Drug Delivery Strategies for Curcumin and Other Natural Nrf2 Modulators of Oxidative Stress-Related Diseases

Abstract

Oxidative stress is associated with a wide range of diseases characterised by oxidant-mediated disturbances of various signalling pathways and cellular damage. The only effective strategy for the prevention of cellular damage is to limit the production of oxidants and support their efficient removal. The implication of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the cellular redox status has spurred new interest in the use of its natural modulators (e.g., curcumin, resveratrol). Unfortunately, most natural Nrf2 modulators are poorly soluble and show extensive pre-systemic metabolism, low oral bioavailability, and rapid elimination, which necessitates formulation strategies to circumvent these limitations. This paper provides a brief introduction on the cellular and molecular mechanisms involved in Nrf2 modulation and an overview of commonly studied formulations for the improvement of oral bioavailability and in vivo pharmacokinetics of Nrf2 modulators. Some formulations that have also been studied in vivo are discussed, including solid dispersions, self-microemulsifying drug delivery systems, and nanotechnology approaches, such as polymeric and solid lipid nanoparticles, nanocrystals, and micelles. Lastly, brief considerations of nano drug delivery systems for the delivery of Nrf2 modulators to the brain, are provided. The literature reviewed shows that the formulations discussed can provide various improvements to the bioavailability and pharmacokinetics of natural Nrf2 modulators. This has been demonstrated in animal models and clinical studies, thereby increasing the potential for the translation of natural Nrf2 modulators into clinical practice.

Efficacy and safety of dietary polyphenol supplementation in the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis

“…Some of them protect against mitochondrial dysfunction and aerobic metabolic dysfunction (102,103). Different polyphenols, such as resveratrol and curcumin, exert their effects through similar molecular targets acting on the Nuclear Factor erythroid 2-Related Factor 2 (Nrf2) pathway, suggesting that these compounds may share the same molecular pathway in lipid metabolism (104,105). At present, several studies have shown the effect of polyphenols in NAFLD (22, 106) (Figure 7).…”

Protective Effects of Curcumin in Cardiovascular Diseases—Impact on Oxidative Stress and Mitochondria

“…In addition to using other natural substances as enhancers of curcumin's bioavailability, a number of different formulations have been shown to improve its uptake and stability. These include dispersions with various carriers, micronized powders, as well as nanoparticle and micellar formulations [191,192]; some of these formulations exhibit a greatly enhanced bioavailability in humans [193]. It will be interesting to systematically compare these various application forms in in vivo models with respect to their effectiveness regarding outcomes on age-and obesity-related processes fostering the development of CVDs.…”

Normal and Pathological NRF2 Signalling in the Central Nervous System

“…In order to restore the oxidative balance, many antioxidant supplementation therapies (e.g., antioxidant vitamins, coenzyme Q, resveratrol, curcumin) have been implemented. However, tests of the effectiveness of such treatments in humans have raised contrasting results [ 199 , 200 , 201 ]. Some NRF2-activating compounds have been described as potential senotherapeutic drugs.…”