Nitric-Oxide-Modulatory Materials for Biomedical Applications.

Nitric oxide (NO) is an endogenous signaling molecule that participates in various physiological and biological pathways associated with vasodilation, immune response, and cell apoptosis. Interestingly, NO has versatile and distinct functions in vivo depending on its concentration and the duration of exposure; it aids cellular proliferation at nanomolar concentrations but causes cellular death at micromolar concentrations. Therefore, achieving the precise and on-demand modulation of microenvironmental NO concentrations has become a major research target in biomedical fields. To this end, many studies have investigated feasible means for developing functional moieties that can either exogenously donate or selectively scavenge NO. However, these advances are limited by poor stability and a lack of target specificity, which represent two significant obstacles regarding the spatiotemporal adjustment of NO in vivo. Our group has addressed this issue by contributing to the development of next-generation NO-modulatory materials over the past decade. Over this period, we utilized various polymeric, inorganic, and hybrid systems to enhance the bioavailability of traditional NO donors or scavengers in an attempt to maximize their clinical usage while also minimizing their unwanted side effects. In this Account, strategies regarding the rational design of NO-modulatory materials are first summarized and discussed, depending on their specific purposes. These strategies include chemical approaches for encapsulating traditional NO donors inside specific vehicles; this prevents spontaneous NO release and allows said donors to be exposed on-demand, under a certain stimulus. The current status of these approaches and the recent contributions of other groups are also comprehensively discussed here to ensure an objective understanding of the topic. Moreover, in this paper, we discuss strategies for the selective depletion of NO from local inflammatory sites, where the overproduction of NO is problematic. Finally, the major challenges for current NO-modulatory systems are discussed, and requirements are outlined that need to be tackled to achieve their future therapeutic development. Starting from this current, relatively early stage of development, we propose that, through continuous efforts to surmount existing challenges, it will be possible in the future to achieve clinical translations regarding NO-modulatory systems. This Account provides insightful guidelines regarding the rational design of NO-modulatory systems for various biomedical applications. Moreover, it can facilitate the achievement of previously unattainable goals while revolutionizing future therapeutics.

Cognitive Behavioral Therapy for Migraine Headache: A Systematic Review and Meta-Analysis.

Background and Objectives: Migraine headaches are chronic neurological diseases that reduce the quality of life by causing severe headaches and autonomic nervous system dysfunction, such as facial flushing, nasal stuffiness, and sweating. Their major treatment methods include medication and cognitive behavioral therapy (CBT). CBT has been used for pain treatment and various psychogenic neurological diseases by reducing pain, disability, and emotional disorders caused by symptoms of mental illness and improving the understanding of mental health. This study aimed to evaluate the effectiveness and safety of CBT in treating migraines. Materials and Methods: Seven electronic databases were searched from the date of inception to December 2020. Randomized controlled studies (RCTs) using CBT as an intervention for migraine were included. The primary outcome of this study was to determine the frequency of migraines and the intensity of migraines on Visual Analog Scale (VAS), the frequency of drug use, Migraine Disability Assessment (MIDAS), and Headache Impact Test (HIT-6) index. The two authors independently conducted the data extraction and quality assessment of the included RCTs, and conducted meta-analysis with RevMan V.5.4. Results: Among the 373 studies, 11 RCTs were included in this systematic review. Seven out of the 11 RCTs were conducted in the USA, and four were conducted in the UK, Germany, Iran, and Italy, respectively. Headache frequency and MIDAS scores were statistically significant reduced. In the subgroup analysis, headache strength was significantly reduced. Two of the included studies reported adverse effects, including worsening of migraine intensity and frequency, respiratory symptoms, and vivid memory of a traumatic event. Conclusions: CBT for migraine effectively reduced headache frequency and MIDAS score in meta-analysis and headache intensity subgroup analysis, with few adverse events. Additional RCTs with CBT for migraine headaches are needed for a more accurate analysis.

Radiometallic Complexes of DO3A-Benzothiazole Aniline for Nuclear Medicine Theranostics.

