Construction Of Tumor Microenvironment-responsive Metal-organic Frameworks And Their Applications To Tumor Therapy

Nowadays,the incidence and mortality of cancer have increased year by year under the influence of environmental pullulation,radiation exposure,bad habits(smoking,drinking,and staying up too late),and other factors.Cancer cells possess strong glycolytic ability,thus leading to hypoxia and slightly acid in tumor site.The characteristic of hypoxia and slightly acid together with higher concentration of H2O2,glutathione and abnormal growth of blood vessels consists of specific tumor microenvironment(TME).TME gives rise to compromised therapeutic efficacy,hypoxia leads to poor effect in chemotherapy and photodynamic therapy,and slightly acid environment made normal cells hard to survive.Therefore,designing materials that specifically respond to or change TME according to the characteristics of the TME can achieve more effective cancer therapeutic effects with minimal side effects.Many multifunctional nanomaterials including manganese dioxide,platinum,carbon nitride have been applied to tumor therapy by responding to TME.But those materials suffer from harsh synthesis conditions,complicated preparation procedures,difficult to modify and load therapeutics,and insensitive to TME,resulting in compromised therapeutic effects.Therefore,construction of multifunctional materials to overcome those above-mentioned barriers for high efficiently treatment of tumors is still a major challenge.Metal-organic frameworks(MOFs)shows great potential in the fields of biomedicine and tumor theranostic due to their advantages such as simple synthesis,chemical diversity,easy modification,and high dose loading of therapeutic agents.Making full use of the advantages of MOFs to design multifunctional nanomodalities that specifically respond to TME can achieve efficient tumor therapeutic effect.For this reason,we have designed and synthesized a variety of MOFs with different structures and properties to efficient cancer treatment by specifically responding to the TME.The main research results of this thesis are as follows:1.Heterogeneously loading of Ce6(Chlorin e6)and DOX(doxorubicin hydrochloride,an antitumor drug)in Ce-MOFs were constructed to realize real-time tumor imaging and combined phototherapy.By choosing the high number of Ce elements as metal nodes and2-methylimidazole as organic linkers,Ce-MOFs heterogeneously load with Ce6 and DOX simultaneously were synthesized through a one-pot method.The heterogeneously loaded Ce6 in the Ce-MOFs achieved synergistic photothermal and photodynamic therapy.Due to its peroxidase-like catalytic activity,the obtained MOF/C&D nanoparticle exhibits the ability to alleviate the hypoxia condition of tumor sites by catalyzing high concentration H2O2 in TME to O2.By modifying the polyethylene glycol(PEG),the as-prepared MOF/C&D-PEG nanoparticles can accumulate in tumors and realize US/PA/CT trimodal imaging-guided chemo-photodynamic and photothermal combinatorial tumor therapy.2.MOFs-derived Mn3O4 nanozyme was designed and applied for nucleolin-targeted enhanced photodynamic therapy.Mn3O4-PEG/C&A nanoprobe was obtained by loading Ce6 and modifying nucleolin-targeting aptamer AS1411 as well as PEG molecules.Functionally,it effectively modulates the TME by catalyzing H2O2 to O2 and compromising excessive glutathione,achieving a highly efficient nuclear-targeted photodynamic therapy.This work opens a new horizon for the design of multi-functional nanozymes for tumor therapy.3.Escherichia coli MG 1655(E.coli)that possesses tumor-targeting ability and ZIF-8(Zeolitic Imidazolate Framework-8)core-shell structure was constructed via a biomineralization strategy and used for drug delivery and synergistic tumor therapy.We fabricated the E.coli@ZIF-8/C&D probe through mineralization of E.coli with ZIF-8 and simultaneously loading with Ce6 and DOX by the one-pot method.Interestingly,E.coli@ZIF-8/C&D can not only accumulate in hypoxia tumor sites in quantity but also realize acid-responsive drug release in slightly acid TME.Thus,it achieves acid-respond concurrently chemo-/photodynamic therapy.This work expands the application potential of living organism mineralization in biomedicine.4.A MOFs-bacterial composite(E.coli-ZIF-8/I&D)was constructed based on metabolic integration and click chemistry,and synergistic chemo/photodynamic/photothermal tumor therapy was achieved by the composite.ZIF-8/I&D was obtained by the one-pot method via simultaneously loading indocyanine green(ICG)and DOX.And then,the as-prepared ZIF-8/I&D nanoparticles were covalently anchored to surface of E.coli through disulfide bondcontained linkers,to obtain the E.coli-ZIF-8 /I&D probe.ZIF-8/I&D can detach from the surface of E.coli by disulfide bond broken due to slightly acidic and reductive TME.In addition,the self-degradation of ZIF-8/I&D in acidic TME further accelerates the release of ICG and DOX in deep tumor tissues,which achieves deep tissue drug delivery.E.coli-ZIF-8 /I&D drug delivery system can respond to the tumor microenvironment cascade,realizing the deep delivery of oncology drugs,and provide a general strategy for preparing the efficient drug delivery system.Based on the above works in this thesis,TME-responsive MOFs and their derivatives with different structures and functions were constructed by the convenient one-pot method.Decidedly,these works provide directions for the future use of MOFs to respond and modulate the TME,and shed light on rational design and controlled fabrication of MOFs,showing significant promises for the development of TME-responsive nano-modalities in the fields of nanomedicine,biomedicine,and biomineralization.