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.
Highlights
The research and development of many pharmaceutical products currently represent exciting scientific and technological fields and have had a tremendous impact on modern healthcare
Together with cysteine-rich Keap1, a repressor protein that binds to nuclear factor erythroid 2-related factor 2 (Nrf2) and facilitates its degradation via the ubiquitin-proteasome pathway [28], these constitute the Nrf2/Keap1 signalling pathway, which is a key player in the regulation of cytoprotective responses to oxidative and electrophilic stresses
As there have been many studies on nanoDDSs for Nrf2 modulator administration, here we provide an overview of selected representative reports of commonly studied nanoDDSs that indicate the potential of these systems for the future
Summary
The research and development of many pharmaceutical products currently represent exciting scientific and technological fields and have had a tremendous impact on modern healthcare Such studies are expected to make even greater improvements to the quality of human life. There are currently over 2500 publications on PubMed in the search for “curcumin drug delivery”, whereas a search of the same database for the term “curcumin Nrf2” only produces ~400 results Among the latter, there is a distinct lack of in vivo studies, as the activities of Nrf modulators on their actual targets are usually evaluated in in vitro cell cultures. Due to the current status of polyphenolic Nrf2-modulating phytochemicals as potential dietary supplements, their oral delivery is likely to be more relevant for disease prevention rather than disease treatment. This paper evaluates the current state-of-the-art technology of natural Nrf modulators and their delivery
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