To develop a radioactive metal complex platform for tumor theranostics, we introduced three radiopharmaceutical derivatives of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid-benzothiazole aniline (DO3A-BTA, L1) labeled with medical radioisotopes for diagnosis (68Ga/64Cu) and therapy (177Lu). The tumor-targeting ability of these complexes was demonstrated in a cellular uptake experiment, in which 177Lu-L1 exhibited markedly higher uptake in HeLa cells than the 177Lu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complex. According to in vivo positron emission tomography imaging, high accumulation of 68Ga-L1 and 64Cu-L1 was clearly visualized in the tumor site, while 177Lu-L1 showed therapeutic efficacy in therapy experiments. Consequently, this molecular platform represents a useful approach in nuclear medicine toward tumor-theranostic radiopharmaceuticals when 68Ga-L1 or 64Cu-L1 is used for diagnosis, 177Lu-L1 is used for therapy, or two of the compounds are used in conjunction with each other.

Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide.

Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyK peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images.

Deep brain stimulation by blood-brain-barrier-crossing piezoelectric nanoparticles generating current and nitric oxide under focused ultrasound.

Deep brain stimulation via implanted electrodes can alleviate neuronal disorders. However, its applicability is constrained by side effects resulting from the insertion of electrodes into the brain. Here, we show that systemically administered piezoelectric nanoparticles producing nitric oxide and generating direct current under high-intensity focused ultrasound can be used to stimulate deep tissue in the brain. The release of nitric oxide temporarily disrupted tight junctions in the blood-brain barrier, allowing for the accumulation of the nanoparticles into brain parenchyma, and the piezoelectrically induced output current stimulated the release of dopamine by dopaminergic neuron-like cells. In a mouse model of Parkinson's disease, the ultrasound-responsive nanoparticles alleviated the symptoms of the disease without causing overt toxicity. The strategy may inspire the development of other minimally invasive therapies for neurodegenerative diseases.

Lymph-Directed Self-Immolative Nitric Oxide Prodrug for Inhibition of Intractable Metastatic Cancer.

There has been a significant clinical demand for lymph-directed anti-metastatic therapy as tumor-draining lymph nodes play pivotal roles in cancer metastasis which accounts for more than 90% of tumor-related deaths. Despite the high potential of nitric oxide (NO) in anti-cancer therapy owing to its biocompatibility and tumor cell-specific cytotoxicity, the poor stability and lack of target specificity of present NO donors and delivery systems have limited its clinical applications. Herein, a redox-triggered self-immolative NO prodrug that can be readily conjugated to various materials containing free thiol groups such as albumin, is reported. The prodrug and its conjugates demonstrate smart release of NO donor via intramolecular cyclization under reductive conditions, followed by spontaneously generating NO in physiological conditions. The albumin-prodrug conjugate inhibits tumor metastasis by inducing cytotoxicity preferentially on tumor cells after efficiently draining into lymph nodes. This novel prodrug can contribute to the development of on-demand NO delivery systems for anti-metastatic therapy and other treatments.

Polymeric Aggregate-Embodied Hybrid Nitric-Oxide-Scavenging and Sequential Drug-Releasing Hydrogel for Combinatorial Treatment of Rheumatoid Arthritis.

Selective depletion of overproduced nitric oxide (NO) with nanoscavengers is a promising approach for treating rheumatoid arthritis (RA), preventing both oxidative/nitrosative stress and the upregulation of immune cells. However, its practical applications are limited owing to the minimum time interval between intra-articular injections and unwanted off-target NO depletion. Herein, the rational design of an injectable in situ polymeric aggregate-embodied hybrid NO-scavenging and sequential drug-releasing (M-NO) gel platform for the combinatorial treatment of RA by incorporating a "clickable" NO-cleavable cross-linker (DA-NOCCL) is reported. This network is held together with polymeric aggregates to achieve a self-healing capability for visco-supplementation and on-demand dual drug (both hydrophilic and hydrophobic)-releasing properties, depending on the NO concentration. Moreover, consecutive NO-scavenging action reduces pro-inflammatory cytokine levels in lipopolysaccharides-stimulated macrophage cell lines in vitro. Finally, the intra-articularly injected M-NO gel with anti-inflammatory dexamethasone significantly alleviates the symptoms of RA, with negligible toxicity, in animal models. It is believed that this novel M-NO gel platform will provide a guideline for the combinatorial treatment of RA and various NO-related diseases.

