Study On The Synthesis And Antitumor/Antibacterial Activities Of Photodynamic Nanodrugs

The development of nanotechnology has laid a solid foundation for nanomedicine.The diversity of structure,composition and physical/chemical properties of nanoparticles greatly enriches their medical application,which also brings new opportunities for photodynamic therapy.Photodynamic therapy（PDT）,as a non-invasive treatment,is based on reactive oxygen species（ROS）produced by photosensitizers（PS）under light irradiation which resulting in cell death.The low toxic side effects of photosensitizers and the high target tissue selectivity and low damage to normal tissues have attracted much attention in the treatment of cancer and bacterial.The current research on photosensitizers is mainly restricted by hydrophobicity,penetration depth of light source and lack of tissue specificity.Nanotechnology can greatly overcome the limitations of current photosensitizers by constructing multifunctional nanoplatform.Photodynamic nanomedicine provides an system with nanomaterials as carriers,photosensitizers and energy transducer.The versatility of inorganic,organic and organic-inorganic hybrid nanosystems allows photodynamic nanoplatforms to be designed for specific targets to achieve efficient therapeutics with reduced side effects.The research of photodynamic nanomedicine has become a hot topic in contemporary nanomedicine.This dissertation designed and synthesized photodynamic nanomedicines with synergistic effects for tumor and bacteria.The main studies are as follows.（1）Hydroxyl-andcarboxy-containingphenylimidazolophilonines,2-（3-carboxy-4-hydroxyphenyl）imidazo[4,5-f]phenanthroline（phcpip）,2-（2-hydroxy-3-carboxyphenyl）imidazo[4,5-f]o-phenanthroline（ohcpip）and their Ru（II）metal complexes[Ru（bpy）₂phcpip]（Cl O₄）₂ and[Ru（bpy）₂ohcpip]（Cl O₄）₂ were synthesized.Both complexes showed high phototoxicity to lung cancer cells A549,breast cancer cells MCF-7 and MDA-MB-231,and liver cancer cells Hep G2 under light,with low toxicity to human normal gastric mucosal cells GES-1 and umbilical vein endothelial cells Huvec.[Ru（bpy）₂ohcpip]（Cl O₄）₂ complexes showed the highest phototoxicity to Hep G2 cells,even higher than cisplatin.Molecular fluorescence and flow cytometric analysis showed that the complex would cause a elevation of intracellular ROS level while leading to cell cycle arrest in the G2/M phase with a decrease in mitochondrial membrane potential under light conditions,which finally induced cell apoptosis.（2）To overcome the limitation of tissue penetration depth,tumor targeting and PDT efficiency of Ru complex,a multifunctional nanodrug with excellent biocompatibility and responsiveness to the tumor environment was constructed.The prepared UCNP@dm Si O₂（Ru）-Fe₃O₄-GOD@m PEG-SS（UDRFGP）contains large pore size dendritic mesoporous silica coating 808 nm excited upconversion nanoparticles,Ru complex,glucose oxidase and Fe₃O₄.m PEG-SS,glutathione-responsive polymer containing disulfide-bonded were coated for drug release.The NPs could produce singlet oxygen under 808 nm near-infrared light.And the loaded GOD could consumed glucose in tumor cells and generated hydroxyl radicals by cascade reaction with Fe₃O₄.The synergistic effect would significantly increase the level of intracellular reactive oxygen species and cause tumor cell death.The in vivo investigation in BALB/c nude mice showed that the nanomedicine exhibited significant inhibitory effects on Hep G2 liver cancer xenograft tumors at a dose of 5mg kg^-1 without causing significant side effects in major organs.The synergistic system of upconversion photodynamic therapy and enzyme-induced chemotherapy has been sucessfully constructed.（3）Upconversion photodynamic therapy is one of the ideal strategies for the treatment of deep tissue infections.However the insufficient efficiency and low prolonged antimicrobial activity in upconversion photodynamic therapy litmits its applicatoin.The upconversion photodynamic therapy and chemotherapeutic combined antibacterial（UCNP-a PCCT）system were constructed.The natural photosensitizer curcumin and chemical antimicrobial substance camellia saponin derivatives were loaded in double-layer silica coated dumbbell-shaped 808nm activated upconversion nanoparticles.The in vitro experiments showed that the nanoparticles maintained good stability in simulated body fluids and could effectively inactivate E.coli and S.aureus under 808 nm NIR light.The synergistic effect of photodynamic and chemotherapy not only improved the bactericidal efficiency,but also prolonged antibacterial activity.Meanwhile,the low cytotoxicity to Huvec cells shows its good biocompatibility.In summary,a novel new natural product-based UCNP-a PCCT system was realized.（4）A novel defective three-dimensional porous graphite-like carbon nitride（pg-C₃N₄）was synthesized using dendritic mesoporous silica as a template.With combination of ultra-small Fe₃O₄ nanoparticles,pg-C₃N₄-Fe₃O₄ with in situ photo-Fenton ablility were constructed.The material exhibits higher light absorption in the visible light range compared to the general g-C₃N₄,while the photo current is significantly higher as its photo-generated electron-hole recombination rate is reduced.The antibacterial experiments showed that the material was able to completely inactivate E.coli at 1×10⁷ cfu m L^-1 within 1 h under visible light irradiation.The scavenger experiments demonstrated that the main active species is hydroxyl radical（·OH）,but the energy level of the composites indicated that the reaction from water to hydroxyl radical is forbidden.Further electrochemical tests confirming that the material would like to produce H₂O₂ via a two-electron reduction pathway under visible light irradiation.These results demonstrated that the efficient photodynamic sterilization of pg-C₃N₄-Fe₃O₄ was achieved through in situ cascade photo-Fenton reactions.