title: 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.
authors.affiliation: Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki 305-8573, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yoshitomi
authors.forename: Aki
authors.initials: A
authors.lastname: Hirayama
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nagasaki
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides; D016207:Cytokines / Q000378:metabolism; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008968:Molecular Conformation; D053758:Nanoparticles / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010316:Particle Size; D020011:Protective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
chemical_list: D003497:Cyclic N-Oxides; D016207:Cytokines; D016166:Free Radical Scavengers; D009589:Nitrogen Oxides; D020011:Protective Agents; D017382:Reactive Oxygen Species; D013481:Superoxides; C039900:nitroxyl; C003959:TEMPO