Application Of Multifunctional Nanoscale Metal-Organic Frameworks In Tumor Theranostics

Cancer,one of major threats to the human health,possesses intricate structure and constituents distinctive from normal organs and tissues.It has been well recognized that the unique tumor microenvironment（TME）would promote tumor progression and metastases,and in the meanwhile result in resistance of tumors to different types of therapies.Therefore,it would be meaningful to design nanomedincine that could respond and improve TME for enhanced cancer therapeutic efficiency.Additionally,nanoscale metal-organic frameworks（NMOFs）and nanoscale coordination polymers（NCPs）are a class of hybrid materials formed by the self-assembly of metal ions or clusters and organic polydentate bridging ligands.Owing to the diversity of structural and physicochemical properties,high loading capacity and natural biodegradability,NMOFs/NCPs have shown great promise in the field of biomedicine.In this dissertation,we construct several NMOFs/NCPs with various morphologies and features based on TME responsive ligands（such as acidity,redox,etc.）or therapeutic ligands（photosensitizers,cisplatin prodrugs,etc.）and different metal ions（manganese,hafnium,etc.）for diagnosis and enhanced treatment of cancer.Furthermore,the metabolic behavior of NMOFs/NCPs in mice is also studied.We find that NMOFs/NCPs could be gradually cleared from mice through feces and urine without causing obvious side effects.The main findings are as follows:Chapter 1:The development of NMOFs/NCPs and its application in biomedicine is briefly summarized.We systematically introduce the synthesis methods and cancer treatment of NMOFs/NCPs.The motivations of our research in this dissertation are discussed.Chapter 2:NMOFs for combined photodynamic&radiation therapy of cancer.We report the rational design of a NMOF composed by hafnium(Hf⁴⁺)and tetrakis（4-carboxyphenyl）porphyrin（TCPP）.In such Hf-TCPP NMOFs,while TCPP is a photosensitizer to allow photodynamic therapy（PDT）,Hf⁴⁺with strong X-ray attenuation ability could serve as a radio-sensitizer to enhance radiotherapy（RT）.Those NMOFs with polyethylene glycol（PEG）coating show efficient tumor homing upon intravenous injection,and thus could be used for in vivo combined RT&PDT,achieving a remarkable anti-tumor effect.Importantly,Hf-TCPP NMOFs show efficient clearance from the mouse body,minimizing concerns regarding their possible long-term toxicity.Chapter 3:Light-controlled drug release from singlet-oxygen sensitive NCPs enabling cancer combination therapy.NCPs constructed from hafnium ions and bis-（alkylthio）alkene（BATA）,a singlet-oxygen responsive linker,are fabricated and applied as nanocarriers to realize light-controlled drug release under a rather low optical power density.In this system,NCPs synthesized through a solvothermal method are sequentially loaded with chlorin e6（Ce6）,a photosensitizer,and doxorubicin（DOX）,a chemotherapeutic drug,and then coated with lipid bilayer to allow modification with polyethylene glycol（PEG）and acquire excellent colloidal stability.The singlet oxygen produced by such NCP-Ce6-DOX-PEG nanocomposite can be used not only for photodynamic therapy,but also to induce the break of BATA linker and thus the destruction of nanoparticle structures under light exposure,thereby triggering effective drug release.Notably,with efficient tumor accumulation after intravenous injection as revealed by CT imaging,those NCP-Ce6-DOX-PEG nanoparticles could be utilized for combined chemo-photodynamic therapy with great antitumor efficacy.Chapter 4:pH-sensitive dissociable nanoscale coordination polymers with drug loading for synergistically enhanced chemo-radiotherapy.We design NCPs based on acidic sensitive linker and high Z number element hafnium（Hf）ions.Chloro（triphenylphosphine）gold（I）（TPPGC）,a chemotherapeutic drug,was successfully loaded into those NCPs after they are coated with polyethylene glycol（PEG）.Owing to the acid-triggered cleavage of the organic linker,such formed NCP-PEG/TPPGC nanoparticles would be dissociated under reduced p H within the tumor,leading to the release of TPPGC to induce mitochondrial damage and arrest the cell cycle of tumor cells into the radio-sensitive phase（G1）.Meanwhile,Hf ions are able to act as radiosensitizers by absorbing X-ray and depositing radiation energy within tumors.With efficient tumor accumulation after intravenous injection,NCP-PEG/TPPGC offers remarkable synergistic therapeutic outcome in chemo-radiotherapy without appreciable toxic side effect.Chapter 5:Nanoscale-coordination-polymer-shelled manganese dioxide composite-nanoparticles:a multi-stage redox/pH/H₂O₂-responsive cancer theranostic nano-platform.In this work,manganese dioxide（MnO₂）nanoparticles stabilized by bovine serum albumin（BSA）are encapsulated by NCP-shells constructed based on high Z element hafnium（Hf）ions and c,c,t-（diamminedichlorodisuccinato）Pt（IV）（DSP）,a cisplatin pro-drug.After further modification with polyethylene glycol（PEG）,the formed BM@NCP（DSP）-PEG could simultaneously serve as a radio-sensitizer owing to the strong X-ray attenuation capability of Hf to enhance radiotherapy,as well as a chemotherapeutic agent resulting from the reduction-induced release of cisplatin.Meanwhile,the in-situ generated oxygen resulting from MnO₂-triggered decomposition of tumor endogenous H₂O₂ would be greatly helpful for overcoming hypoxia-associatedradio-resistance.Uponintravenousinjection,BM@NCP（DSP）-PEG shows efficient tumor homing as well as rapid renal excretion,as illustrated by magnetic resonance（MR）imaging and confirmed by biodistribution measurement.Notably,excellent in vivo tumor growth inhibition effect is observed with BM@NCP（DSP）-PEG nanoparticles after the combined chemo-radiotherapy treatment.Chapter 6:pH sensitive NCPs as collagenase（CLG）carrier for TME modulation and enhanced PDT.We fabricate a novel NCPs based on acidic sensitive linker and Mn²⁺in aqueous solution.After adding CLG into this system,the nanoparticles would grow around the enzyme and encapsulate them in the nanostructure,obtaining NCP@CLG nanoparticles.After PEGylation,NCP@CLG-PEG nanoparticles show great water solubility and physiological stability.Upon i.v.injection,NCP@CLG-PEG would accumulated at the tumor site and release CLG due to the disruption of the NCPs structure under weak acidity of TME.The released CLG degrades collagen of extracellular matrix in TME and then leading to the lowered interstitial fluid pressure,increased blood perfusion and relieved hypoxia in the tumor.Furthermore,the following i.v.injected therapeutic agents Liposome@Ce6 would penetrate deeply into the tumor and realize improved PDT effect.In summary,NMOFs/NCPs with various structures are fabricated through different methods for cancer combination therapies.Importantly,these NMOFs/NCPs show great responsibility to TME and then leading to the drug release or enhanced cancer therapy.It would be useful for the development of NMOFs/NCPs in biomedicine.