How to Continuously Release Nitric Oxide

Nitric Oxide Release

More interestingly, NO release occurs (albeit with low yields) upon irradiation with 660-nm light, a wavelength within the therapeutic window.

From: Advances in Inorganic Chemistry , 2015

From Zeolites to Porous MOF Materials - The 40th Anniversary of International Zeolite Conference

Bo Xiao , ... Russell E. Morris , in Studies in Surface Science and Catalysis, 2007

2.5. NO release experiments

Dynamic NO release experiments were conducted by passing nitrogen gas of given humidity through the sample bed. The concentration of NO released from zeolites varying with time was measured using a Sievers NOA 280i chemiluminescence NO analyzer. The instrument was calibrated by passing air through a zero filter (Sievers, <1 ppb NO) and NO gas (89.48 ± 0.9 ppm mol, Air Products, balance nitrogen) prior to NO releasing experiment. The flow rate of nitrogen carrying gas was set to 180 mL/min with a cell pressure of 8.5 Torr and an oxygen pressure of 6.1 psig.

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Nitric oxide-releasing polyurethanes

J. Pant , ... H. Handa , in Advances in Polyurethane Biomaterials, 2016

14.2 Nitric oxide-releasing/generating polyurethanes

PUs offer several applications in blood-contacting devices. Many strategies have been studied to create localized NO release/generation from various PU materials. As discussed above, NORel polymers are prepared by covalently or noncovalently incorporating NO donor molecules into polymer matrices. Diazeniumdiolates have been incorporated into polymers for a variety of potential applications. Taite et al., incorporated poly(ethylene glycol) and a diazeniumdiolate NO donor into the backbone of PU in addition to incorporating the laminin-derived cell adhesive peptide sequence tyrosine–isoleucine–glycine–serine–arginine (YIGSR) (Taite et al., 2008 ). Nitric oxide release was sustained over a 2  month period as measured by Griess assay. The NO release and YIGSR sequence worked synergistically, where NO improved thromboresistance and endothelial cell proliferation while YIGSR promoted endothelial cell adhesion and migration.

Reynolds et al. suggested two novel strategies for the synthesis of NO-releasing PU with covalently linked diazeniumdiolated secondary amines (Reynolds et al., 2006). To achieve this, the diazeniumdiolate moiety was covalently attached onto amines within the polymer backbone of Pellethane 2363-80AE. However the NO-releasing polymers resulting from this synthetic strategy required incorporation of countercations to stabilize the diazeniumdiolates. In the second approach, the polymer was derivatized to contain pendant polyamine sites, which act as a linker to covalently bind the diazeniumdiolates. These diazeniumdiolates were found to be stable without additives, likely because the pendant amines are less rigid than the polymer backbone and allow the zwitterionic diazeniumdiolate to form more easily. Covalently bound NO donors have the advantage that the by-products remain covalently bound to the polymer matrix. The results showed an initial NO flux of 14   pmol/cm²/s when immersed in pH 7.4 buffer at 37   °C for up to 6   days. Other diazeniumdiolate-based NO-releasing implants have proved helpful in decreasing the local chronic inflammation response by 33% and enhancing formation of blood vessels by >77% in vivo in adult male Sprague–Dawley rats (Hetrick et al., 2007). In addition, NO release helped in reducing collagen capsule thickness in rat models by >50% around the implant as compared to controls.

Success in using NO donors for preventing thrombosis either by covalently linking NO donors to the polymer or by embedding them within the polymers (NORel polymers) has been reported. However, the utility of NORel PUs can be limited by their sensitivity toward heat, light, and moisture, leading to decreased NO release lifetimes. One of the obstacles in delivering NO from the polymers is rapid leaching of the NO donor species, resulting in nonlocalized NO release. For example, rapid leaching of SNAP from PUs with high water uptake such as Techophilic SP-60D6-and Tecoflex SG80A was observed, while PUs with low water uptake such as CarboSil and Elast-eon E2As had minimal leaching (Brisbois et al., 2013). Another concern, especially with diazeniumdiolated-based polymers, is the formation of potentially toxic decomposition products such as N-nitrosoamines, which can lead to cancer (Mowery et al., 2000; Annich et al., 2000). Other limitations include issues with sustained NO release and stability of the NO donor, which could limit shelf life or ability to be sterilized.

