Antioxidant Nanotherapies for the Treatment of Inflammatory Diseases

Abstract

Reactive oxygen species (ROS) are essential in regulating various physiological functions. However, overproduction of ROS is implicated in the pathogenesis of various inflammatory diseases. Antioxidant therapy has thus represented an effective strategy for the treatment of oxidative stress relevant inflammatory diseases. Conventional anti-oxidative agents showed limited in vivo effects owing to their non-specific distribution and low retention in disease sites. Over the past decades, significant achievements have been made in the development of antioxidant nanotherapies that exhibit multiple advantages such as excellent pharmacokinetics, stable anti-oxidative activity, and intrinsic ROS-scavenging properties. This review provides a comprehensive overview on recent advances in antioxidant nanotherapies, including ROS-scavenging inorganic nanoparticles, organic nanoparticles with intrinsic antioxidant activity, and drug-loaded anti-oxidant nanoparticles. We highlight the biomedical applications of antioxidant nanotherapies in the treatment of different inflammatory diseases, with an emphasis on inflammatory bowel disease, cardiovascular disease, and brain diseases. Current challenges and future perspectives to promote clinical translation of antioxidant nanotherapies are also briefly discussed.

Keywords: ROS; antioxidant nanotherapies; inflammatory diseases; nanoparticles; oxidative stress.

Figure 1

Schematic, characterization, and in vivo evaluation of CeO₂ nanoparticles (NPs). (A) Schematic illustration of therapeutic mechanisms of CeO₂NPs. (B) High-resolution transmission electron microscopy (HR-TEM) photomicrograph at low (43,000×) magnification revealing loose CeO₂NPs agglomerates. (C) High magnification image (400,000×) of individual 4 nm CeO₂NPs with spherical shape. (D) (Left) The HR-TEM image of single CeO₂ NP showing the spherical morphology; (middle) atomistic simulation of CeO₂NP with a characteristic fluorite-like electronic structure; (right) FFT of the selected nanoparticle with indicated atomic planes. (E) TEM image of liver tissue obtained from a CCl₄-treated rat receiving vehicle and a CCl₄-treated rat receiving CeO₂NPs. Hepatocyte intracellular space containing mitochondria (M), organelles, fat droplets (asterisk), glycogen inclusions (arrow head), and aggregates of CeO₂NPs (arrows). (F) Effect of CeO₂NPs on hepatic steatosis, fibrogenic and infiltrating cells. Reproduced with permission from Oró et al. (2016).

Figure 2

Characterization and antioxidative activity of manganese-based nanoparticles. (A,B) Scanning electron microscopy (SEM) (A) and TEM (B) images of Mn₃O₄ nanoparticles with flower-like morphology (Mnf). (C–E) A comparison of CAT (C), glutathione peroxidase (D), and SOD (E)-like activity of Mnf with other metal oxide nanoparticles. (F) TEM image of Mn₃O₄ nanoparticles synthesized via a hydrothermal method. (G–I) Dependence between the elimination of •O²⁻ (G), •OH (H), H₂O₂ (I) and concentrations of Mn₃O₄ and CeO₂ nanoparticles. (J) In vivo fluorescence imaging of mice with PMA-induced ear inflammation after treatment with Mn₃O₄ nanoparticles. Images in (A–E) are reproduced with permission from Singh et al. (2017). Images in (F–J) are reproduced with permission from Yao et al. (2018).

Figure 3

Design and preparation broad-spectrum ROS-scavenging nanoparticles for treatment of acute lung injury (ALI). (A) Schematic illustration of engineering of a broad-spectrum ROS-scavenging material and its nanoparticles based on functionalized β-CD. (B) The synthetic route of β-CD conjugated with Tempol (Tpl) and PBAP units (TPCD). CDI, 1,1-carbonyldiimidazole; DMAP, 4-dimethylaminopyridine; TCD, Tpl-conjugated β-CD; PBAP, 4-(hydroxymethyl) phenylboronic acid pinacol ester. (C–H) Treatment of ALI with TPCD nanoparticles (i.e., TPCD NP) in mice. (C) The lung wet-to-dry weight ratios after different treatments. (D–G) The expression levels of TNF-α (D), IL-1β (E), and H₂O₂ (F) in bronchoalveolar lavage fluid from mice with LPS-induced ALI and subjected to different treatments. (G) Quantified neutrophil counts in pulmonary tissues of ALI mice. (H) H&E-stained pathological sections of lung tissues. Data are mean ± standard error (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001. Reproduced with permission from Li et al. (2018).

Figure 4

Applications of the engineered exosomes loaded with CAT mRNA in Parkinson's disease. (A) Schematic illustration of protection against neurotoxicity in an in vitro experimental model of Parkinson's disease by CAT mRNA delivery. (B) Engineered exosome producer cells were subcutaneously implanted with Matrigel in living mice. (C) Immunostaining result of tyrosine hydroxylase (TH)-positive neurons. Scale bars, 500 μm. (D) Attenuation of neuroinflammation caused by systemic LPS injection with catalase mRNA delivery in vivo. Reproduced with permission from Kojima et al. (2018). *p < 0.05, **p < 0.01; n.s., no significance.

Figure 5

A proresolving peptide nanotherapy for site-specific treatment of inflammatory bowel disease. (A,B) Schematic illustration of engineering of a ROS-responsive peptide nanotherapy (AON) (A) and targeted treatment of colitis (B). (C,D) TEM (C) and SEM (D) images of AON. Scale bars, 200 nm. (E) Selective accumulation of AON in the inflamed colons of mice with acute colitis. (F) Representative mini-endoscopic images of colons from colitic mice at day 7 after different treatments. ON, blank nanoparticles based on the ROS-responsive material of PBAP-conjugated β-CD (i.e., OxbCD); APN, Ac2-26-containing nanoparticles based on a non-responsive polymer PLGA. Reproduced with permission from Li C. et al. (2019).

Figure 6

Engineering of different inflammation-responsive nanotherapies for targeted treatment of restenosis. (A) Design of inflammation-triggerable nanoparticles. (B) Evans Blue staining indicates successful establishment of injury in the carotid artery. (C) DHE-stained cryosections showing oxidative stress in injured carotid arteries. The image at day 0 was acquired from the sample immediately collected after injury. (D) The levels of hydrogen peroxide in the carotid artery with or without injury. (E) H&E stained histological sections of carotid arteries isolated from rats subjected to various treatments. Scale bars, 200 μm (the upper panel), 50 μm (the lower panel). PLGA NP, Ac-bCD NP, and Ox-bCD NP represents nanoparticles based on a non-responsive polymer PLGA, a pH-responsive material of acetelated β-CD, and a ROS-responsive material of PBAP-conjugated β-CD, respectively. Data are mean ± standard deviation (n = 3). ***P < 0.001. Reproduced with permission from Feng et al. (2016).