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Pinostrobin demonstrated anticancer properties, but its hydrophobic feature led to a reduction in bioavailability. The mitochondria-targeted approach successfully synthesized eight new alkyl triphenylphosphonium pinostrobin derivatives (1-8) with good yield in this study. Seven compounds (1-3, 5-8) showed greater cytotoxic potency against the human MCF-7 breast cancer cell line than pinostrobin. Molecular docking studies were performed with two important targets in hormone-dependent anticancer strategies, estrogen receptor α (ERα) ligand binding domains, 3ERT (antagonist recognition and antiproliferative function), and 1GWR (agonist recognition and pro-proliferative function). In addition, the MD simulation study of the two most potent compounds (2 and 3) complexed with both ERα forms suggested that compounds 2 and 3 could serve as favourable antagonists. Furthermore, the in silico ADMET prediction indicated that compounds 2 and 3 could be potential drug candidates., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Melioidosis, a human infectious disease with a high mortality rate in many tropical countries, is caused by the pathogen Burkholderia pseudomallei (B. pseudomallei). The function of the B. pseudomallei sigma S (RpoS) transcription factor in survival during the stationary growth phase and conditions of oxidative stress is well documented. Besides the rpoS, bioinformatics analysis of B. pseudomallei genome showed the existence of two rpoN genes, named rpoN1 and rpoN2. In this study, by using the mouse macrophage cell line RAW264.7 as a model of infection, the involvement of B. pseudomallei RpoS and RpoN2 in the invasion, intracellular survival leading to the reduction in multinucleated giant cell (MNGC) formation of RAW264.7 cell line were illustrated. We have demonstrated that the MNGC formation of RAW264.7 cell was dependent on a certain number of intracellular bacteria (at least 5 × 10 4 ). In addition, the same MNGC formation (15%) observed in RAW264.7 cells infected with either B. pseudomallei wild type with multiplicity of infection (MOI) 2 or RpoN2 mutant (∆rpoN2) with MOI 10 or RpoS mutant (∆rpoS) with MOI 100. The role of B. pseudomallei RpoS and RpoN2 in the regulation of type III secretion system on bipB-bipC gene expression was also illustrated in this study., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Vitamin D 3 plays a vital role in bone health, with low levels of vitamin D 3 being related to skeletal fragility, fractures, and metabolic disorders such as diabetes. Metformin is known as an antihyperglycemic agent for regulating blood sugar. A correlation between diabetes mellitus and osteoporosis is attracting considerable interest, and research to find the prevention and treatment is gradually being studied. In this study, we investigated the effect of metformin and vitamin D 3 on osteogenic differentiation of human adipose tissue-derived mesenchymal stem cells (AT-MSCs) under high d-glucose concentrations and optimized by combining vitamin D 3 and metformin in the process., Methods: ROS production of AT-MSCs under high d-glucose conditions was measured by DCFH-DA assay. The differentiated AT-MSCs were analyzed by Alizarin Red S staining and optical density measurement. The investigation involved the examination of osteogenic master genes' expressions using quantitative reverse transcription polymerase chain reaction (qRT-PCR) techniques., Results: Interestingly, the results have shown that human AT-MSCs will exhibit high ROS accumulation and low osteogenic differentiation capabilities, indicated by low calcium deposition, as well as low expression of indicative genes such as ALP , Runx-2 under high d-glucose conditions. The combination of vitamin D 3 and metformin remarkedly accelerated the osteogenic differentiation of AT-MSCs under high d-glucose concentrations more effectively than the administration of either agent., Conclusions: This study partially explains an aspect of an in vitro model for pre-clinical drug screening for osteoporosis-related diabetic pathological mechanisms, which can be applied for further research on the prevention or treatment of osteoporosis in diabetic patients., Competing Interests: The authors have no competing financial interests to declare., (© 2023 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

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 RNP N and siRNP, respectively) with ROS scavenging features have been designed to encapsulate DOX and reduce its cytotoxicity., Experimental Approach: DOX-loaded RNP N (DOX@RNP N ) and DOX-loaded siRNP (DOX@siRNP) were prepared by co-dissolving DOX with RNP N 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@RNP N and DOX@siRNP were identified by measuring the absorbance of DOX. Finally, the cytotoxicity of DOX@RNP N 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 RNP N exhibited a pH-sensitive character while silanol moieties improved the stability of siRNP in physiological conditions. DOX@RNP N 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@RNP N 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@RNP N and DOX@siRNP could effectively suppress the adverse effect of DOX, suggesting the potential to become promising nanomedicines for cancer treatments., Competing Interests: Conflict of interest: The authors have no conflicts of interest to declare., (Copyright © 2023 by the authors.)

