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

Wenyue Zhang,Shuwen Cao,Baoming Luo,Phei Er Saw,Shunung Liang,Chee Hwee Tan,Xiaoding Xu

doi:10.3389/fbioe.2020.00537

Abstract

Macrophages are mainly divided into two phenotypes: M1-like (anti-tumoral, pro-inflammatory) 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 super-paramagnetic 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.

Highlights

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME); in some solid tumors, it counts for up to 50% of the cell population (Komohara et al, 2014; Vitale et al, 2019)
The morphology of differently charged Super-paramagnetic iron oxide nanoparticles (SPIONs) were characterized by transmission electron microscopy (TEM)
TEM images showed that S+ aggregated followed by S−, while SN due to the polyethylene glycol (PEG) coating, did not show any aggregations (Figure 1B)

Summary

Introduction

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME); in some solid tumors, it counts for up to 50% of the cell population (Komohara et al, 2014; Vitale et al, 2019). Researchers investigated many ways to modulate TAMs, to change from M2 into M1-like phenotype, and effectively suppress tumor growth (Gunderson et al, 2016; Kaneda et al, 2016a,b; Song et al, 2016; Rodell et al, 2018), including signaling molecules, inhibitors, transcription factors, agonists, and miRNAs. Iron oxide nanoparticles have been widely used in biomedicine, imaging and drug delivery in preclinical, and clinical settings (Anderson et al, 2019), including photodynamic therapy, anemia, magnetic drug targeting, and modulating macrophage polarization (Ma et al, 2007; Bloemen et al, 2012; Macdougall and Geisser, 2013). Previous studies have shown that surface modified SPION nanoplatforms can be used for multimodal imaging and tumor therapy, such as photodynamic therapy (Kievit et al, 2012; Sivakumar et al, 2017; Zhang and Song, 2017; Zhuang et al, 2019)

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Discussion

Conclusion