Reduction‐responsive polymers for drug delivery in cancer therapy—Is there anything new to discover?

Advanced Review

Patrícia F. Monteiro, Alessandra Travanut, Claudia Conte, Cameron Alexander

Published Online: Nov 05 2020

DOI: 10.1002/wnan.1678

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Abstract Among various types of stimuli‐responsive drug delivery systems, reduction‐responsive polymers have attracted great interest. In general, these systems have high stability in systemic circulation, however, they can respond quickly to differences in the concentrations of reducing species in specific physiological sites associated with a pathology. This is a particularly relevant strategy to target diseases in which hypoxic regions are present, as polymers which are sensitive to in‐situ expressed antioxidant species can, through a local response, release a therapeutic at high concentration in the targeted site, and thus, improve the selectivity and efficacy of the treatment. At the same time, such reduction‐responsive materials can also decrease the toxicity and side effects of certain drugs. To date, polymers containing disulfide linkages are the most investigated of the class of reduction‐responsive nanocarriers, however, other groups such as selenide and diselenide have also been used for the same purpose. In this review article, we discussed the rationale behind the development of reduction‐responsive polymers as drug delivery systems and highlight examples of recent progress. We include the most popular design methods to generate reduction‐responsive polymeric carriers and their applications in cancer therapy, and question what areas may still need to be explored in a field with already a very large number of research articles. Finally, we consider the main challenges associated with the clinical translation of these nanocarriers and the future perspectives in this area. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies

Structures of glutathione in its two states encountered in cells: oxidized glutathione (GSSG) reaction occurring through the glutathione peroxidase and reduced glutathione (GSH) through the reaction leaded by the enzyme glutathione reductase. Structures are presented in their fully protonated forms

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Illustration of l‐cysteine‐based poly (disulfide amide) (Cys‐PSDA) and intracellular delivery of docetaxel‐loaded redox‐responsive Cys‐PDSA nanoparticles (Reprinted with permission from J. Wu et al. (2015). Copyright 2015 John Wiley and Sons)

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Illustration of reduction and pH dual‐sensitive core‐crosslinked lipoic acid and cis‐1,2‐cyclohexanedicarboxylic acid decorated poly(ethylene glycol)‐b‐poly(l‐lysine) micelles for active loading and triggered intracellular release of DOX (Reprinted with permission from L. Wu et al. (2013). Copyright 2013 Elsevier Ltd)

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Illustration paclitaxel‐citronellol conjugates containing thioether, disulfide, sulfur, selenoether, diselenide, carbon or carbon–carbon bonds as prodrug nanoassemblies for cancer therapy (Reprinted with permission from B. Sun et al. (2019). Spring Nature 2019)

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