To address this stability issue, several NO-generating PUs have been studied. These NOGen polymers have the advantage that they could potentially generate NO for long periods, provided that there is a constant source of endogenous RSNOs. One approach has been the use of various covalently linked Cu(II)–cyclen moieties that have been immobilized onto PU backbones (Oh and Meyerhoff, 2003). Hwang et al. covalently linked Cu(II)–cylen moieties to Tecophilic SP-93A-100, which could potentially be applied to various biomedical devices to improve their hemocompatibility by catalytically generating NO from endogenous RSNOs (Hwang and Meyerhoff, 2008). Puiu et al. derivatized two different PUs, Pellethane™ and Tecophilic^®, to incorporate NO-generating Cu(II)–cyclen moieties on the backbone of the PU (Puiu et al., 2009). Tecophilic^® thermoplastic PUs are aliphatic, polyether-based PUs, which have high water uptakes (up to 150% of the weight of the dry resin). In contrast, Pellethane™ is a high-strength, aromatic thermoplastic PU. A three-step synthetic approach is used to prepare Cu(II)–cyclen–PU material with these polymers. This NOGen polymer was able to produce physiological levels of NO in the presence of RSNOs without the use of an aminated linker. Tecophilic^® thermoplastic PU, due to its lower reactivity, had a lower percentage of incorporation of isocyanate (NCO) and therefore fewer cyclen/Cu(II) sites. However, higher water uptake allows for greater NO generation due to better diffusion of the RSNO species to the active Cu(II) sites. Owing to these properties, the newly developed material possesses great potential to be utilized in vivo as a coating material for various blood-contacting device applications.

These examples demonstrate the various chemistries that have been used to incorporate NO-releasing/generating materials in medical grade PUs. Below are specific examples of NO-releasing/generating PUs that have been examined for some specific biomedical applications.

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Multistimuli-responsive magnetic assemblies

Abdulhadi Baykal , ... Abdelhamid Elaissari , in Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications, 2019

6.6.1 Glucose and magnetic responsive for hyperglycemia theranostic

Nitric oxide (NO) is one of the most important biological signaling modulators in different physiological processes. To control in the glucose hemostasis and spatiotemporally regulation NO release and delivery, and based on specific enzymatic reactions between glucose and glucose oxidase (GOx), it had been developed the glucose and magnetic-responsive NO bubble generation theranostic delivery system. As shown in Fig. 6.15, GOx-MMVs structure includes of l-arginine (NO pro-drug) in the inner core, in the shell MNPs, and on the surface GOx assembled. Firstly, to reduce the hyperglycemia levels, the GOx-MMVs carrier is applied as a smart glucose stimuli system. Then by helping of AMF, spatiotemporally controlling the NO gas generation and delivery can be realized by invoking the reaction of H₂O₂ and l-arginine [125,126]. The NO molecule can work as both efficient ultrasound scatters to develop ultrasound imaging and diabetic nephropathy therapeutic agents. As a result, in vivo, the sequential in situ conversion has been possible in db/db type 2 diabetic mice for dose regulation of hyperglycemic levels and NO therapy for renal hypoxia [125].

Fig. 6.15. Schematic diagram of microvesicles encapsulated MNPs and glucose oxidase for dual-stimuli responsive programmable delivery model [125].

Glucose level in the human body needs to a quick monitoring. Enzymatic glucose sensors require highly sensitive. The environmental factors, such as toxic chemicals, humidity, temperature, and pH values, are some of the factors that effect on the sensors. Moreover, due to cross-linking and electro-polymerization, glucose oxidase immobilization which is contained adsorption is an expensive and complicated process [127]. Thus, nonenzymatic glucose sensors became more attractive in the biosensor industry, because they have many advantages like, long-term stability, high selectivity, resistance to thermal implications with low cost and simple synthesis techniques [128]. Core-shell nanocomposite based on chemical oxidative polymerization of pyrrole on ZnFe₂O₄ NPs surface for an amperometric enzyme less glucose sensor has electro catalytic activity for the oxidation of glucose in alkaline solution. The sensor offered good activity for the determination of glucose with the linear concentration range of 0.1–8   mM [129].

