Dual inhibitors of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase as anti-inflammatory payloads in polymer-based nanoparticles

Originated from the enzymatic oxygenation of polyunsaturated fatty acids, lipid mediators (LM) conduct inflammatory and resolving responses of the innate immune system to restore homeostasis after infections or injuries1. In current pharmacotherapy the production of pro-inflammatory prostaglandins (PG) and leukotrienes (LT) is reduced by inhibition of cyclooxygenase (COX)-1 and -2 or 5-lipoxygenase (LOX), which ameliorates inflammation but also exerts severe side effects upon long-term therapy, because the mediators that are crucial for homeostasis are influenced or substrates are redirected to other metabolic pathways, resulting in dysregulation of the lipid mediator network2. Therefore, new pharmacological strategies to specifically modify the production of different lipid mediators are under constant development and the impact of drugs interfering with these metabolic pathways needs to be understood. This thesis reveales the necessity for new pharmacological options for intervention in inflammatory diseases and disclosed a promising new approach to effectively deliver potent dual inhibitors to the site of action via NPs that would otherwise fail to act due to high lipophilicity and overall poor bioavailability. The sophisticated mode of action of these dual inhibitors not only reduces pro-inflammatory mediators but can actively induce the resolution phase by promoting SPM formation. These findings could contribute to a paradigm shift in inflammatory therapy via the combination of novel smart molecules and nanomedicine.