Biomedical Application Of Iron-Based Nanomaterials In Tumor Immunotherapy

Cancer immunotherapy has become one of the most innovative treatment and received great attention.Immunotherapy produces anti-tumor response based on the mechanism of patient's own defense and has specificity for specific tumor,which can overcome the non-specific shortcomings of the traditional cancer treatment.Meanwhile,immunotherapy can prolong the anti-cancer immune response of patients through immunological memory,leading to the inhibition of tumor metastasis and recurrence as well as the improvement of the patients' survival rate.Tumor immunotherapy methods include tumor vaccine,adoptive cell therapy,monoclonal antibody immune checkpoint,the remodulation of immune tumor microenvironment(TME)et al.At the present,nanomaterials have been widely used as carriers to deliver vaccines,adjuvants and immune checkpoint antibodies for tumor immunotherapy.Iron based nanomaterials have been applied to tumor treatment because of their special physicochemical properties on the repolarization of tumor associated macrophages(TAMs).Additionally,iron-based materials perform unique advantages over other inorganic materials on the excellent biocompatibility.In this paper,various iron-based nanomaterials were designed to construct the combined tumor immunotherapy system,realize the remodeling of immune TME through reprograming TAMs,and combine immunotherapy with chemotherapy and gas therapy to realize tumor treatment.The main contents are as follows:1.Designing an immuno-gas therapy system for breast cancer.Hollow iron oxide(Fe3O4)nanoparticles,coated with acid responsive polyacrylic acid on its outer layer,were prepared to loading L-arginine and the functional nanoparticle(LPFe3O4)was obtained.When LPFe3O4 reached the tumor region,Fe3O4 nanoparticles reprogramed TAMs from M2 to M1.Considering the important regulatory role of TAMs,the immune TME has also changed from immunosupressive to immunostimulatory,which was along with recruiting of CD4+and CD8+T cells,secreting of antitumor inflammatory cytokines,attacking tumor cells to realize tumor immunotherapy.Meanwhile,LPFe3O4 could loosen the polyacrylic acid polymer chain in response to the acidic TME and release L-arginine.Because of the high expression of nitric oxide synthase(iNOS)in M1 TAMs,L-arginine can be catalyzed to produce NO and kill tumor cells.The gasous immunotherapy could kill the tumor efficiently,inhibit the tumor metastasis and recurrence,improve the survival rate of mice.2.Designing an immuno-chemotherapy system for the multi drug resistance of breast cancer.The Au nanocage was synthesized and the chemotherapeutic drug DOX was encapsulated into the cavity of the Au nanocage by phase change material(PCM).The carbonate layer(FeCaC)was wrapped on the outer layer of the Au nanocage to form the functional nanoparticle(DPAu@FeCaC).When DPAu@FeCaC was enriched in tumor area,the Fe element on the FeCaC layer promoted the repolarization of TAMs.The effector molecule produced by M1 macrophages could inhibit the expression of Pglycoprotein(P-gp)in MCF-7/ADR cells,which removed the obstacle of chemotherapy.Acidic TME availed the degradation of FeCaC shell.After near-infrared light irradiation,photothermal effect caused the phase change of PCM and released Dox,performing the effect of chemotherapy.The combined immuno chemotherapy treatment function has greatly improved the treatment efficiency of multi drug-resistance in breast cancer.3.A series of polyacrylic acid encapsulated hydroxyl iron oxide(PFeOOH)nanorods with the same aspect ratio but the different scale were designed and prepared to explore the effect of nanorod size effect on the reprograming ability of TAMs,and confirmed its potential combined immunochemotherapy efficiency.It was found that the cellular uptake and iron ion release ability of PFeOOH nanorods could affect their reprograming ability.The more cellular uptake,the more iron ions release,and the stronger the reprograming ability;The shortest PFeOOH has the strongest reprograming ability.Based on the result,when PFeOOH-1 nanorods delivered Dox to the tumor area,the released Dox could cause immunogenic death(ICD)and the immune TME remodeling caused by PFeOOH-1 enhanced the antitumor immune response including stimulating dendritic cell maturation,recruiting T cells.and inhibiting tumor growth,metastasis and recurrence.