Insights on Localized and Systemic Delivery of Redox‐Based Therapeutics

Abstract

Reactive oxygen and nitrogen species are indispensable in cellular physiology and signaling. Overproduction of these reactive species or failure to maintain their levels within the physiological range results in cellular redox dysfunction, often termed cellular oxidative stress. Redox dysfunction in turn is at the molecular basis of disease etiology and progression. Accordingly, antioxidant intervention to restore redox homeostasis has been pursued as a therapeutic strategy for cardiovascular disease, cancer, and neurodegenerative disorders among many others. Despite preliminary success in cellular and animal models, redox-based interventions have virtually been ineffective in clinical trials. We propose the fundamental reason for their failure is a flawed delivery approach. Namely, systemic delivery for a geographically local disease limits the effectiveness of the antioxidant. We take a critical look at the literature and evaluate successful and unsuccessful approaches to translation of redox intervention to the clinical arena, including dose, patient selection, and delivery approach. We argue that when interpreting a failed antioxidant-based clinical trial, it is crucial to take into account these variables and importantly, whether the drug had an effect on the redox status. Finally, we propose that local and targeted delivery hold promise to translate redox-based therapies from the bench to the bedside.

Exposure to Static Magnetic and Electric Fields Treats Type 2 Diabetes

“…Unfortunately, redox-based interventions for the management of T2D have not been translated to clinical settings because they require frequent or continuous administration due to short-half-lives (e.g. GSH <10 mins) and are associated with side effects which negatively impacts adherence (Buglak et al, 2018;Elbatreek et al, 2019;Sabaté, 2003). New methods are needed to modulate systemic redox homeostasis to address an underlying pathomechanism of T2D.…”

Age as a risk factor in vasculitis

“…Aging entails various detrimental effects on extracellular and cellular components in vascular tissues. Much emphasis has been put on the potential injurious impact of reactive oxygen species, but therapeutic attempts to ameliorate cardiovascular disease with antioxidant therapies have proven largely unsuccessful [73]. With age, the disturbed balance between the production and neutralization of ROS leads to oxidative damage to DNA and cellular structures and changes in intracellular signaling [74].…”

Antioxidant Response Activating nanoParticles (ARAPas) localize to atherosclerotic plaque and locally activate the Nrf2 pathway

“…8 Targeted nanomedicine is a promising, and understudied approach to counter this challenge in CVD. [9][10][11][12][13] Encapsulation of pharmacological therapeutics into nanoparticles can endow them with the capacity to exploit the enhanced permeability retention effect present in atherosclerotic plaque due to gaps in the dysfunctional endothelium, 14 as well as exploit internalization by plaque-resident macrophages. 15,16 A promising mechanistic approach to limit oxidative stress and inflammation associated with atherosclerosis is activation of the Kelch-like ECH-associated protein 1/Nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) transcription factor pathway.…”