Ultrasmall polymer-coated cerium oxide nanoparticles as a traumatic brain injury therapy.

No medication has been approved for secondary injuries after traumatic brain injury (TBI). While free radicals are considered a major mediator of secondary injury, conventional antioxidants only have modest clinical efficacy. Here, we synthesized CX201 consisting of core cerium oxide nanoparticles coated with 6-aminocaproic acid and polyvinylpyrrolidone in aqueous phase. CX201 with 3.49 ± 1.11 nm of core and 6.49 ± 0.56 nm of hydrodynamic diameter showed multi-enzymatic antioxidant function. Owing to its excellent physiological stability and cell viability, CX201 had a neuroprotective effect in vitro. In a TBI animal model, an investigator-blinded randomized experiment showed a single intravenously injected CX201 significantly improved functional recovery compared to the control. CX201 reduced lipid peroxidation and inflammatory cell recruitment at the damaged brain. These suggest ultrasmall CX201 can efficiently reduce secondary brain injuries after TBI. Given the absence of current therapies, CX201 may be proposed as a novel therapeutic strategy for TBI.

Ceria Nanoparticles Fabricated with 6-Aminohexanoic Acid that Overcome Systemic Inflammatory Response Syndrome.

Systemic inflammatory response syndrome (SIRS) is self-destructive and uncontrollable inflammatory response of the whole body triggered by infection, trauma, or a variety of severe injuries. Although reactive oxygen species play a pivotal role in the development of SIRS, the trials with conventional antioxidants have failed to improve patient outcome. Ceria nanoparticles (CeNPs) have potent, autocatalytic reactive oxygen species scavenging activities, which may have sufficient therapeutic effects for SIRS. Herein, 3 nm CeNPs are fabricated totally in aqueous phase by using 6-aminohexanoic acid (6-AHA) and their Ce3+ to Ce4+ ratio is increased to enhance antioxidative properties. The obtained 6-AHA-CeNPs demonstrate strong antioxidative and anti-inflammatory effects in various biofluids and inflammatory cells. In SIRS animal models, 6-AHA-CeNPs are demonstrated to reduce multiple organ injuries and inflammation. Moreover, 6-AHA-CeNPs decrease mortality and improve clinical scores of SIRS models. These findings suggest that 6-AHA-CeNPs have potential as a therapeutic nanomedicine for SIRS.

Ceria Nanoparticles Synthesized With Aminocaproic Acid for the Treatment of Subarachnoid Hemorrhage.

Background and Purpose- Despite early aneurysm repair and aggressive management for complications, subarachnoid hemorrhage (SAH) results in at least 25% mortality rate and 50% persistent neurological deficit. We investigated whether ceria nanoparticles which have potent antioxidative activities can protect against subarachnoid hemorrhage via attenuating fatal brain injuries. Methods- Uniform, 3 nm, water-dispersed ceria nanoparticles were prepared from short sol-gel reaction of cerium (III) ions with aminocaproic acid in aqueous phase. SAH was induced by endovascular perforation of middle cerebral artery of rats. A single dose of ceria nanoparticles (0.5 mg Ce/kg) or saline control was randomly administered intravenously at an hour post-SAH. Neuronal death, macrophage infiltration, SAH grade, and brain edema were evaluated at 72 hours. Mortality and neurological function were assessed for 14 days. Results- The obtained ceria nanoparticles with high Ce3+ to Ce4+ ratio demonstrated potent antioxidative, cytoprotective, and anti-inflammatory activities in vitro. In rodent SAH models, the severity of hemorrhage was comparable between the ceria nanoparticles- and saline-treated groups. However, ceria nanoparticles significantly reduced neuronal death, macrophage infiltration, and brain edema after SAH. Ceria nanoparticles successfully improved survival rates (88.2% in the ceria nanoparticles group versus 21.1% in the control group; P<0.001) and neurological outcomes (modified Garcia score: 12.1±0.5 in the ceria nanoparticles group versus 4.4±0.5 in the control group; P<0.001) of the animals with SAH. Conclusions- Ceria nanoparticles, totally synthesized in aqueous phase using aminocaproic acid, demonstrated promising results against SAH via potent antioxidative, neuroprotective and anti-inflammatory activities. Given the obvious limitations of current therapies for SAH, ceria nanoparticles can be a potential therapeutic agent which might result in a paradigm shift in SAH treatment.

Ceria-Zirconia Nanoparticles as an Enhanced Multi-Antioxidant for Sepsis Treatment.

The two oxidation states of ceria nanoparticles, Ce3+ and Ce4+ , play a pivotal role in scavenging reactive oxygen species (ROS). In particular, Ce3+ is largely responsible for removing O2- and . OH that are associated with inflammatory response and cell death. The synthesis is reported of 2 nm ceria-zirconia nanoparticles (CZ NPs) that possess a higher Ce3+ /Ce4+ ratio and faster conversion from Ce4+ to Ce3+ than those exhibited by ceria nanoparticles. The obtained Ce0.7 Zr0.3 O2 (7CZ) NPs greatly improve ROS scavenging performance, thus regulating inflammatory cells in a very low dose. Moreover, 7CZ NPs are demonstrated to be effective in reducing mortality and systemic inflammation in two representative sepsis models. These findings suggest that 7CZ NPs have the potential as a therapeutic nanomedicine for treating ROS-related inflammatory diseases.