy that has not yet been fully exploited.In Chapter 1,the application of COFs in tumor therapy is reviewed.First,the structural characteristics and synthesis methods of COFs are briefly described.Then,the application of COFs in tumor therapy is summarized,including drug delivery,photodynamic therapy,photothermal therapy,chemodynamic therapy,sonodynamic therapy,radiotherapy,gene therapy,and combination therapy.Finally,the remaining challenges and possible future development trends of COFs in oncotherapy are discussed to inspire further contributions and developments in this nascent but promising field.In Chapter 2,a series of imine-linked COFs are synthesized using benzyl ethers and aromatic amines as organic monomers via visible-light-induced photocatalytic oxidation and imine condensation.The synthesis is performed under ambient conditions and is expanded to the gram-scale.This strategy,which results in imine-linked COFs possessing a uniform particle size with regular spherical morphology that may be particularly suitable for biomedical applications,is an improvement to the conventional solvothermal method.For example,the resulting RT-COF-1 has a particle size of less than200 nm and is a promising nanocarrier for loading lonidamine for selective tumor treatment via chemotherapy.It is believed that this concept of COF synthesis based on photocatalytic cascade reactions expands the scope for imine-linked COFs and significantly enriches the nanoscale COF synthetic methodology.In Chapter 3,a porphyrin photosensitizer and a naphthalocyanine photothermal agent are incorporated into COF nanoparticles via bonding defect functionalization and guest encapsulation,respectively,and the multifunctional nanomedicine VONc@COF-Por for combined photodynamic and photothermal therapy is designed and synthesized.Upon visible（red LED）and NIR（808 nm laser）irradiation,the obtained VONc@COF-Por exhibits high ¹O2 generation and photothermal conversion ability（55.9%）,thus providing an excellent combined therapeutic effect on inhibiting MCF-7 tumor cell proliferation and metastasis,which is well demonstrated by in vitro and in vivo experiments.This combination therapy based on nanoscale COFs not only provides a method for large-scale synthesis of highly crystalline COFs at room temperature,but also promotes the application of COFs in biomedical fields.In Chapter 4,a multifunctional COF nanomedicine,CaCO₃@COF-BODIPY-2I@GAG,for photodynamic therapy and inducing calcium overload against colorectal cancer is prepared by integrating the BODIPY photosensitizer,CaCO₃ nanoparticles,and glycosaminoglycan targeting agent on a COF nanoplatform.Under green LED irradiation,singlet oxygen generated by BODIPY can not only kill tumor cells directly,but also cause calcium overload by destroying mitochondrial function.The glycosaminoglycan coating,as a specific targeting agent of the CD44 receptor on the surface of gastrointestinal tumor cells,significantly promotes the accumulation of the nanoparticles in HCT-116 colorectal cancer cells and tumor tissues.The resulting nanomaterial exhibits high antitumor activity against colorectal cancer and negligible side effects against normal tissues.This combination therapy strategy not only highlights the feasibility of COFs as a nanoplatform for multifunctional combination therapy,but also suggests that modulation of cell homeostasis may be one of the effective strategies for cancer therapy.In Chapter 5,a vinyl-decorated nanoscale COF was prepared in aqueous solution.After encapsulating a Ru（Ⅱ）-based photocatalyst,the obtained Ru（Ⅱ）@COF-V efficiently catalyzes the thiol–ene click reaction between vinyl and cysteine upon visible-light irradiation.Ru（Ⅱ）@COF-V preferentially accumulates in lipid droplets of tumor cells via lipid raft-and caveolin-related endocytosis and induces lipid peroxidation and ferroptosis by consuming cysteine,exhibiting powerful therapeutic activity against colon cancer.It believe that this study both enriches the ambient synthesis of nanoscale COFs and highlights the feasibility of intracellular photochemical reactions for tumor therapy.In summary,we have developed room-temperature synthesis methods of nanoscale COFs and synthesized a variety of COF-based nanomedicines by a series of functional methods,which may facilitate the development of cancer therapeutics.