Resveratrol nanoemulsions target inflammatory macrophages to prevent

25.3 million (11.2%) American adults suffer from daily chronic pain (Nahin, J Pain, 2015), with treatments often providing inadequate pain relief, adverse events, tolerance, dependence, and addiction. Natural products offer a safer alternative. Resveratrol was shown to be effective in mouse models of diabetic neuropathy (Sharma, Kulkarni and Chopra, Fundam Clin Pharmacol, 2007), chronic constriction injury (Tao, Ding et al., Int Immunopharmacol, 2016), and incision-induced allodynia (Tillu, Melemedjian et al., Mol Pain, 2012). However, resveratrol is rapidly metabolized, poorly water soluble, and chemically unstable, all of which can limit its efficacy in vivo. Here, we present progress towards the development of a resveratrol nanoemulsion platform for the targeted treatment of ANP. We hypothesized that targeted delivery of resveratrol to macrophages via nanoemulsions will improve resveratrol's therapeutic efficacy. Resveratrol nanoemulsions are readily phagocytized by macrophages, provide extended release of resveratrol, and are highly stable (350 day shelf life) (Herneisey, Williams et al., Ther Deliv, 2016). Resveratrol nanoemulsions reported here reduce levels of nitric oxide (NO) and tumor necrosis factor-α (TNF-α) in vitro in a RAW 264.7 macrophage cell line. TNF-α inhibition with nanoemulsions was achieved at lower doses when compared to a free resveratrol solution, suggesting that targeted delivery of resveratrol to inflammatory macrophages improves its efficacy. When injected intravenously, resveratrol loaded nanoemulsion effectively reduces pain for 14 days in a mouse surgical incision model. Further, treatment with resveratrol nanoemulsion blocks the development of subsequent chronic pain in mice, as shown by the lack of response to administration of an inflammatory mediator, prostaglandin E2 (PGE2). Near infrared (NIR) and histological analyses confirm uptake of resveratrol nanoemulsion by macrophages in vivo. These proof of concept experiments demonstrate that the resveratrol nanoemulsion rapidly targets macrophages in vivo, and has tissue protective effects in preventing chronic pain.