Application Of Functional Nanoscale Metal-organic Frameworks For Cancer Theranostics

With the rapid development of nanomedicine,fabricating a multi-functional nanoplatform integrating cancer diagnosis and therapy has shown a great prospect in precision theranostics and clinical applications of tumors.Due to the unique properties,especially its versatile crystal structure,metal-organic framework(MOF)nanomaterials hold great potential for personalized nanomedicine.In this dissertation,four kinds of multifunctional MOF nanostructures have been designed and constructed for multi-modal imaging diagnosis and effective synergetic therapy of tumors.1.MOF nanoshuttles for synergistic photodynamic therapy(PDT)and low-temperature photothermal therapy(PTT):new style zirconium-ferriporphyrin(Zr-FeP)MOF nanoshuttles were developed using a facile one-pot hydrothermal method.Under a near-infrared(NIR)laser irradiation,Zr-FeP MOF nanoshuttles could generate abundant reactive oxygen species(ROS)with high cytotoxicity.Zr-FeP MOF had also shown a significant photothermal effect with photothermal conversion efficiency high to 33.7%.With irradiation of a single 635 nm laser,Zr-FeP MOF nanoshuttles loaded with heat shock protein 70 siRNA enabled efficiently to suppress the tumor growth owing to the synergistic effect of PDT and low-temperature PTT.Meanwhile,it exhibited good photothermal imaging,computed tomography and photoacoustic imaging with tri-mode tumor-specific imaging capability for cancer accurate diagnosis.This work has designed an "all-in-one"nanosystem which realized multimodal imaging for diagnosis as well as PDT and low-temperature PTT synergistic treatments of tumor.2.A bacteriochlorin-based MOF nanosheets superoxide radical generator for photoacoustic imaging-guided highly efficient PDT:versatile MOF nanosheets(DBBC-UiO)constructed with bacteriochlorin ligand and Hf6(?3-O)4(?3-OH)4 clusters were designed.Under a 750 nm NIR laser irradiation,the resultant DBBC-UiO MOF could generate numerous superoxide anion radical(O2-·)via a type ?mechanism,a part of which transformed to high toxic hydroxyl radical(·OH)and O2 through superoxide dismutase(SOD)-mediated catalytic reactions under severe hypoxic tumor microenvironment(2%O2),and the partial recycled O2 could further enhance the generation of O2-·.Owing to the synergistic ROS,the advanced antitumor performance of DBBC-UiO MOF exhibited a cell mortality of 91%in vitro,and highly efficient hypoxic solid tumor ablation in vivo.It also acted as a photoacoustic imaging agent for cancer diagnosis.This DBBC-UiO,taking advantage of superb penetration depth of the 750 nm laser and distinct antihypoxia activities,highlighted the great promise for PDT against clinically hypoxic cancer.3.A single NIR light induced multi-mode photodynamic therapy based on upconversion nanoparticles/MOF/TiO2 nanocomposite:a nanoplatform by decorating upconversion nanoparticles(UCNPs)onto the surface of MOFs and covering ultra-small TiO2 nanoparticles were developed,realizing multi-mode PDT through Type I and Type II mechanisms.Under a NIR laser irradiation,UCNPs could generate ultraviolet and NIR light,which not only enabled to stimulate different photochemical reactions of TiO2 and porphyrin,but also accomplished deep penetration of photodynamic therapy.Our photosensitive agent exhibited good biocompatibility and high photodynamic effect,which could meet the needs of different situations of PDT in the future.4.Enhanced cancer therapy and microRNA imaging in vivo by hypoxia-responsive copper-MOF nanosystem(Cu-MOF):a hypoxia-responsive Cu-MOF nanoparticle(NP)loaded with sonosensitizers chlorin e6(Ce6)was developed for glutathione(GSH)-depletion chemodynamic therapy and sonodynamic therapy(CDT/SDT).Meanwhile,Cu-MOF enabled to efficiently carry DNA probe to realize the sensitive imaging detection and real-time dynamic monitoring target microRNA in tumor cells and living tumor tissues.The large size Cu-MOF NPs could be effectively accumulated in the tumor via enhanced permeability and retention effect(EPR),and it degraded and released Cu2+and Ce6 when exposed to hypoxic tumor microenvironment(TME),significantly reinforced the intratumoral penetration.The redox reaction between internalized and GSH induced GSH depletion and reduced Cu2+to Cu+,and Cu+subsequently reacted with endogenous H2O2 to produce high cytotoxic·OH through Fenton-like reaction for CDT,while the released Ce6 fulfilled SDT under US irradiation.The synergistic SDT/CDT efficacy was significantly strengthened due to the reduction of GSH level,achieving selectively and effectively MCF-7 cell killing.Owing to the prolonged blood circulation time,high intratumoral penetration and enhanced CDT/SDT synergistic effect,the Cu-MOF NPs represented as a promising anticancer agent.