The ROS scavenging and renal protective effects of pH-responsive nitroxide radical-containing nanoparticles

Abstract

The ultimate objective of nanoparticle-based therapy is to functionalize nanomedicines in a micro-disease environment without any side effects. Here, we reveal that our pH-responsive nitroxide radical-containing nanoparticles (RNP(pH)) disintegrate within the renal acidic lesion and act as scavengers of reactive oxygen species (ROS), leading to a relief of acute kidney injury (AKI). RNP(pH) was prepared using amphiphilic block copolymers possessing 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) moieties via amine linkage as a side chain of the hydrophobic segment. The self-assembled RNP(pH) disintegrated at pH below 7.0 because of a protonation of the amino groups in the hydrophobic core of the nanoparticles, thereby resulting in an improvement in ROS scavenging activity. Using a renal ischemia-reperfusion AKI model in mice, the therapeutic effect of RNP(pH) on ROS damage was evaluated. Unlike the RNP without pH-triggered disintegration (RNP(Non-pH)), the RNP(pH) showed extremely high ROS scavenging activity and renal protective effects. It is interesting to note that the side effect of nitroxide radicals was markedly suppressed due to the compartmentalization of nitroxide radicals in the core of RNP(pH) in untargeted area. The morphology changes in RNP(pH) were confirmed by analyzing electron spin resonance spectra, and these findings provide the evidence of the real therapeutic effect of the environment-sensitive specific disintegration of nanoparticles in vivo.

An aerogel obtained from chemo-enzymatically oxidized fenugreek galactomannans as a versatile delivery system

“…The amount of laccase and TEMPO in the final product can be roughly estimated around 10 mg/g (GM) and 15 mg/g (GM) , respectively. TEMPO is considered as non-toxic and it is used in a wide number of biomedical applications (Narain, 2011;Yoshitomi, Hirayama, & Nagasaki, 2011;Yoshitomi, Yamaguchi, Kikuchi, & Nagasaki, 2012). Therefore, neither residual components of the oxidation reaction should be considered as drawbacks in future practical applications of this new biomaterial.…”

Creation of a blood-compatible surface: A novel strategy for suppressing blood activation and coagulation using a nitroxide radical-containing polymer with reactive oxygen species scavenging activity

“…In previous studies, we had developed polymeric micelles composed of an amphiphilic block copolymer possessing TEMPO moieties as side chains and confirmed their ROS-scavenging activity in vivo or in vitro [31][32][33][34].…”

“…Core-shell-type polymeric micelles containing nitroxide radicals have already been developed for the treatment of oxidative stress injuries and in vivo ESR imaging [29,30]. It has been confirmed that they not only strongly scavenge ROS in vivo or in vitro but also significantly prevent oxidative stress damage in an cerebral ischemia-reperfusion injury model in rats [31], renal ischemia-reperfusion injury model in mice [32] and a neuron cell line used as a model for Alzheimer's disease [33,34], in which excess ROS is generated. In the process, we have hypothesized that ROS-scavenging characteristics play a crucial role in blood activation and coagulation when blood comes in contact with material surfaces.…”

Design and Preparation of a Nanoprobe for Imaging Inflammation Sites

“…We developed a nitroxide radical-containing nanoparticle (RNP) for use as a nanomedicine for oxidative stress injury [16][17][18][19][20] and as a bioimaging nanoprobe for MRI and ESRI [21], which is composed of a poly(ethylene glycol)-b-poly(methylstyrene) block copolymer possessing TEMPO moieties via an amine linkage (PEG-b-PMNT) [22]. This PEG-b-PMNT forms core-shell-type micelles in the physiological environment; the cumulant average diameter of the RNP is about 40 nm, and it emits an intense ESR signal.…”

“…The RNP was confirmed to have long-term spin circulation in the blood due to the formation of polymeric micelles in the blood stream. Disintegration of RNP is caused by protonation of the amino groups in response to acidic pH, which typically occurs at inflammation sites, since amino groups are introduced into the hydrophobic segments of amphiphilic block copolymers [17]. Along with the decreasing in pH, ESR signals of RNP gradually change from broad to sharp triplets.…”