The behavior of ROS-scavenging nanoparticles in blood

Abstract

Here, we report an interaction between blood and redox nanoparticles, prepared by self-assembly of amphiphilic block copolymers possessing 2,2,6,6-tetramethylpiperidine-N-oxyls as a side chain of hydrophobic segment. When 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl was added to rat whole blood, its electron spin resonance signal disappeared rapidly. In contrast, the signal from redox nanoparticles remained for a long period of time, indicating that nitroxide radicals were protected in the blood by their compartmentalization in the core of nanoparticle. Although most 2,2,6,6-tetramethylpiperidine-N-oxyls were located in the nanoparticle core, reactive oxygen species-scavenging activity was found outside of blood cells. For example, redox nanoparticles suppressed superoxide anion-induced hemolysis effectively, while 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl did not. It was revealed that redox nanoparticles were not internalized into the healthy blood cells, which was in sharp contrast to 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl. Due to its internalization into healthy platelets, 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl induced mitochondrial dysfunction, while redox nanoparticles did not. Redox nanoparticles suppressed platelet adhesion and extended blood coagulation time, in contrast to 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl. These results indicate that redox nanoparticles scavenge reactive oxygen species outside of cells, but do not interfere with normal redox reactions inside of the cell. Based on these results, we determine that an anti-oxidative strategy based on nanotechnology is a rational and safe therapeutic approach.

Recovery of Cognitive Dysfunction via Orally Administered Redox-Polymer Nanotherapeutics in SAMP8 Mice

“…Thus far, we have confirmed the remarkable therapeutic effect of intravenously administered RNP N for various oxidative stress injuries such as ischemia-reperfusion injuries of the kidney [ 11 ], brain [ 12 ], and heart (Asanuma, et al, submitted for publication), and intracerebral hemorrhage [ 13 ]. Although LMW nitroxide radicals cause severe adverse effects because of internalization in healthy cells and disturbance of the important electron transport chain in mitochondria [ 14 ], redox polymer nanoparticles do not cause adverse effects because of no internalization in healthy cells such as blood cells [ 15 ] and colon mucosal cells [ 16 ]. Since we have already confirmed that RNP N shows an anti-apoptotic effect on amyloid beta-induced cell death in vitro [ 17 ], in this study, we applied RNP N as an orally administered redox polymer nanotherapeutics for the treatment of senescence-accelerated neural dysfunction.…”

Redox Nanoparticles as a Novel Treatment Approach for Inflammation and Fibrosis Associated With Nonalcoholic Steatohepatitis

“…However, TEMPOL administration leads to a significant lowering of blood pressure, thus limiting its potential clinical utility [11]. TEM-POL is also internalized in normal cells nonspecifically [9][10][11]. Therefore, we developed a novel way to deliver TEMPO to the site of injury (high ROS production) with minimal exposure to the blood stream, thus reducing TEMPO's side effects.…”

“…However, these compounds have not been able to advance to the clinical setting, due in part to problems with their short half-life and several observed side effects [8]. One of the most important issues for low-molecular-weight (LMW) antioxidants such as TEMPOL is that excessive uptake in healthy cells may disrupt normal redox reactions triggering mitochondrial dysfunction and apoptosis [9,10]. It has also been reported that the administration of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) derivatives, such as TEMPOL, future science group Research Article Eguchi, Yoshitomi, Lazic et al in animals may induce a dramatic reduction in blood pressure [11].…”

“…Since the RNPs are not internalized in healthy cells due to the intact cell membrane, almost no cellular dysfunction is observed in healthy cells [9]. Because RNPs possess amine linkages in the core, they disintegrate under acidic conditions due to the protonation of amino groups.…”

Reactive Oxygen Species‐Scavenging Nanomedicines for the Treatment of Oxidative Stress Injuries

“…Moreover, LMW TEMPO derivatives have been reported to induce mitochondrial dysfunction because they pass through the cell membrane and lead to non‐essential redox reactions. Given that the nanoparticles can suppress its uptake into normal cells unlike LMW compounds, RNPs suppress LMW nitroxide radical‐induced mitochondrial dysfunction . This is one of the reasons for the extremely low toxicity of RNPs both in vivo and in vitro.…”