Suppression of NSAID-induced small intestinal inflammation by orally administered redox nanoparticles

Patients regularly taking non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin (IND) have a risk of small intestinal injuries. In this study, we have developed an oral nanotherapeutics by using a redox nanoparticle (RNPO), which is prepared by self-assembly of an amphiphilic block copolymer that possesses nitroxide radicals as side chains of hydrophobic segment via ether linkage, to reduce inflammation in mice with IND-induced small intestinal injury. The localization and accumulation of RNPO in the small intestine were determined using fluorescent-labeled RNPO and electron spin resonance. After oral administration, the accumulation of RNPO in both the jejunum and ileum tissues was about 40 times higher than those of low-molecular-weight nitroxide radical compounds, and RNPO was not absorbed into the bloodstream via the mesentery, thereby avoiding the adverse effects of nitroxide radicals in the entire body. RNPO remarkably suppressed inflammatory mediators such as myeloperoxidase, superoxide anion, and malondialdehyde in the small intestines of IND-treated mice. Compared to low-molecular-weight nitroxide radical compounds, RNPO also significantly increased the survival rate of mice treated daily with IND. On the basis of these results, RNPO is promising as a nanotherapeutics for treatment of inflammation in the small intestine of patients receiving NSAIDs

Preparation of self-assembly silica redox nanoparticles to improve drug encapsulation and suppress the adverse effect of doxorubicin

Background and Purpose: The utilization of doxorubicin (DOX) in clinal trials is also challenging owing to its adverse effects, including low oral bioavailability, generation of reactive oxygen species (ROS), cardiotoxicity, and epithelial barrier damage. Recently, scavenging of ROS reduced the cytotoxicity of DOX, suggesting a new approach for using DOX as an anticancer treatment. Thus, in this study, non-silica and silica redox nanoparticles (denoted as RNPN and siRNP, respectively) with ROS scavenging features have been designed to encapsulate DOX and reduce its cytotoxicity. Experimental Approach: DOX-loaded RNPN (DOX@RNPN) and DOX-loaded siRNP (DOX@siRNP) were prepared by co-dissolving DOX with RNPN and siRNP, respectively. The size and stability of nanoparticles were characterized by the dynamic light scattering system. Additionally, encapsulation efficiency, loading capacity, and release profile of DOX@RNPN and DOX@siRNP were identified by measuring the absorbance of DOX. Finally, the cytotoxicity of DOX@RNPN and DOX@siRNP against normal murine fibroblast cells (L929), human hepatocellular carcinoma cells (HepG2), and human breast cancer cells (MCF-7) were also investigated. Key results: The obtained result showed that RNPN exhibited a pH-sensitive character while silanol moieties improved the stability of siRNP in physiological conditions. DOX@RNPN and DOX@siRNP were formed at several tens of nanometers in diameter with narrow distribution. Moreover, DOX@siRNP stabilized under different pH buffers, especially gastric pH, and improved encapsulation of DOX owing to the addition of silanol groups. DOX@RNPN and DOX@siRNP maintained anticancer activity of DOX against HepG2, and MCF-7 cells, while their cytotoxicity on L929 cells was significantly reduced compared to free DOX treatment. Conclusion: DOX@RNPN and DOX@siRNP could effectively suppress the adverse effect of DOX, suggesting the potential to become promising nanomedicines for cancer treatments

Chronic treatment with a smart antioxidative nanoparticle for inhibition of amyloid plaque propagation in Tg2576 mouse model of Alzheimer’s disease

The present study aimed to assess whether our newly developed redox nanoparticle (RNPN) that has antioxidant potential decreases Aβ levels or prevents Aβ aggregation associated with oxidative stress. The transgenic Tg2576 Alzheimer’s disease (AD) mice were used to investigate the effect of chronic ad libitum drinking of RNPN solution for 6 months, including memory and learning functions, antioxidant activity, and amyloid plaque aggregation. The results showed that RNPN-treated mice had significantly attenuated cognitive deficits of both spatial and non-spatial memories, reduced oxidative stress of lipid peroxide, and DNA oxidation. RNPN treatment increased the percent inhibition of superoxide anion and glutathione peroxidase activity, neuronal densities in the cortex and hippocampus, decreased Aβ(1-40), Aβ(1-42) and gamma (γ)-secretase levels, and reduced Aβ plaque observed using immunohistochemistry analysis and thioflavin S staining. Our results suggest that RNPN may be a promising candidate for AD therapy because of its antioxidant properties and reduction in Aβ aggregation, thereby suppressing its adverse side effect

Nitric Oxide Nano-Delivery Systems for Cancer Therapeutics: Advances and Challenges

Nitric oxide (NO) plays important roles in various physiological and pathological functions and processes in the human body. Therapeutic application of NO molecules has been investigated in various diseases, including cardiovascular disease, cancer, and infections. However, the extremely short half-life of NO, which limits its clinical use considerably, along with non-specific distribution, has resulted in a low therapeutic index and undesired adverse effects. To overcome the drawbacks of using this gaseous signaling molecule, researchers in the last several decades have focused on innovative medical technologies, specifically nanoparticle-based drug delivery systems (DDSs), because these systems alter the biodistribution of the therapeutic agent through controlled release at the target tissues, resulting in a significant therapeutic drug effect. Thus, the application of nano-systems for NO delivery in the field of biomedicine, particularly in the development of new drugs for cancer treatment, has been increasing worldwide. In this review, we discuss NO delivery nanoparticle systems, with the aim of improving drug delivery development for conventional chemotherapies and controlling multidrug resistance in cancer treatments

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

<div><p>Excessively generated reactive oxygen species are associated with age-related neurodegenerative diseases. We investigated whether scavenging of reactive oxygen species in the brain by orally administered redox nanoparticles, prepared by self-assembly of redox polymers possessing antioxidant nitroxide radicals, facilitates the recovery of cognition in 17-week-old senescence-accelerated prone (SAMP8) mice. The redox polymer was delivered to the brain after oral administration of redox nanoparticles via a disintegration of the nanoparticles in the stomach and absorption of the redox polymer at small intestine to the blood. After treatment for one month, levels of oxidative stress in the brain of SAMP8 mice were remarkably reduced by treatment with redox nanoparticles, compared to that observed with low-molecular-weight nitroxide radicals, resulting in the amelioration of cognitive impairment with increased numbers of surviving neurons. Additionally, treatment by redox nanoparticles did not show any detectable toxicity. These findings indicate the potential of redox polymer nanotherapeutics for treatment of the neurodegenerative diseases.</p></div