Inhibition of Phosphoinositol 3 Kinase Contributes to Nanoparticle-Mediated Exaggeration of Endotoxin-Induced Leukocyte Procoagulant Activity

Abstract

Aim Disseminated intravascular coagulation is an increasing concern for certain types of engineered nanomaterials. Recent studies have shed some light on the nanoparticle physicochemical properties contributing to this toxicity; however, the mechanisms are poorly understood. Leukocyte procoagulant activity (PCA) is a key factor contributing to the initiation of this toxicity. We have previously reported on the exaggeration of endotoxin-induced PCA by cationic dendrimers. Herein, we report an effort to discern the mechanism. Materials & methods Poly(amidoamine) dendrimers with various sizes and surface functionalities were studied in vitro by the recalcification test, flow cytometry and other relevant assays. Results & conclusion Cationic dendrimers exaggerated endotoxin-induced PCA, but their anionic or neutral counterparts did not; the cationic charge prompts this phenomenon, but different cationic surface chemistries do not influence it. Cationic dendrimers and endotoxin differentially affect the PCA complex. The inhibition of phosphoinositol 3 kinase by dendrimers contributes to the exaggeration of the endotoxin-induced PCA.

Current understanding of interactions between nanoparticles and the immune system

“…Several interesting mechanisms have been recently described. For example, the inhibition of phosphoinositol-3-kinase (PI3K) by cationic PAMAM dendrimers has been suggested to contribute to the exaggeration of lipopolysaccharide (LPS)-induced leukocyte PCA in human peripheral blood mononuclear cells by these particles (Ilinskaya et al, 2014). The activation of mitogen-activated protein kinase (MAPK) p38 by gold nanoparticles functionalized with α-lipoyl-ω–methoxy poly(ethylene glycol) was proposed as a mechanism for exaggeration of LPS-triggered nitric oxide and IL-6 secretion in murine macrophages (Liu et al, 2012).…”

“…Moreover, some nanomaterials, while not inflammatory themselves, were able to potentiate endotoxin-mediated inflammation. Silica- and carbon-based nanomaterials, as well as some metal oxides, have been shown to exaggerate endotoxin-mediated inflammation in the lungs (Inoue et al, 2006; Inoue et al, 2007; Shi et al, 2010; Inoue, 2011; Inoue and Takano, 2011), while cationic PAMAM dendrimers were reported to exaggerate endotoxin-induced leukocyte PCA (Dobrovolskaia et al, 2012; Ilinskaya et al, 2014). Strategies for endotoxin detection have been discussed elsewhere (Dobrovolskaia, 2015).…”

Pre-clinical immunotoxicity studies of nanotechnology-formulated drugs: Challenges, considerations and strategy

“…Moreover, some nanomaterials are not inflammatory themselves but potentiate endotoxin-mediated inflammation. For example, cationic polyamidoamine (PAMAM) dendrimers exaggerate endotoxin-induced leukocyte procoagulant activity, which is an essential prerequisite to a serious coagulopathy known as disseminated intravascular coagulation (DIC) [35, 36]. Likewise, silica- and carbon-based nanomaterials, as well as some metal oxides, are known to exaggerate endotoxin-mediated inflammation in the lungs [54–58].…”

“…siRNA) using different nanotechnology-carrier. Avoiding the use of nanocarriers able to amplify immunostimulatory properties of low concentrations of endotoxin [35, 128] when formulating drugs inherently prone to containing traces of endotoxin due to production using bacterial cells (e.g. recombinant proteins) is important to prevent increased immunostimulation by the carrier and antigenicity of the therapeutic payload [129–131].…”

Immunosuppressive and Anti-Inflammatory Properties of Engineered Nanomaterials

“…It is generally recognized that a nanoparticle's physicochemical properties determine their interactions with the immune system. Such structure activity relationships have been described for a variety of components of the immune system in the context of adverse immunostimulation, including, but not limited to, complement activation, platelet activation and induction of leukocyte procoagulant activity (Dobrovolskaia et al, 2012;Ilinskaya et al, 2013). However, studies investigating immunosuppressive properties of nanoparticles per se are scarce (Chen et al, 2004;Mitchell et al, 2009;Yamashita et al, 2009;Shen et al, 2011;2012).…”