Compounds containing benzimidazole moiety occupy privileged chemical space for discovering new bioactive substances. In continuation of our recent work, 69 benzimidazole derivatives were designed and synthesized with good to excellent yields of 46-99% using efficient synthesis protocol i.e. sodium metabisulfite catalyzed condensation of aromatic aldehydes with o -phenylenediamines to form 2-arylbenzimidazole derivatives followed by N -alkylation by conventional heating or microwave irradiation for diversification. Potent antibacterial compounds against MSSA and MRSA were discovered such as benzimidazole compounds 3k (2-(4-nitrophenyl), N -benzyl), 3l (2-(4-chlorophenyl), N -(4-chlorobenzyl)), 4c (2-(4-chlorophenyl), 6-methyl, N -benzyl), 4g (2-(4-nitrophenyl), 6-methyl, N -benzyl), and 4j (2-(4-nitrophenyl), 6-methyl, N -(4-chlorobenzyl)) with MIC of 4-16 μg mL -1 . In addition, compound 4c showed good antimicrobial activities (MIC = 16 μg mL -1 ) against the bacteria strains Escherichia coli and Streptococcus faecalis . Moreover, compounds 3k, 3l, 4c, 4g, and 4j have been found to kill HepG2, MDA-MB-231, MCF7, RMS, and C26 cancer cells with low μM IC 50 (2.39-10.95). These compounds showed comparable drug-like properties as ciprofloxacin, fluconazole, and paclitaxel in computational ADMET profiling. Finally, docking studies were used to assess potential protein targets responsible for their biological activities. Especially, we found that DHFR is a promising target both in silico and in vitro with compound 4c having IC 50 of 2.35 μM., Competing Interests: The authors have stated that there is no conflict of interest associated with the publication and no financial support, which could have influenced the outcome., (This journal is © The Royal Society of Chemistry.)

Addressing the growing burden of cancer and the shortcomings of chemotherapy in cancer treatment are the current research goals. Research to overcome the limitations of curcumin and to improve its anticancer activity via its heterocycle-fused monocarbonyl analogues (MACs) has immense potential. In this study, 32 asymmetric MACs fused with 1-aryl-1 H -pyrazole ( 7a-10h ) were synthesized and characterized to develop new curcumin analogues. Subsequently, via initial screening for cytotoxic activity, nine compounds exhibited potential growth inhibition against MDA-MB-231 (IC 50 2.43-7.84 μM) and HepG2 (IC 50 4.98-14.65 μM), in which seven compounds showing higher selectivities on two cancer cell lines than the noncancerous LLC-PK1 were selected for cell-free in vitro screening for effects on microtubule assembly activity. Among those, compounds 7d , 7h , and 10c showed effective inhibitions of microtubule assembly at 20.0 μM (40.76-52.03%), indicating that they could act as microtubule-destabilizing agents. From the screening results, three most potential compounds, 7d , 7h , and 10c , were selected for further evaluation of cellular effects on breast cancer MDA-MB-231 cells. The apoptosis-inducing study indicated that these three compounds could cause morphological changes at 1.0 μM and could enhance caspase-3 activity (1.33-1.57 times) at 10.0 μM in MDA-MB-231 cells, confirming their apoptosis-inducing activities. Additionally, in cell cycle analysis, compounds 7d and 7h at 2.5 μM and 10c at 5.0 μM also arrested MDA-MB-231 cells in the G 2 /M phase. Finally, the results from in silico studies revealed that the predicted absorption, distribution, metabolism, excretion, and the toxicity (ADMET) profile of the most potent MACs might have several advantages in addition to potential disadvantages, and compound 7h could bind into (Δ G -10.08 kcal·mol -1 ) and access wider space at the colchicine-binding site (CBS) than that of colchicine or nocodazole via molecular docking studies. In conclusion, our study serves as a basis for the design of promising synthetic compounds as anticancer agents in the future., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Liver fibrosis is a chronic disease resulting from repetitive or prolonged liver injury with limited treatment options. Sorafenib has been reported to be a potential antifibrotic agent; however, its therapeutic effect is restricted because of its low bioavailability and severe adverse effects in the gastrointestinal (GI) tract. In this study, we developed sorafenib-loaded silica-containing redox nanoparticles (sora@siRNP) as an oral nanomedicine to treat liver fibrosis. The designed siRNP were prepared by self-assembly of amphiphilic block copolymers, which possess antioxidant nitroxide radicals as a side chain of the hydrophobic segment and porous silica particles in the nanoparticle core. The silica moieties in the core formed a crosslink between the self-assembling block copolymers to afford stable drug absorption, which could be useful in harsh GI conditions after oral drug administration. Based on in vitro evaluation, sora@siRNP exerted antiproliferative and antifibrotic effects against hepatic stellate cells (HSCs) and low toxicity against normal endothelial cells. A pharmacokinetic study showed that siRNP significantly improved the bioavailability and distribution of sorafenib in the liver. In an in vivo study using a mouse model of CCl 4 -induced liver fibrosis, oral administration of sora@siRNP significantly suppressed the fibrotic area in comparison to free sorafenib administration. In mice with CCl 4 -induced fibrosis, free sorafenib administration did not suppress the expression of α-smooth muscle actin; however, mice treated with sora@siRNP showed significantly suppressed expression of α-smooth muscle actin, indicating the inhibition of HSC activation, which was confirmed by in vitro experiments. Moreover, oral administration of free sorafenib induced severe intestinal damage and increased leakage into the gut, which can be attributed to the generation of reactive oxygen species (ROS). Our antioxidant nanocarriers, siRNP, reduced the adverse effects of local ROS scavenging in the GI tract. Our results suggest that sora@siRNP could serve as a promising oral nanomedicine for liver fibrosis., (Copyright © 2022. Published by Elsevier B.V.)

