Preparation Of Multifunctional Iron-based Nanoplatform And Application In Tumor Therapy

Malignant tumors have become a severe threat to human health because of the high incidence and difficulty of cure.However,traditional approaches(such as surgical resection,chemotherapy,and radiation therapy)have limitations such as significant side effects and undesirable complications.Therefore,there is an urgent demand to develop tumor treatment strategies with biosafety and specificity.In recent years,chemodynamic therapy(CDT)and ferroptosis have been widely studied as precise tumor treatment strategies.In the tumor microenvironment(TME),CDT selectively induces the Fenton reaction to generate reactive oxygen species(ROS)to eliminate tumors.Ferroptosis induces the accumulation of lipid peroxidation(LPO)in tumor cells by iron ions,causing oxidative death of tumor cells.Nevertheless,the therapeutic efficacy of CDT and ferroptosis are affected by the rate of Fenton reaction,and the level of glutathione(GSH)and hydrogen peroxide(H2O2).Combined with other therapeutic modalities,the efficacy of CDT and ferroptosis can be improved,resulting in efficient tumor elimination.Herein,a series of multifunctional iron-based nanomaterials was designed and constructed for tumor treatment.The specific contents are as follows:Part Ⅰ:Preparation of a multifunctional polypyrrole/iron nanoplatform for tumor cell therapy.Fenton reaction-induced CDT,near-infrared laser-mediated photothermal therapy(PTT)and photodynamic therapy(PDT)were integrated into a simple nanocomposite to achieve a tri-modal synergistic treatment.Firstly,FeCl3 was used as an oxidizer for pyrrole monomer polymerization to obtain polypyrrole/Ferrum(PPy(Fe))nanoparticles.PPy(Fe)was surface-modified with bovine serum albumin(BSA)and loaded with photosensitizer IR820 to produce PPy(Fe)-IR820-BSA.The physicochemical analysis data revealed that PPy(Fe)-IR820-BSA was successfully prepared.They had good photothermal conversion properties and concentration-dependent ROS generation ability.PPy(Fe)-IR820-BSA has good cytocompatibility and can be effectively internalized by cells.The percentage of positive tumor cells can reach up to 80%when incubated with 40 ppm PPy(Fe)-IR820-BSA for 4 h.Under NIR laser irradiation,PPy(Fe)-IR820-BSA could generate heat and ROS effectively for tumor treatment.Furthermore,immunogenic cell death was also activated in the treatment process.The developed multifunctional polypyrrole/Ferrum nanoplatform has potential in synergistic tumor treatment applications.Part Ⅱ:Preparation of an autophagy-inhibiting iron-based nanoplatform for enhanced ferroptosis against tumor.Herein,ferric phosphate(FePi)nanosheets were prepared by hydrothermal method,followed by polyethylene glycol(PEG)modification to improve biocompatibility.After doxorubicin(DOX)loading,FePi-PEG@DOX nanosheets were prepared.FePi-PEG@DOX can respond to the acidic tumor microenvironment to release DOX,Fe3+,and PO43-.DOX provides H2O2 for Fenton reaction,and Fe3+ irons are converted into Fe2+by GSH to generate ROS.When GSH is depleted to destroy the intracellular redox balance,lipid peroxidation(LPO)is continuously produced and accumulated to induce ferroptosis.PO43-regulates lysosomal pH to inactivate its self-repairing capacity,further enhancing the therapeutic effect of ferroptosis.The physicochemical analysis data revealed that FePi-PEG@DOX was successfully prepared.They display good stimuli-responsive performance.Under the acidic and GSH-containing conditions,about 81.2%of DOX can be released from FePiPEG@DOX within 24 h.The cell study showed that the FePi-PEG and FePi-PEG@DOX groups had more cytotoxicity than the DOX group.The killing mechanism of FePiPEG@DOX against tumor cells was ascribed to the produced ROS,indicating that ferroptosis played a vital role in cell death.Western blotting results showed that essential proteins of apoptosis,and autophagy,such as Caspase-3,p62,and LC3B,were overexpressed in tumor cells.Meanwhile,GSH and LPO levels were decreased and increased,respectively.Finally,the synergistic therapeutic effect of FePi-PEG@DOX in vivo was proved to be effective.FePi-PEG@DOX also displayed good biocompatibility.These autophagy-inhibiting iron-based nanosheets have great potential in future tumor therapy applications.