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Development of a nanostructured system for controlled release of lipid pro-resolution: Analgesic effects on inflammation and neuropathy, anti-inflammatory, on infection and tissue repair

Abstract

Maresin 1 (MaR1) is a lipid derived from docosahexaenoic acid that not only reduces inflammation as anti-inflammatories, but also activates endogenous pro-resolution mechanisms for the end of inflammation. The MaR1 also features a different class of macrophages, the resolving macrophage. This macrophage has characteristics such as maintaining microbicidal activity such as M1 macrophages whereas it does not release pro-inflammatory molecules, similar to M2 macrophages. Because of this, resolving macrophages kill pathogenic microorganisms and do not ignite tissue. That is, the understanding is that MaR1 could lead to homeostasis inhibiting the development of chronic diseases. The UEL research group, involved in this project, verified the analgesic effect and novel neuroimmune mechanisms involved in the activity of MaR1. It has been shown how MaR1 acting on nociceptive neurons inhibits the release of neuropeptides, reducing peripheral inflammation and neuroinflammation. We also demonstrated the pharmacological activity of MaR1 in a model of inflammation and oxidative stress of the skin induced by UVB radiation (a pre-cancer phase). In unpublished data we demonstrate the effect of MaR1 on the cutaneous tissue repair and in a septic arthritis model, in which MaR1 reduces pain, inflammation and bacterial burden in septic arthritis caused by Staphylococcus aureus. The MaR1 activity occurs in the nanogram range and depending on the experimental model the effect of a single dose can last for 5 days. In theory, the delivery of MaR1 by controlled release systems could increase its activity and increase the duration of its effect, since the activity of pro-resolution lipids is limited by the expression of its receptors by cells. To improve its activity, it is necessary to generate the ideal balance between agonist and receptor. In this project, we propose to develop a nanostructured system based on ferritin for controlled release of MaR1 (nanoMaR1) in order to increase its effectiveness and duration of effect. Ferritin based nanostructured systems have a number of characteristics such as uniform structure, low toxicity, ability to evade the immune system (they will not cause inflammation per se) and the fact that they are easily degraded after fulfilling their function, which are highly desirable properties for nanocarriers in clinical use and, therefore, make them interesting to be evaluated in the delivery of MaR1 in order to allow a prolonged effect of this lipid mediator when compared to its administration in solution. We will use 5 models to validate the therapeutic importance of nanoMaR1: 1) Inflammation and oxidative stress induced by UVB radiation (evaluates an essential precancerous stage); 2) Tissue repair of cutaneous wound (wide application after surgery); 3) Inflammation by complete Freund's Adjuvant (CFA) (in this model we can evaluate chronic pain and inflammation and neuroimmune regulation); 4) Neuropathy due to sciatic nerve injury (chronic neuropathic pain allowing the verification of central neuroinflammatory mechanisms); 5) Septic arthritis (model in mice and translation using samples from patients with septic arthritis and volunteers' peripheral blood mononuclear cells). These models encompass a wide variety of pathophysiological mechanisms of chronic diseases. In this way, we hope to contribute by developing a new therapeutic technology for the treatment of several diseases in which it is important to reduce chronic pain (neuropathic and inflammatory), inflammation and infections, subvert the neuro-immune interaction in favor of the patient and induce tissue repair using a nanostructured ferritin system for controlled release of MaR1, nanoMaR1. (AU)