Facile Preparation Of Iron-Based Nanomaterials And Its Applications For Tumor Theranostics

As an important endogenous trace element,iron is widely distributed in various tissues of human body.Recent advances in the development of new iron-based nanomaterials(IONMs)have shown promise in the development of new therapeutic approaches for clinical management of cancer patients.The unique physicochemical properties of IONMs endow them with novel multifunctional capabilities for MR imaging,drug delivery and tumor therapy.However,there still exist many problems and challenges.Firstly,the preparation is complicated with harsh conditions,poor production,diagnosis and treatment efficiency.Thus,the clinical transformation process is hindered to a certain extent.Secondly,the specificity,responsiveness and contrast effect of iron-based nanoparticles used in Ti-weighted MRI imaging of tumors as reported need to be further improved.Thirdly,innovative oncology therapies based on iron nanomaterials still need to be explored.Therefore,this thesis aims to design and construct different iron-based nanotheranostic systems with simple synthesis,good biosafety,high responsiveness to tumor microenvironment,sensitive MRI diagnosis and outstanding therapeutic performance.The first part presented a glutathione(GSH)-responsive hyaluronic acid-coated iron oxide nanoparticle(HIONP)for highly sensitive diagnosis of liver metastases and MRI-guided tumor photothermal therapy through a facile one-pot method.In brief,the ferrous sulfate was added to the pre-mixed aqueous solution containing HA-DA and tannic acid(TA),and then NaOH was used to create an alkaline environment.The oxygen in the air and alkaline solution facilitated the oxidation of ferrous ions to IONP with the assistance of tannic acid,and the HA conjugated with dopamine was attached onto the nanoparticle surface through phenol-metal coordination,leading to the formation of HIONP.The coordination effect could be broken up by high concentration of GSH,leading to the accumulation of the iron oxide nanoparticles and changes of MRI properties.Therefore,as HIONP accumulates in the liver,the high GSH in the liver induce the aggregation of IONPs,which decrease MRI signal in the liver as a T2 contrast agent(CA).By contrast,HIONP that enters metastatic tumors increases the MRI signal in the tumors as a T1 CA.As a result,the contrast between metastatic tumors and normal tissues will be greatly enhanced,remarkably increasing the sensitivity of metastatic tumor diagnosis by MRI.Moreover,HIONP has excellent photothermal therapy property due to the IONPs in it,making it also a promising theranostic agent for MRI-guided photothermal therapy.In the second part,we proposed to prepare an iron-based a coordinated nanosystem(LPNP)with cascade amplified oxidative stress and immunogenic cell death for enhanced synergistic chemodynamic-immune cancer therapy.LPNP was engineered by self-assembly of the superior ROS inducer(β-lapachone,β-LP),HA-DA,TA,and ferric iron via metal phenolic coordination.LPNP could accumulate in the tumor tissues and acidic tumor microenvironment made the outside coating degrade to release Fe3+,TA,HA-DA accompanied by exposure of β-LP.The release of β-LP made a remarkable increase of the H2O2 via NQO1 catalysis.Meanwhile,the released TA could reduce Fe3+into Fe2+due to its reductive ability.The elevated H2O2 would subsequently react with Fe2+,leading to a sequential and amplified-OH generation,thus collectively resulting in elevated intracellular oxidative stress and remarkably improved immunogenic cell death(ICD).As such,the above nanosystem formed remarkable synergism with PDL1 peptide,exhibiting excellent anticancer performance for both treated primary tumor and untreated distant tumors.Briefly,this nanosystem with a simple fabrication process could achieve pH-sensitive decomposition with cascade amplified oxidative stress,enhanced ICD,and thus greatly merits their clinical translation.In the third part,we have developed a degradable metal-polyphenol complex(SNP)containing a core of simvastatin(Siva),a GPx4 inhibitor,and Fe3+-hyaluronic acid conjugated with dopamine(HA-DA)-tannic acid(TA)shell via coordination interaction.The Fe3+ could be easily reduced to Fe2+ by TA in acidic conditions,and then Fenton reaction occured with endogenous H2O2 and Fe2+,causing lipid peroxidation(LPO).The Siva induced inhibition of GPx4 promoted the ferroptosis via Fenton reaction caused by Fe3+ under acid tumor environments.Taken together,the rationally designed SNP provided a new strategy for self-amplified ferroptosis therapy with good biocompatibility.