Camptothecin (CPT) is a potent anticancer agent for the treatment of colorectal cancer; however, it exhibits some limitations, including poor solubility, low stability, and low bioavailability via oral administration, which restrict its usability in clinical treatments. In addition, overproduction of reactive oxygen species (ROS) during chemotherapy induces drug resistance and severe intestinal side effects. In this study, silica-installed ROS scavenging nanoparticles (siRNP) with 50-60 nm in diameter were employed to overcome the aforementioned drawbacks of CPT. The solubility of CPT was significantly improved by incorporating it into the core of the nanoparticle, forming CPT-loaded siRNP (CPT@siRNP). The anticancer activity of CPT@siRNP against colorectal cancer cells (C-26) in vitro was significantly improved as compared to free CPT through higher efficiency of intracellular internalization and induction of apoptosis. Owing to its antioxidant properties, CPT@siRNP reduced cytotoxicity to normal endothelial cells, which was in sharp contrast to the high toxicity of free CPT. Oral administration of CPT and CPT@siRNP to the C-26 tumor-bearing mice exhibited antitumor activity, accompanied by effective suppression of tumor growth. Although CPT treatment suppressed tumor progression, it caused severe side effects, including intestinal damage and significant bodyweight loss. Interestingly, such noticeable side effects were not observed in the mice treated with CPT@siRNP, and the effect of tumor growth inhibition tended to be similar to or higher than that of CPT treatment. The results obtained in this study indicate that CPT@siRNP is a potential therapeutic nanomedicine for the treatment of colon cancer. STATEMENT OF SIGNIFICANCE: Here we employed silica-containing antioxidant nanoparticle (siRNP) as promising oral delivery nanocarrier of campothecin (CPT) to treat colon cancer. The design of siRNP via covalent conjugation of antioxidant nitroxide radicals and the silanol groups in the polymer backbone contributes to a significant increase in the absorption of hydrophobic drug molecules inside the core and enhances the stability of nanoparticles in the gastrointestinal environment for oral drug delivery. CPT-loaded siRNP (CPT@siRNP) significantly improved solubility of CPT. As compared to free CTP, the CPT@siRNP treatment showed a significantly higher toxicity to colon cancer cell, inhibition of cancer cell migration, and induction of apopotosis. With the antioxidant feature, siRNP also significantly suppressed the intestinal side effects caused by CPT treatment in tumor-bearing mouse model., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Biodegradable periodic mesoporous organosilica nanoparticles (B-PMO) are an outstanding nanocarrier due to their biodegradability and high drug load capacities. The present study describes a synthesis of a phenylene-containing tetrasulfide based B-PMO, named P4S. The incorporation of aromatic phenylene groups into the framework creates a strong interaction between nanoparticles (NPs) with aromatic rings in the cordycepin molecules. This results in the low release profile under various conditions. In addition, the replacement of this linker slowed the degradation of nanoparticles. The physicochemical properties of the nanoparticles are evaluated and compared with a biodegradable ethane-containing tetrasulfide based PMO and a non-degradable MCM-41. The biodegradability of P4S is also demonstrated in a reducing environment and the 100 nm spherical nanoparticles completely decomposed within 14 days. The porous structure of P4S has a high loading of hydrophilic cordycepin (approximately 731.52 mg g -1 ) with a slow releasing speed. The release rates of P4S NPs are significantly lower than other materials, such as liposomes, gelatin nanoparticles, and photo-crosslinked hyaluronic acid methacrylate hydrogels, in the same solution. This specific release behavior could guarantee drug therapeutic effects with minimum side-effects and optimized drug dosages. Most importantly, according to the in vitro cytotoxicity study, cordycepin-loaded P4S NPs could retain the toxicity against liver cancer cell (HepG2) while suppressed the cytotoxicity against normal cells (BAEC)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chronic inflammatory diseases such as inflammatory bowel diseases (IBD), which are strongly related to the overproduction of reactive oxygen species (ROS), have become more threatening to health. Silymarin is an active compound with the effect of expressing anti-inflammatory activity; however, it exhibits poor bioavailability due to the rapid metabolism and secretion, low permeability across the intestinal epithelial cells, and poor water solubility. In this study, we developed silica-containing redox nanoparticles (siRNP) with 50-60 nm in diameter to improve the bioavailability of silymarin by improving its uptake into the bloodstream and delivery to the targeted tissues of the colon. Silymarin-loaded siRNP (SM@siRNP) significantly increased the antioxidant capacity and anti-inflammatory efficacy in vitro by scavenging 2,2-diphenyl-1-picrylhydrazyl free radical and suppressing nitric oxide and pro-inflammatory cytokines as compared to the other treatments such as free silymarin, siRNP, and silymarin-loaded si-nRNP (the control nanoparticle without ROS scavenging property). Orally administered SM@siRNP significantly improved the bioavailability of silymarin and its retention in the colonic mucosa. The anti-inflammatory effects of SM@siRNP were also investigated in dextran sodium sulfate (DSS)-induced colitis in mice and it was observed that SM@siRNP treatment significantly improved the damage in the colonic mucosa of DSS colitis mice as compared to the other treatments. The results in this study indicate that SM@siRNP is a promising nanomedicine for enhancing the anti-inflammatory activity of silymarin and has a high potential for the treatment of IBD., (Copyright © 2020. Published by Elsevier B.V.)

