Differently Charged Super-Paramagnetic Iron Oxide Nanoparticles Preferentially Induced M1-Like Phenotype of Macrophages

Abstract

Macrophages are mainly divided into two phenotypes: M1-like (anti-tumoral, proinflammatory) and M2-like (pro-tumoral, anti-inflammatory). The more abundant M2-like phenotype of tumor associated macrophages (TAMs) has been associated with poor prognosis in various cancers, therefore, many studies have been carried out to modulate TAMs to change from an M2 to M1-like phenotype as an effective way to suppress tumor growth. Previous study indicated that the FDA-approved Ferumoxytol is an iron oxide nanoparticle that has intrinsic tumor inhibiting properties and is accompanied by the increased presence of the pro-inflammatory, anti-tumoral M1-like phenotype. Intrigued by this finding, we hypothesize that differently charged superparamagnetic iron oxide nanoparticles (SPIONs) would have preferential differences in polarizing macrophages. Herein, we report that differently charged SPIONs have distinct preferences in the modulation of TAM phenotypes. Positively charged SPION (S+) had the highest cellular uptake and highest macrophage polarization effect. Interestingly, although negatively charged SPION (S−) should present charge-charge repulsion with cell membranes, they showed considerably high uptake in vitro, nevertheless presenting the highest cellular toxicity. Neutrally charged SPION (SN) showed minimal uptake and cellular toxicity in vitro. Both S+ and S− could effectively re-polarize M2-like macrophages toward M1-like macrophages in vitro, and significantly increased the Fenton effect and chemotaxis of macrophages. When macrophages pre-treated with these SPIONs were co-injected with tumor cells to obtain a tumor xenograft, S+ and S− treated macrophages significantly induced tumor retardation, indicating the successful repolarization of tumor macrophages by these SPIONs. Taken together, we provide an insight on the importance of SPION charge in immunomodulation of macrophages.

The Iron Curtain: Macrophages at the Interface of Systemic and Microenvironmental Iron Metabolism and Immune Response in Cancer

“…Such nanoparticles are able to polarize RAW264.7 macrophages to an M1-like phenotype characterized by elevated expression levels of TNF-α, INOS, CD11b, and CD80. ROS is also enhanced in tumor cells by iron nanoparticles that triggers caspase 9 expression and apoptosis ( 77 ). Additionally, nanoparticles alone and in combination with other therapeutic intervention such as photothermal therapy promote tumor associated antigen release and recruitment of T-helper and T-effector cells at the tumor site through repolarization of M2 TAMs to the M1 phenotype ( 78 ).…”

Activatable superparamagnetic iron oxide nanoparticles scavenge reactive oxygen species in macrophages and endothelial cells

“…It is well established that iron oxide triggers increased reactive oxygen species production in cells through the Fenton reaction. [61][62][63] Yarjanli et al reported that iron oxide contributes to the Fenton reaction by a catalytic process that converts mitochondrial hydrogen peroxide to hydroxyl free radicals, thereby increasing intracellular ROS. 64 The Fenton reaction occurs when ferric iron (Fe 3+ ) reacts with cellular hydrogen peroxide to produce ferrous iron (Fe 2+ ), hydroperoxyl free radical (HO 2 ), and hydrogen ion (H + ).…”

The Use of Iron Oxide Nanoparticles to Reprogram Macrophage Responses and the Immunological Tumor Microenvironment

“…Two opposite charged IONPs induced an M1-like phenotype in RAW 264.7 macrophages, although negatively charged IONPs appeared to be more potent in promoting this effect (98) and neutral IONPs have a negligible impact. The crucial role that such M1-differentiated macrophages can play within the TIME was also addressed and there was significant tumor growth retardation when IONP + or IONPtreated macrophages were co-inoculated with HT1080 human fibrosarcoma cells, reflecting the anti-tumor effect of these repolarized M1-like macrophages (98).…”