Synthesis Of Nano-Metal-Organic Frameworks And Its Application In Cancer Diagnosis And Therapy

Cancer has been a major threat to human health,which cause nearly 10 million death each year;what’s more,cancer incidence is still rapidly increasing with relatively slow progress made every year in diagnosis and treatment.Over the past quarter of the century,the development of nanotechnology has provided a new solution to cancer theranostics.By combining nanotechnology with previously established cancer research results,a large number of nanomaterials,overcoming the limitations of traditional theranostics effectively,have been widely used in biomedical fields.One of the nanoscale materials-nano-MOFs,have attracted more and more attention in the past decade.A combination of the inherent properties of MOFs and the merits of nanostructures makes nanoMOFs ideal agents for biomedical fields.Nano-MOFs,integrating the merits of nanostructures and MOFs,exhibit many advantages:(1)Nanoparticles with appropriate size range would get enhanced accumulation at tumor sites through the enhanced permeability and retention(EPR)effect,and the prefered accumulation at tumor sites would be further strengthened after active targeting moieties incorporating.(2)As a porous material with a high specific surface area and large pore size,it can load or encapsulate drugs or other biomolecules in large quantities as a carrier;it could also adapt to a variety of different biomolecules due to the tuabable pore size.;(3)Imaging modalities can be introduced by selecting building blocks with imaging capabilities,for example,some fluorescent organic dyes as bridging organic ligand or some specific metal ions could serve as the building units to construct MOFs,thus bringing in magnetic resonance or fluorescence imaging abilities.(4)The surface or inner pores of MOFs could be easily tailored to introduce new features,for example,surface modification with targeting molecules could realize active targeting to cancerous tissues.(5)Many MOFs are biodegradable and can therefore be excreted through metabolic system,and researchers could selectively build MOFs with good biocompatible components,all of which could reduce potential long-term systemic toxicity in human body.With all the advantages above,nano-metal-organic frameworks have great potential to be applied to cancer diagnosis and treatment.Therefore,the superiority of nano-MOFs mentioned above have driven us tosynthesize several novel MOFs based on the work of our group,and further explored their potential application as photothermal agents,MRI contrast agents,two-photon fluorescence probes,drug vehicles.The specific researches are shown as follows:(1)We utilize bio-safe materials including ellagic acid(EA),polyvinyl pyrrolidone(PVP)and iron element as the building blocks,and successfully fabricate homogeneous nanosized Fe-EA framework with rhombohedral morphology for the first time by a facile and green method.As expected,the cytotoxicity tests in vitro,as well as complete blood panel test and serum biochemistry assay in vivo reveal the good biocompatibility of this novel nanoagent,and microenvironment responsiveness(to pH and H2O2)makes it biological degradability.Photothermal potentials of the nanoparticles are demonstrated with relevant features of strong NIR light absorption,good photothermal stability,fairish photothermal conversion efficiency,and in-vivo photothermal therapy also achieved effective tumor ablation with no apparent toxicity.On the other hand,it also exhibit pH-responsive T2 MR imaging ability originated from ferric ions.Our work highlights the promise of Fe-EA framework for imaging-guided photothermal therapy.(2)ZIF-8 has received great attention in recent years as a potential drug vehicle for treatment of cancer due to its acid-responsiveness and moderate biocompatibility.However,its congenital deficiency of intrinsic imaging capability limits its wider applications,therefore a postsynthetic exchange(PSE)approach was utilized to introduce paramagnetic manganese(Ⅱ)ions into ZIF-8 matrix.As a result,manganese doped zeolitic imidazolate framework(Mn-Zn-ZIF)was thus fabricated and exhibited pH-responsive T1-weighted MRI contrast effect.Remarkably,we also found its own fluorescence derived from of 2-methylimidazole,which is the first time to report the intrinsic two-photon fluorescence imaging of ZIFs to our knowledge.Mn-Zn-ZIF still preserve original properties of ZIF-8 as a drug carrier with high surface areas,microporosity and acid-sensitivity.After further PEGylation of Mn-Zn-ZIF,the nanoparticles showed no obvious toxicity and its MRI contrast effect has also been enhanced.Our work highlights the promise of modified zeolitic imidazolate frameworks as potential cancer theranostic platforms.(3)Nanosized Gd-doped hollow coordination polymer has been prepared and after silica coating,the nanoparticles exhibit excellent dual-mode MRI contrast effect with longitudinal relaxivities(r1)of 13.57 mM-1s-1 and transverse relaxivities(r2)of 304.8 mM-1s-1 respectively,higher than those reported for dual T1&T2 probes with single component.Irradiated by laser beams of various wavelengths,the nanoparticles emit multicolor fluorescence due to the π-π*transition of-C≡N-.The multimodal imaging could have complementary effects to make up for the defects of single modality.On the other hand,the hollow-structured nanoparticles have a high loading capacity(1166 mg/g)of the chemotherapeutic drug doxorubicin,showing potentials as a drug delivery system.In vitro cytotoxicity tests reveal the obtained nanoparticles have good biocompatibility.Integrating a multi-modality imaging probe and a drug carrier into a single component enables simultaneous diagnosis and treatment of cancer.