A photoacoustic finder fully integrated with a solid-state dye laser and transparent ultrasound transducer.

The standard-of-care for evaluating lymph node status in breast cancers and melanoma metastasis is sentinel lymph node (SLN) assessment performed with a handheld gamma probe and radioisotopes. However, this method inevitably exposes patients and physicians to radiation, and the special facilities required limit its accessibility. Here, we demonstrate a non-ionizing, cost-effective, handheld photoacoustic finder (PAF) fully integrated with a solid-state dye laser and transparent ultrasound transducer (TUT). The solid-state dye laser handpiece is coaxially aligned with the spherically focused TUT. The integrated finder readily detected photoacoustic signals from a tube filled with methylene blue (MB) beneath a 22 mm thick layer of chicken tissue. In live animals, we also photoacoustically detected both SLNs injected with MB and subcutaneously injected melanomas. We believe that our radiation-free and inexpensive PAF can play a vital role in SLN assessment.

Gold nanoparticles functionalized by gadolinium-DTPA conjugate of cysteine as a multimodal bioimaging agent.

The synthesis and characterization of gold nanoparticles coated with Gd-chelate (Au@GdL), where L is a conjugate of DTPA and cysteine, is described. These particles are obtained by the replacement of citrate from the gold nanoparticle surfaces with gadolinium chelate (GdL). The average size of Au@GdL is 14 nm with a loading of GdL reaching up to 2.9x10(3) per particles, and they demonstrate very high R1 relaxivity (approximately 10(5) mM(-1) s(-1)) as well as X-ray attenuation. The R1 relaxivity per [Gd] is 17.9 mM(-1) s(-1). The present system also exhibits macrophage-specific property, as demonstrated by histological and TEM images as well as CT and MR, rendering itself as a new class of T1 multimodal CT/MR contrast agent.

Therapeutic application of metallic nanoparticles combined with particle-induced x-ray emission effect.

Metallic nanoparticles (MNP) are able to release localized x-rays when activated with a high energy proton beam by the particle-induced x-ray emission (PIXE) effect. The exploitation of this phenomenon in the therapeutic irradiation of tumors has been investigated. PIXE-based x-ray emission directed at CT26 tumor cells in vitro, when administered with either gold (average diameter 2 and 13 nm) or iron (average diameter 14 nm) nanoparticles (GNP or SNP), increased with MNP solution concentration over the range of 0.1-2 mg ml(-1). With irradiation by a 45 MeV proton therapy (PT) beam, higher concentrations had a decreased cell survival fraction. An in vivo study in CT26 mouse tumor models with tumor regression assay demonstrated significant tumor dose enhancement, thought to be a result of the PIXE effect when compared to conventional PT without MNP (radiation-only group) using a 45 MeV proton beam (p < 0.02). Those receiving GNP or SNP injection doses of 300 mg kg(-1) body weight before proton beam therapy demonstrated 90% or 75% tumor volume reduction (TVR) in 20 days post-PT while the radiation-only group showed only 18% TVR and re-growth of tumor volume after 20 days. Higher complete tumor regression (CTR) was observed in 14-24 days after a single treatment of PT with an average rate of 33-65% for those receiving MNP compared with 25% for the radiation-only group. A lower bound of therapeutic effective MNP concentration range, in vivo, was estimated as 30-79 µg g(-1) tissue for both gold and iron nanoparticles. The tumor dose enhancement may compensate for an increase in entrance dose associated with conventional PT when treating large, solid tumors with a spread-out Bragg peak (SOBP) technique. The use of a combined high energy Bragg peak PT with PIXE generated by MNP, or PIXE alone, may result in new treatment options for infiltrative metastatic tumors and other diffuse inflammatory diseases.

Synthesis and nuclear factor-kappaB inhibitory activities of 6- or 7-methylchroman-2-carboxylic acid N-(substituted) phenylamides.

