A Robust Nanoparticle Platform for RNA Interference in Macrophages to Suppress Tumor Cell Migration.

Shi Liang,Wei Wu,Xiaoding Xu,Yandan Yao,Phei Er Saw,Herui Yao,Junmeng Zheng,Jianing Chen,Quan Li

doi:10.3389/fphar.2018.01465

Shi Liang, Wei Wu + Show 7 more

Open Access

https://doi.org/10.3389/fphar.2018.01465

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Abstract

Macrophages are one of the most abundant immune cells in the solid tumor and their increased density is associated with the specific pathological features of cancers, including invasiveness, metastasis, immunosuppression, neovascularization, and poor response to therapy. Therefore, reprogramming macrophage behavior is emerging as a promising therapeutic modality for cancer treatment. RNA interference (RNAi) technology is one of the powerful strategies for the regulation of macrophage activities by silencing specific genes. However, as polyanionic biomacromolecules, RNAi therapeutics such as small interfering RNA (siRNA) cannot readily cross cell membrane and thus specific delivery vehicles are required to facilitate the cytosolic siRNA delivery. Herein, we developed a robust nanoparticle (NP) platform for efficient siRNA delivery and gene silencing in macrophages. This NP platform is composed of biodegradable poly (ethylene glycol)-b-poly (𝜀-caprolactone) (PEG-b-PCL), poly (𝜀-caprolactone)-b-poly (2-aminoethyl ethylene phosphate) (PCL-b-PPEEA), and PCL homopolymer. We chose CC-chemokine ligand 18 (CCL-18) as a proof of concept therapeutic target and our results demonstrate that the CCL-18 silencing in macrophages can significantly inhibit the migration of breast cancer cells. The successful regulation of the macrophage behavior demonstrated herein shows great potential as an effective strategy for cancer therapy.

Highlights

Macrophages are important cells of immune system with two major phenotypes, i.e., proinflammatory phenotype (M1) and anti-inflammatory phenotype (M2) (Mantovani et al, 2008; Noy and Pollard, 2014; Ostuni et al, 2015)
The amphiphilic polymer PCL-b-PPEEA was prepared by ring-opening polymerization (ROP) method (Sun et al, 2008), in which the cationic PPEEA segment was used to complex small interfering RNA (siRNA) via electrostatic interaction
By mixing these three polymers in acetonitrile and methyl alcohol (v/v, 50:50) followed by the addition to deionized water, well-defined NPs can be formed with spherical morphology (Figure 2A). In this self-assembly system, the amphiphilic PEG-b-PCL and PCL-b-PPEEA can spontaneously self-assemble into NPs with hydrophobic PCL chains embedded in the cores and hydrophilic PEG and PPEEA chains positioned on the surface that can, respectively, stabilize the NPs and complex negatively charged siRNA

Summary

Introduction

Macrophages are important cells of immune system with two major phenotypes, i.e., proinflammatory phenotype (M1) and anti-inflammatory phenotype (M2) (Mantovani et al, 2008; Noy and Pollard, 2014; Ostuni et al, 2015). Numerous clinical and epidemiological studies have demonstrated that TAMs are primary M2-like macrophages (Gordon and Martinez, 2010; Sica and Mantovani, 2012; Bronte and Murray, 2015) and their increased density is associated with the specific pathological features of cancers, including invasiveness, metastasis, immunosuppression, neovascularization, and poor response to therapy (Qian and Pollard, 2010; McAllister and Weinberg, 2014; Bronte and Murray, 2015). Macrophages represent an important therapeutic target and strategies that can effectively regulate undesirable macrophage activities are always pursued for future cancer therapy. One of the promising strategies for the regulation of macrophage activities is using RNA interference (RNAi) technology to silence specific genes (Aouadi et al, 2009; Kortylewski et al, 2009; Yu et al, 2013). Modest effort has been made to develop RNAi NPs for the modulation of undesirable macrophage activities

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