Amino acids have attracted considerable attention in drug development because they play important roles in many physiological and pathological processes. In the past several decades, various amino acid supplementations have been reported to have potential therapeutic efficacy for the treatment of many disorders in clinical trials. However, their effectiveness is controversially reported, which may be explained by poor pharmacokinetic properties of such low-molecular-weight agents. Amino acid-based self-assembled macromolecules could overcome the aforementioned drawbacks by improving the pharmacokinetic profile and accumulation of specific molecules at target sites to enhance the therapeutic effect. In this review, we have discussed the current therapeutic applications of certain amino acids, and have introduced our approach of using amino acid-based self-assembled nanostructures as novel therapeutic agents., Competing Interests: Declaration of Competing Interest The authors have no competing financial interests to declare., (Copyright © 2020. Published by Elsevier B.V.)

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.

Although Levodopa (l-DOPA), a dopamine precursor, exhibits a high risk of dyskinesia, it remains the primary treatment in Parkinson's disease (PD), a progressive neurodegenerative disorder. In this study, we designed poly(l-DOPA)-based self-assembled nanodrug (Nano DOPA ) from amphiphilic block copolymer possessing poly(l-DOPA(OAc) 2 ), which is a precursor of l-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatment, the poly(l-DOPA(OAc) 2 ) in the block copolymer was hydrolyzed to liberate l-DOPA gradually. Using the MPTP-induced PD mouse model, we observed that mice treated with Nano DOPA demonstrated a significant improvement of PD symptoms compared to the l-DOPA treatment. Interestingly, the Nano DOPA treatment did not cause the dyskinesia symptoms, which was clearly observed in the l-DOPA-treated mice. Furthermore, Nano DOPA exhibited remarkably lower toxicity in vitro compared to l-DOPA, in addition with no noticeable Nano DOPA toxicity observed in the treated mice. These results suggested that self-assembled Nano DOPA is a promising therapeutic in the treatment of PD. STATEMENT OF SIGNIFICANCE: In this study, we proposed a therapeutic approach for the effective treatment of Parkinson's disease (PD) using newly designed poly(l-DOPA)-based self-assembled nanodrug (Nano DOPA ) prepared from amphiphilic block copolymers possessing poly(l-DOPA(OAc) 2 ), which is a precursor of l-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatments, Nano DOPA was hydrolyzed to liberate l-DOPA gradually, improving the pharmacokinetic value of l-DOPA. The mice treated with Nano DOPA significantly improved PD symptoms compared to the l-DOPA treatment in a neurotoxin-induced PD mouse model. Interestingly, Nano DOPA treatment did not cause dyskinesia symptoms, which was observed in the l-DOPA-treated mice. The obtained results in this study suggested that self-assembled Nano DOPA is a promising therapeutic in the treatment of PD., Competing Interests: Declaration Competing of Interest The authors have no competing financial interests to declare., (Copyright © 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Oligo-peptides, including monomeric amino acids, have received much attention as bioactive molecules and drugs. One of the biggest problems of these compounds, however, is their very short bioavailability due to instant metabolism and rapid excretion. To solve this problem, we newly designed a poly(ethylene glycol) (PEG)-block-polypeptide self-assembling based drug for the treatment of acute liver injury. Here, PEG-block-poly(L-Ornithine) (PEG-b-POrn) was synthesized via a ring opening polymerization, and a nano-sized polyion self-assembling complex (Nano Orn ) was prepared by simply mixing polycationic PEG-b-POrn with polyanionic chondroitin sulfate. The obtained Nano Orn was quite stable under high ionic strength and different pH conditions and Nano Orn exhibited extremely low toxicity in vitro and in vivo as compared to the original PEG-b-POrn. As compared to monomeric L-ornithine, administration of Nano Orn to mice significantly improved bioavailability of liberated ornithine, especially in the liver. Interestingly, Nano Orn treatment in acetaminophen (APAP)-induced acute liver injury mice remarkably suppressed blood ammonia levels and liver injury markers, resulting in more effective improvement of liver damage compared to monomeric ornithine via activation of ornithine transcarbomylase. These results show that the self-assembling polypeptide Nano Orn may provide a new concept and promising therapeutics as nanomedicines., (Copyright © 2019. Published by Elsevier B.V.)