A series of 6- or 7-methylchroman-2-carboxylic acid N-(substituted) phenylamides (2a-s, 3a-s) were synthesized. Their abilities to inhibit nuclear factor-kappaB (NF-kappaB) activity were evaluated in lipopolysaccharide (LPS)-stimulated macrophage RAW 264.7 cells. Compounds with substituents such as -H, -CH(3), and -CF(3) on the phenyl ring were poor inhibitors of NF-kappaB. The most active NF-kappaB inhibitors contained 4-Cl (3s) and 4-OMe (3g) in the 7-methylchroman-2-carboxamide derivatives and 2-OH (2b) and 4-Cl (2s) in the 6-methylchroman-2-carboxamide derivatives (IC(50): 20.2-24.0 microM). These were slightly more potent than a reference compound, KL-1156 (1) (IC(50): 43.9 microM).

rac-N,N'-Bis(1-ferrocen-yleth-yl)pyridine-2,6-dicarboxamide.

The title compound, [Fe(2)(C(5)H(5))(2)(C(21)H(21)N(3)O(2))], a potential novel N,N',N''-tridentate ligand with (non-crystallographic) C(2) axial symmetry, adopts a U-shaped molecular conformation.

Gold nanoparticles functionalised by Gd-complex of DTPA-bis(amide) conjugate of glutathione as an MRI contrast agent.

The work is directed toward the synthesis of gold nanoparticles (Au NPs) coated with paramagnetic Gd-complex of DTPA-bis(amide) conjugate of glutathione (GdL) for use as a highly efficient MRI contrast agent. Well-dispersed spherical Au NPs coated with gadolinium complexes, abbreviated as Au@GdL, have been obtained; the mean size of Au@GdL is 5-7 nm, and the numbers of GdL are 1.36x10(4) per Au NP. Au@GdL exhibits high longitudinal (r1) and transverse (r2) relaxivities of 1.87x10(5) and 3.02x10(5) mM(-1) s(-1), respectively.

Synthesis and control of physical properties of titania nanoparticles as a function of synthetic parameters.

TiO2 nanoparticles were prepared by a two step acid-base catalyzed sol-gel method. The effects of key synthetic parameters, including water/alkoxide ratio, pH, reaction time, and calcination temperature on the physical properties of the final product were investigated. The current study revealed that the desired properties can be inherited in to TiO, by controlling the key parameters to the optimized values. It was found that the grain size decreased with an increase in water/alkoxide ratio and reaction time, increased with calcination temperature while remained unaffected by variation in pH. The longer reaction time not only increases surface area but also anatase phase formation can be accomplished even under high pH. Band-gap was also found to reduce with reaction time >48 h. Change of pH during synthesis to high value resulted into mesoporous TiO2 with anatase as a sole phase. The TiO2 nanoparticles were also doped by first row transition metals in order to investigate their effects on the photophysical properties. The photoluminescence characteristic of the TiO2 was altered differently by different doping metals. Doping with first row transition metals reduces the band-gap of TiO2 in the following order: Cr > Mn > Fe approximately V > Co approximately Ni > Cu approximately Zn.

Synthesis of chroman-2-carboxylic acid N-(substituted)phenylamides and their inhibitory effect on nuclear factor-kappaB (NF-kappaB) activation.

A series of chroman-2-carboxylic acid N-(substituted)phenylamides (2a-s, 3a-j) were synthesized. Their ability to inhibit nuclear factor-kappaB (NF-kappaB) activity was evaluated in lipopolysaccharide (LPS)-stimulated macrophage RAW 264.7 cells and their antioxidant activity was examined. NF-kappaB inhibition by chroman compounds was not related to their antioxidant activity. Compounds with -H, -NO2 monosubstituents and -OCH3, -CF3 disubstituents on the phenyl ring were poor inhibitors of NF-kB activity. Compounds with -CH3, -CF3, -CI monosubstituents or -CI, -CH3 disubstituents exhibited moderate to good NF-kappaB activity inhibition (IC50: 18.2-95.8 microM). The most active NF-kappaB inhibitor, 2s, contained a 4-CI (IC50: 18.2 microM) substituent on the phenyl ring and was slightly more potent than the compound KL-1156 (1) (IC50: 43.9 microM).

Surface modification of magnetite nanoparticles using lactobionic acid and their interaction with hepatocytes.

