Gold nanorods have promising applications in drug delivery and cancer treatment and are generally administered via direct injection into circulation. Thus it is necessary to evaluation their potential adverse effects on blood vessels. Herein we use gold nanorods with various surface modifications to evaluate the toxicity and cellular uptake of gold nanorods into vascular endothelial and smooth muscle cells of isolated rat aortic rings. Surfactant-capped gold nanorods (GNRs) were synthesized and either: 1) coated with polyelectrolytes (PE) in order to prepare PE-GNRs; or 2) modified with thiolated polyethylene glycol (PEG) in order to prepare PEG-GNRs. Using toxicity assays, small vessel myography, fluorescence microscopy and electron microscopy, we show that therapeutic concentrations of PE-GNRs but not PEG-GNRs are toxic to the vascular endothelium, which leads to impaired relaxation function of aortic rings. However, no toxicity to smooth muscles was observed. Moreover, electron microscopy analysis confirmed the cellular uptake of PE-GNRs but not PEG-GNRs into the endothelium of exposed aortic rings. The difference in toxicity and cellular uptake for PE-GNRs versus PEG-GNRs is explained and linked to free surfactant molecules and protein adsorption, respectively. Our results indicate that toxicity and cellular uptake in vascular endothelium in blood vessels are potential adverse effects of systemically administered gold nanorod solutions, which can be prevented by appropriate surface functionalization.
Vitamin E (VE) deficiency results in pronounced muscle weakness and atrophy but the cell biological mechanism of pathology is unknown. We previously showed that VE supplementation promotes membrane repair in cultured cells and that oxidants potently inhibit repair. Here we provide three independent lines of evidence that VE is required for skeletal muscle myocyte plasma membrane repair in vivo. We also show that when another lipid-directed antioxidant, glutathione peroxidase 4 (Gpx4), is genetically deleted in mouse embryonic fibroblasts, repair fails catastrophically, unless cells are supplemented with VE. We conclude that lipid-directed antioxidant activity provided by VE, and possibly also Gpx4, is an essential component of the membrane repair mechanism in skeletal muscle. This work explains why VE is essential to muscle health and identifies VE as a requisite component of the plasma membrane repair mechanism in vivo.
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