The medical treatment for stroke has advanced greatly in recent years. Thrombolytic therapy with tissue plasminogen activator (t-PA) is one of the mainstream treatments, but it still has many problems, including short half-life, and t-PA-induced reperfusion and oxidative injuries. To broaden the therapeutic window of t-PA and reduce its associated oxidative stress after reperfusion, t-PA-installed, nitroxide radical-containing, self-assembled polyion complex nanoparticles (t-PA@iRNP) were designed. Encapsulation of t-PA in the self-assembled antioxidant nanoparticles improved its bioavailability and extended its therapeutic window. To suppress reactive oxygen species (ROS) in the ischemic penumbra area, the low-molecular-weight nitroxide antioxidant 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl was covalently conjugated with the nanoparticle matrix, thus suppressing oxidative damage in the brain after reperfusion. t-PA and nitroxide radicals were confined and protected in the core of t-PA@iRNP, thereby preventing their rapid metabolism and excretion out of the body after systemic circulation for prolonged period. The nano-sized formulation prevented non-specific internalization of t-PA@iRNP in healthy cells, thereby preserving the normal function of redox reactions in the cells, especially important redox reactions such as electron transport chains. This improved pharmacological performance of t-PA@iRNP remarkably extended the in vivo half-life of t-PA in systemic circulation. Using a mouse model of photo-thrombotic middle cerebral artery occlusion, we found that t-PA@iRNP treatment, compared with naked t-PA, void iRNP, or t-PA@niRNP (non-ROS scavenging nanoparticle as a control), significantly suppressed increases in cerebral infarct volume and improved neurological deficit after brain ischemia. t-PA-induced subarachnoid hemorrhage was also suppressed by t-PA@iRNP treatment through elimination of overproduced ROS. Based on these data, t-PA@iRNP presents therapeutic potential through synergistic effect of thrombolysis and antioxidant effects for preventing and treating ischemia-reperfusion injury., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Nitric oxide (NO) possesses various functions in cardiovascular diseases; however, due to an extremely short half-life and low bioavailability, its therapeutic application is limited. In inflamed tissues, overproduced reactive oxygen species (ROS) rapidly react with the endogenous NO, reducing its bioavailability. Here, we developed a controllable NO-releasing redox injectable hydrogel (NO-RIG) formed by the electrostatic crosslinking between the polyion complex flower-type micelles composing of functional polymers to scavenge overproduced ROS and regulate the local NO expression level simultaneously. After the intracardiac injection to mice, NO-RIG converted to gel via physiological temperature-responsive character, distributed homogeneously, and retained in the myocardial tissue for more than 10 d. Treatment with NO-RIG remarkably decreased the infarction size and improved the heart function after myocardial infarction when compared to control injectable hydrogels, such as a simple NO-releasing or ROS-scavenging injectable gels. We found that NO-RIG treatment significantly enhanced the angiogenesis and new blood vessels formation in mice through the regulation of the NO sustained release and redox equilibrium. NO-RIG presents high potential in preventing and treating cardiovascular diseases., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although oral drug delivery is the most common route of drug administration, the conventional polymeric nanocarriers exhibit a low drug loading capacity and low stability in the gastrointestinal (GI) environments. In this study, a newly designed silica-containing redox nanoparticle (siRNP) with reactive oxygen species (ROS) scavenging capacity is developed as an ideal oral nanocarrier for a novel hydrophobic anticancer compound BNS-22 to treat colitis-associated colon cancer in vivo. Crosslinking of silica moieties significantly enhances the stability under acidic conditions and improves BNS-22 loading capacity of siRNP compared to the conventional redox nanoparticle. After oral administration to mice, BNS-22-loaded siRNP (BNS-22@siRNP) remarkably improves bioavailability and colonic tumor distribution of BNS-22. As the result, BNS-22@siRNP significantly inhibits the tumor progression in colitis-associated colon cancer mice compared to other control treatments. It is noteworthy that no systemic absorption of siRNP carrier is observed after oral administration. Interestingly, orally administered BNS-22@siRNP significantly suppresses the adverse effects of BNS-22 owing to its ROS scavenging capacity, and no other noticeable toxicities are observed in mice treated with BNS-22@siRNP although siRNP is localized in the GI tract. Our results indicate that siRNP is a promising oral drug nanocarrier for cancer therapy., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The present study aimed to assess whether our newly developed redox nanoparticle (RNP N ) 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 RNP N solution for 6 months, including memory and learning functions, antioxidant activity, and amyloid plaque aggregation. The results showed that RNP N -treated mice had significantly attenuated cognitive deficits of both spatial and non-spatial memories, reduced oxidative stress of lipid peroxide, and DNA oxidation. RNP N 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 RNP N may be a promising candidate for AD therapy because of its antioxidant properties and reduction in Aβ aggregation, thereby suppressing its adverse side effect.