In the current study, superparamagnetic magnetite nanoparticles were surface-modified with lactobionic acid (LA) to improve their intracellular uptake and ability to target hepatocytes. Maltotrionic acid (MA)-modified nanoparticles were also synthesized as a control. Cell culture experiment showed that LA-modified nanoparticles were internalized into hepatocytes and atomic absorption spectrometer (AAS) measurement indicated that the uptake amount of LA-modified magnetite into hepatocytes was higher than that of unmodified and MA-modified nanoparticles. LA-modified nanoparticle solution was injected in rabbit and the magnetic resonance (MR) images obtained showed that LA-coated nanoparticles were selectively accumulated onto the hepatocytes. This result demonstrates that the LA-modified magnetite nanoparticles have a great potential to be used as contrast agent for liver diagnosis.

Manganese Complex of Ethylenediaminetetraacetic Acid (EDTA)-Benzothiazole Aniline (BTA) Conjugate as a Potential Liver-Targeting MRI Contrast Agent.

A novel manganese(II) complex based on an ethylenediaminetetraacetic acid (EDTA) coordination cage bearing a benzothiazole aniline (BTA) moiety (Mn-EDTA-BTA) was designed and synthesized for use as a liver-specific MRI contrast agent with high chelation stability. In addition to forming a hydrophilic, stable complex with Mn2+, this new Mn chelate was rapidly taken up by liver hepatocytes and excreted by the kidneys and biliary system. The kinetic inertness and R1 relaxivity of the complex were much higher than those of mangafodipir trisodium (MnDPDP), a clinically approved liver-specific MRI contrast agent. The diagnostic utility of this new Mn complex in MRI was demonstrated by high-sensitivity tumor detection in an animal model of liver cancer.

Gadolinium Complex of 1,4,7,10-Tetraazacyclododecane-1,4,7-trisacetic Acid (DO3A)-Ethoxybenzyl (EOB) Conjugate as a New Macrocyclic Hepatobiliary MRI Contrast Agent.

We report the synthesis of a macrocyclic Gd chelate based on a 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) coordinationn cage bearing an ethoxybenzyl (EOB) moiety and discuss its use as a T1 hepatobiliary magnetic resonance imaging (MRI) contrast agent. The new macrocyclic liver agent shows high chelation stability and high r1 relaxivity compared with linear-type Gd chelates, which are the current clinically approved liver agents. Our macrocyclic, liver-specific Gd chelate was evaluated in vivo through biodistribution analysis and liver MRI, which demonstrated its high tumor detection sensitivity and suggested that the new Gd complex is a promising contrast agent for liver cancer imaging.

Chiral (iminophosphoranyl)ferrocenes: highly efficient ligands for rhodium- and iridium-catalyzed enantioselective hydrogenation of unfunctionalized olefins.

A series of chiral (iminophosphoranyl)ferrocenes (1-3) are highly efficient ligands for Rh- and Ir-catalyzed hydrogenation of a number of unfunctionalized olefins; almost perfect enantiomeric excesses (up to 99% ee) have been achieved under mild reaction conditions.

A new action potential detector using the MTEO and its effects on spike sorting systems at low signal-to-noise ratios.

This paper considers neural signal processing applied to extracellular recordings, in particular, unsupervised action potential detection at a low signal-to-noise ratio. It adopts the basic framework of the multiresolution Teager energy operator (MTEO) detector, but presents important new results including a significantly improved MTEO detector with some mathematical analyses, a new alignment technique with its effects on the whole spike sorting system, and a variety of experimental results. Specifically, the new MTEO detector employs smoothing windows normalized by noise power derived from mathematical analyses and has an improved complexity by utilizing the sampling rate. Experimental results prove that this detector achieves higher detection ratios at a fixed false alarm ratio than the TEO detector and the discrete wavelet transform detector. We also propose a method that improves the action potential alignment performance. Observing that the extreme points of the MTEO output are more robust to the background noise than those of the action potentials, we use the MTEO output for action potential alignment. This brings not only noticeable improvement in alignment performance but also quite favorable influence over the classification performance. Accordingly, the proposed detector improves the performance of the whole spike sorting system. We verified the improvement using various modeled neural signals and some real neural recordings.