M2 Macrophage-Targeted Iron Oxide Nanoparticles For Magnetic Resonance Image-Guided Magnetic Hyperthermia Therapy

Cancer has become a common public health problem in the world.Its morbidity and mortality are increasing year by year,and it has become the main cause of death in many countries including China.Tumors have complex microenvironments that play a fundamental role in malignant tumor progression as well as therapeutic resistance.As a crucial driver of tumour-promoting inflammation,macrophages are a main component of the immune cell infiltration in tumor microenvironments(TME)and also known as tumor-associated macrophages(TAMs).Hyperthermia therapy is an emerging tumor treatment method,it has many advantages,such as a wide range of applications,no radiation,and enhancing other therapies.In hyperthermia,tumor tissues are particularly impressionable to high temperature due to their rapid cell proliferation,enhanced hypoxia,low pH,and insufficient temperature regulation ability.At a mild temperature exceeding 42?,the tumor cells killed by destroying the natural enzymatic process.Magnetic hyperthermia therapy(MHT)is a classical hyperthermia approach,which have the excellent tissue penetration ability.Today,MHT has already demonstrated desirable therapeutic efficacy for the treatment of deep tumors in clinic.In cancer MHT,superparamagnetic iron oxide(SPIO)nanoparticles have been attracting attention.They have excellent biocompatibility and can not only be used as hyperthermia agents,but also as a contrast agent for magnetic resonance imaging,which can provide diagnostic information and visualize their distribution in vivo to guide the optimal therapeutic time window.In addition,previous studies have shown that SPIO nanoparticles can induce the polarization of macrophages to the M1 phenotype(anti-tumor)and inhibit tumor growth and metastasis.Therefore,SPIO-based multifunctional nanoplatform has great potential for clinical treatment.TAMs contribute to tumour progression at different levels.It can promoting genetic instability,nurturing cancer stem cells,supporting metastasis,and taming protective adaptive immunity.M2 TAM is a polarization state of TAM,which can promote tumor growth by facilitating tumor progression and malignant behaviors.Therefore,selectively targeted elimination of M2 TAMs to inhibit tumor progression is of great significance for cancer treatment.According to recent reports,an M2 macrophage-binding peptide(M2pep)identified by phage display has high-efficiency targeting ability to M2 macrophages and is an excellent candidate for the targeted delivery of theranostic nanoagents to M2 macrophages in cancer treatment.Accordingly,this article developed a typical M2 macrophage-targeted peptide(M2pep)functionalized superparamagnetic iron oxide(SPIO)nanoparticle for magnetic resonance imaging(MRI)-guided MHT in an orthotopic breast cancer mouse model.The main work is as follows:(1)This article has developed M2pep functionalized SPIO nanoparticles(SPIO-M2pep),and its morphology,particle size,surface modification,magnetic properties and the magnetocaloric performance are evaluated.The research results show that SPIO-M2pep is spherical magnetic nanoparticles with a particle size of about 20 nm.The hydrodynamic diameter is about 38.95 nm,and the zeta potential is about-36.4 mV.SPIO-M2pep have similar magnetic properties and magnetic hyperthermia properties to SPIO,and have the potential to be used in magnetic resonance imaging and magnetic hyperthermia.(2)This paper studies the in vitro M2 macrophage targeting ability,magnetic hyperthermia performance and magnetic resonance imaging ability of SPIO-M2pep.The research results show that SPIO-M2pep has good biological safety,can effectively targets M2 type macrophages and mediate magnetic hyperthermia.At the same time,SPIO-M2pep has excellent in vitro magnetic resonance imaging capabilities.(3)This article studies SPIO-M2pep mediated magnetic resonance imaging-guided magnetic hyperthermia in vivo,and explores its anti-tumor mechanism.The results of the study show that SPIO-M2pep can display tumor regions in the body through T2 magnetic resonance imaging,and mediated M2 TAM targeted MHT which can effectively inhibit tumor growth and metastasis,and has good safety.SPIO-M2pep based MHT can effectively eliminate M2 TAM in tumor tissues and cause M2 TAM to polarize to the M1 phenotype.After MHT targeting M2 TAM,the tumor immune microenvironment(TIME)changes,the tumor infiltration and activation of CD8+T cells are enhanced,and the cytokines in TME tend to be anti-tumor.The SPIO-M2pep developed in this paper has the ability to target M2 macrophages,high magnetic hyperthermia efficiency,MR imaging capability and the ability to remodeling TIME,so it has great potential to improve clinical cancer therapy outcomes.