Recently, we have been developing polymer and nanoparticle-based antioxidative nanotherapeutics. Our strategy is to eliminate overproduced reactive oxygen species (ROS), which are strongly related to various diseases. In order to facilitate the transition of the nanotherapeutics into clinical studies, we investigated the toxicity and antioxidant activity of our nanoparticles in a zebrafish model. In this study, zebrafish larvae were exposed to our highly ROS-scavenging nanoparticle (RNP(O)), which was prepared using our original amphiphilic block copolymer, methoxy-poly(ethylene glycol)-b-poly[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)oxymethylstyrene] (MeO-PEG-b-PMOT). When the larvae were exposed to 10-30 mM of low-molecular-weight (LMW) nitroxide radical (4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl; TEMPOL), all were dead after 12 h, whereas no larva death was observed after exposure to RNP(O) at the same high concentrations. By staining mitochondria from the larvae, we found that LMW TEMPOL significantly induced mitochondrial dysfunction. In contrast, RNP(O) did not cause any significant reduction in the mitochondrial function of zebrafish larvae. It is important to reaffirm that RNP(O) treatment significantly enhanced survival of larvae treated with ROS inducers, confirming the antioxidant activity of RNP(O). Interestingly, RNP(O) exposure induced the expression of Nrf2 target gene (gstp1) in the larvae's intestines and livers. The results obtained in this study indicate that the antioxidative nanoparticle RNP(O) has great potential for clinical trials as it exhibits a potent therapeutic effect and extremely low toxicity to zebrafish embryos.

Conventional chemotherapeutic drugs such as doxorubicin (DOX) are associated with severe adverse effects such as cardiac, hepatic, and gastrointestinal (GI) toxicities. Excessive production of reactive oxygen species (ROS) was reported to be one of the main mechanisms underlying these severe adverse effects. Recently, we have developed 2 types of novel redox nanoparticles (RNPs) including pH-sensitive redox nanoparticle (RNP(N)) and pH-insensitive redox nanoparticle (RNP(O)), which effectively scavenge overproduced ROS in inflamed and cancerous tissues. In this study, we investigated the effects of these RNPs on DOX-induced adverse effects during cancer chemotherapy. The DOX-induced body weight loss was significantly attenuated in the mice treated with RNPs, particularly pH-insensitive RNP(O). We also found that cardiac ROS levels in the DOX-treated mice were dramatically decreased by treatment with RNPs, resulting in the reversal of cardiac damage, as confirmed by both plasma cardiac biomarkers and histological analysis. It was interesting to notice that, during cotreatment with DOX and RNPs, the DOX uptake was significantly enhanced in the cancer cells, but not in healthy aortic endothelial cells in vitro. Treatment with RNPs also improved anticancer efficacy of DOX in the colitis-associated colon cancer model mice in vivo. On the basis of these results, a combination of the novel antioxidative nanotherapeutics (RNPs) with conventional anticancer drugs seems to be a robust strategy for well-tolerated anticancer therapy.

