Polyvinylpyrrolidone-coated gold nanoparticles inhibit endothelial cell viability, proliferation, and ERK1/2 phosphorylation and reduce the magnitude of endothelial-independent dilator responses in isolated aortic vessels

Azzawi, M, Mohamed, T, Matou-Nasri, S, Farooq, A and Whitehead, D (2017) Polyvinylpyrrolidone-coated gold nanoparticles inhibit endothelial cell viability, proliferation, and ERK1/2 phosphorylation and reduce the magnitude of endothelial-independent dilator responses in isolated aortic vessels. International Journal of Nanomedicine, 12. pp. 8813-8830. ISSN 1176-9114

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Abstract

Background: Gold nanoparticles (AuNPs) demonstrate clinical potential for drug delivery and imaging diagnostics. As AuNPs aggregate in physiological fluids, polymer surface modifications are utilised to allow their stabilisation and enhance their retention time in blood. However, the impact of AuNPs on blood vessel function remains poorly understood. In the present study, we investigated the effects of AuNPs and their stabilisers on endothelial cell (EC) and vasodilator function. Methods: Citrate-stabilised AuNPs (12±3 nm) were synthesised and surface-modified using mercapto polyethylene glycol - (mPEG) and polyvinilpyrrolidine (PVP) polymers. Their uptake by isolated ECs and whole vessels was visualised using transmission electron microscopy (TEM) and quantified using inductively coupled plasma-mass spectrometry (ICP-MS). Their biological effects on EC proliferation, viability, apoptosis and extracellular signal-regulated kinase (ERK) 1/2 signalling pathway were determined using the automated cell counter, flow cytometry, and western blotting, respectively. Endothelial-dependent and independent vasodilator functions were assessed using isolated murine aortic vessel rings, ex vivo. Results: AuNPs were located in endothelial endosomes within 30 min exposure, while their surface modification delayed this cellular uptake over time. After 24 hr exposure, all AuNPs (including polymer-modified AuNPs) induced apoptosis and decreased cell viability/proliferation. These inhibitory effects were lost after 48 hr exposure (except for the PVP-modified AuNPs). Furthermore, all AuNPs decreased acetylcholine (ACh)-induced phosphorylation of ERK1/2, a key signalling protein of cell function. mPEG-modified AuNPs had lower cytostatic effects than PVP-modified AuNPs. Citrate-stabilised AuNPs did not alter endothelial-dependent vasodilation induced by ACh but attenuated endothelial-independent responses induced by sodium nitroprusside (SNP). PVP-modified AuNPs attenuated ACh-induced dilation whereas mPEG-modified AuNPs did not, though this was dose-related. Conclusions: We demonstrate that mPEG-modified AuNPs, at a therapeutic dosage, show lower cytostatic effects and are less detrimental to vasodilator function than PVP-modified AuNPs, indicating greater potential as agents for diagnostic imaging and therapy.