Although current medications for ulcerative colitis (UC) are effective to some extent, there are still some limitation of their use due to the non-specific distribution, drug metabolism in the gastrointestinal tract, and severe adverse effects. In our previous studies, we developed oral redox nanoparticles (RNP(O)) that specifically accumulated and scavenged overproduced reactive oxygen species (ROS) in an inflamed colon. However, the mechanism leading to specific accumulation of RNP(O) in an inflamed colon is still unclear. In this study, we investigated the cellular uptake of RNP(O) into ROS-treated epithelial colonic cells in vitro, and compared to the untreated cells, found a significantly increased uptake in ROS-treated cells. In vivo, we discovered that orally administered RNP(O) were not internalized into the cells of a normal colon. A significant amount of disintegrated RNP(O) was detected in the cells of an inflamed colon of dextran sodium sulfate (DSS)-induced colitis mice, resulting in scavenging of ROS and suppression of inflammation with low adverse effects. Furthermore, we confirmed a significant reduction of disease activity and a robust dose response efficacy following RNP(O) treatment in acute DSS-induced colitis mice, outperforming the positive control 5-aminosalicylic acid. Oral administration of RNP(O) is a promising approach to develop a new therapy for UC disease., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Oral chemotherapy is the preferred treatment for colon cancer. However, this strategy faces many challenges, including instability in the gastrointestinal (GI) tract, insufficient bioavailability, low tumor targeting, and severe adverse effects. In this study, we designed a novel redox nanoparticle (RNP(O)) that is an ideal oral therapeutics for colitis-associated colon cancer treatment. RNP(O) possesses nitroxide radicals in the core, which act as reactive oxygen species (ROS) scavengers. Orally administered RNP(O) highly accumulated in colonic mucosa, and specifically internalized in cancer tissues, but less in normal tissues. Despite of long-term oral administration of RNP(O), no noticeable toxicities were observed in major organs of mice. Because RNP(O) effectively scavenged ROS, it significantly suppressed tumor growth after accumulation at tumor sites. Combination of RNP(O) with the conventional chemotherapy, irinotecan, led to remarkably improved therapeutic efficacy and effectively suppressed its adverse effects on GI tract. Therefore, RNP(O) is promising oral nanotherapeutics for cancer therapies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.

Aim: Oxidative stress (OS) is largely thought to be a central mechanism responsible for liver damage, inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Our aim was to investigate whether suppression of OS in the liver via redox nanoparticles (RNPs) reduces liver damage in a mouse model of NASH., Materials & Methods: RNPs were prepared by self-assembly of redox polymers possessing antioxidant nitroxide radicals and were orally administered by daily gavage for 4 weeks., Results: The redox polymer was delivered to the liver after disintegration of nanoparticle in the stomach. RNP treatment in NASH mice via gavage led to a reduction of liver OS, improvement of fibrosis, and significant reduction of inflammation., Conclusion: These findings uncover RNP as a novel potential NASH therapy., Competing Interests: Financial & competing interests disclosure This study was presented in part during an oral ePOSTER presentation of the Annual Meeting of the European Association for the Study of the Liver (ESAL), held in Amsterdam, The Netherlands, April 2013 and in one of the Poster of Distinction of Falk symposium 191, held in London, October 2013. This work was supported by NIH grants U01AA022489 and DK082451 to AE Feldstein, supported by a Grant-in-Aid for Scientific Research S (no. 25220203) and the World Premier International Research Center Initiative (WPI Initiative) on Materials Nanoarchitronics to Y Nagasaki, and supported by a Grant-in-Aid for challenging Exploratory Research (no. 24659014) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan to T Yoshitomi. UCSD Neuroscience Core for microscopy is supported by a grant P30 CA23100. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Silica nanoparticles were synthesized via a sol-gel method in which tetraethyl orthosilicate was hydrolyzed by the alkaline core of the nitroxide radical-containing nanoparticle (RNP). The silica nanoparticles were successively captured in the RNP core to obtain silica/RNP nanocomposite (siRNP). Alternatively, siRNP was prepared using commercially available silica nanoparticles. The amount of elemental Si present in the siRNPs was controlled from 3 wt% to 12 wt%. Notably, the obtained siRNPs were stable in acidic media, whereas the starting RNP disintegrated immediately. Crosslinking of the RNP by the entrapped silica might improve stability of the siRNPs under such acidic conditions. Rebamipide was found to be stably encapsulated in the cores of the prepared siRNPs even under acidic conditions, probably due to the both basic environment of the cores and absorption tendencies of the entrapped silica. Under neutral to alkaline conditions, release of the rebamipide is accelerated, which is probably due to the repulsion between the anionic silica surface and the anionic rebamipide. Rebamipide-loaded siRNPs (rebamipide@siRNP) were orally administered to mice, and the plasma level of rebamipide was checked at predetermined time intervals, showing a significantly higher uptake of rebamipide in the plasma when compared to orally-administered free rebamipide. Because siRNP possesses nitroxide radicals in the core, it is confirmed that dextran sodium sulfate-induced colon inflammation was effectively suppressed by the oral administration of rebamipide@siRNP in mice.

Background: Patients with ulcerative colitis (UC) exhibit overproduction of reactive oxygen species (ROS) and imbalance of colonic microflora. We previously developed a novel redox nanoparticle (RNP(O)), which effectively scavenged ROS in the inflamed mucosa of mice with dextran sodium sulfate (DSS)-induced colitis after oral administration. The objective of this study was to examine whether the orally administered RNP(O) changed the colonic microflora in healthy mice and those with colitis., Methods: RNP(O) was synthesized by self-assembly of an amphiphilic block copolymer that contains stable nitroxide radicals in hydrophobic side chain via ether linkage. Colitis was induced in mice by supplementing DSS in drinking water for 7 days, and RNP(O) was orally administered daily during DSS treatment. The alterations of fecal microflora during treatment of DSS and RNP(O) were investigated using microbiological assays., Results: We investigated that RNP(O) did not result in significant changes to the fecal microflora in healthy mice. Although total aerobic and anaerobic bacteria were not significantly different between experimental groups, a remarkable increase in commensal bacteria (Escherichia coli and Staphylococcus sp.) was observed in mice with DSS-induced colitis. Interestingly, orally administered RNP(O) remarkably reduced the rate of increase of these commensal bacteria in mice with colitis., Conclusions: On the basis of the obtained results, it was confirmed that the oral administration of RNP(O) did not change any composition of bacteria in feces, which strongly suggests a protective effect of RNP(O) on healthy environments in intestinal microflora. RNP(O) may become an effective and safe medication for treatment of UC.

Background: Continuous administration of low-dose nonsteroidal anti-inflammatory drugs such as indomethacin (IND) is associated with an increased risk of gastrointestinal damage. In this study, the authors developed IND-loaded redox nanoparticles (IND@RNP(O)) with core-shell-type polymeric micelles possessing nitroxide radicals as reactive oxygen species scavengers., Results: Orally administered IND@RNP(O) significantly accumulated in the intestinal mucosa and improved blood uptake of IND. Because of the reactive oxygen species-scavenging effect, IND@RNP(O) did not cause severe inflammation in the small intestine; this effect sharply contrasted with those of orally administered free-IND and IND-loaded polymeric micelles that do not possess reactive oxygen species scavengers., Conclusion: Oral IND@RNP(O) administration is a useful approach for improving the oral bioavailability of IND and suppressing its adverse effects.

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 (RNP(O)), 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 RNP(O) in the small intestine were determined using fluorescent-labeled RNP(O) and electron spin resonance. After oral administration, the accumulation of RNP(O) in both the jejunum and ileum tissues was about 40 times higher than those of low-molecular-weight nitroxide radical compounds, and RNP(O) was not absorbed into the bloodstream via the mesentery, thereby avoiding the adverse effects of nitroxide radicals in the entire body. RNP(O) 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, RNP(O) also significantly increased the survival rate of mice treated daily with IND. On the basis of these results, RNP(O) is promising as a nanotherapeutics for treatment of inflammation in the small intestine of patients receiving NSAIDs., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background & Aims: Drugs used to treat patients with ulcerative colitis are not always effective because of nonspecific distribution, metabolism in the gastrointestinal tract, and side effects. We designed a nitroxide radical-containing nanoparticle (RNP(O)) that accumulates specifically in the colon to suppress inflammation and reduce the undesirable side effects of nitroxide radicals., Methods: RNP(O) was synthesized by assembly of an amphiphilic block copolymer that contains stable nitroxide radicals in an ether-linked hydrophobic side chain. Biodistribution of RNP(O) in mice was determined from radioisotope and electron spin resonance measurements. The effects of RNP(O) were determined in mice with dextran sodium sulfate (DSS)-induced colitis and compared with those of low-molecular-weight drugs (4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl [TEMPOL] or mesalamine)., Results: RNP(O), with a diameter of 40 nm and a shell of poly(ethylene glycol), had a significantly greater level of accumulation in the colonic mucosa than low-molecular-weight TEMPOL or polystyrene latex particles. RNP(O) was not absorbed into the bloodstream through the intestinal wall, despite its long-term retention in the colon, which prevented its distribution to other parts of the body. Mice with DSS-induced colitis had significantly lower disease activity index and less inflammation following 7 days of oral administration of RNP(O) compared with mice with DSS-induced colitis or mice given low-molecular-weight TEMPOL or mesalamine., Conclusions: We designed an orally administered RNP(O) that accumulates specifically in the colons of mice with colitis and is more effective in reducing inflammation than low-molecular-weight TEMPOL or mesalamine. RNP(O) might be developed for treatment of patients with ulcerative colitis., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)