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Enteric Nervous System: Structure, Relationships and Functions☆

J.B. Furness , in Reference Module in Biomedical Sciences, 2015

Muscle motor neurons

The ENS contains two types of muscle motor neurons, enteric excitatory neurons that release acetylcholine (ACh) and tachykinins as transmitters, and enteric inhibitory neurons that release nitric oxide (NO), ATP or related nucleotides, and the peptides vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP). For the excitatory neurons, the primary transmitter is ACh and blockers of muscarinic receptors for ACh inhibit excitatory transmission and propulsion along the gastrointestinal tract (Fink, 1959; Trendelenburg, 1917). After muscarinic block there remains a minor component of excitatory transmission that is attributable to the release of tachykinin peptides, the principal tachykinin being substance P (Shimizu et al., 2008).

The control exerted through the co-transmitters of the inhibitory motor neurons is a little complicated and their relative roles vary between species and regions of the gastrointestinal tract (Furness et al., 1995; Goyal et al., 2013; Sanders et al., 2010). The contribution of NO to inhibitory transmission is shown by the attenuation caused by block or knockout of nitric oxide synthase (Mashimo et al., 2000; Rivera et al., 2011; Sanders and Ward, 1992). The purine component is mediated through P2Y receptors and their pharmacological block reduces the effectiveness of inhibitory transmission (Zhang et al., 2010). The inhibitory peptides, VIP and PACAP appear to have relatively minor roles (Furness, 2006).

Enteric excitatory and inhibitory motor neurons innervate the smooth muscle of the muscularis externa and muscularis mucosae throughout the digestive tract. They are responsible for nerve-mediated contractions and relaxations of the muscle that are associated with mixing and propulsive movements, with contraction and relaxation of sphincters to regulate passage between regions, and with adjustment of volumes of reservoirs, such as the stomach.

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Lasers in orthopaedic surgery

E.N. Sobol , ... A.V. Baskov , in Lasers for Medical Applications, 2013

21.4.2 Mechanisms of low-intensity laser therapy

A number of types of reactions can occur in cells induced by light: ⁶⁶ first, electronic excitation of the photoacceptor leading to changes in redox properties and acceleration of the electron transfer in cytochrome c oxidase, then nitric oxide release from the catalytic center of cytochrome c oxidase, then electron oxidation of oxygen molecules. Also local transient heating of the absorbing chromophores leads to changes in general biochemical activity. The primary physical and chemical reactions in the photoacceptor molecules are followed by a cascade of biochemical reactions in the cell which require no further light activation and occur in the dark (photo signal transducer and amplification chains). These reactions are associated with the changes in the cellular homeostasis parameters. The crucial step is thought to be alteration of the cellular redox potential and pH. ⁶⁶

The direct effect of laser radiation on the cells is connected mainly with the effect on the respiratory chain. In some cases along the respiratory chain, light may activate some specific chemical reactions controlling cellular homeostasis, for example liberation of NO in irradiated macrophages. ⁶⁷ A mitochondrial light-activated cellular signalling pathway (retrograde signalling) has been investigated by Karu. ⁶⁸ The results evidenced that cytochrome c oxidase can work as a signal generator as well as a signal transducer in irradiated cells. It can be suggested that NO, a physiological inhibitor of cytochrome c oxidase (binding to its catalytic center), dissociates from the catalytic center when the enzyme is reduced by irradiation. This event could transiently relieve a block in cytochrome c oxidase that causes a reverse of signalling consequences. Cytochrome c oxidase is an enzyme that catalyses the final step in the mitochondrial respiratory chain: the transfer of electrons from cytochrome c to molecular oxygen. Photoacceptors for light-activated regulation of cellular metabolism are natural components of the cells. Cu and Fe in cytochrome c oxidase generate electronically excited states. Radiation can modulate cell metabolism through the mediation of a universal photoacceptor (terminal enzymes of the respiratory chains). Light can cause physiological responses in cells via the activation of cytochrome c oxidase. Also, it is necessary to take into account that mitochondria have not only life supporting but also death promoting (apoptosis) functions. ⁶⁶

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Nitric Oxide

L.J. Ignarro , in Reference Module in Biomedical Sciences, 2014

Demonstration of Release

The labile nature of NO initially made it difficult to demonstrate unequivocally its existence and release from vascular endothelial cells. Using bioassay techniques, in which an intact arterial segment is perfused through the lumen and the perfusate is allowed to bathe a nearby isolated and mounted strip or ring of endothelium-denuded artery, NO release from the perfused artery in the presence of added endothelium-dependent vasodilators can be easily demonstrated. Modified bioassay procedures, in which the perfusate is directed over a series of several arterial or venous strips arranged in a cascade, such that each strip is separated by about 3 s in flow time, reveal the short biological half-life of NO (Figure 1). This technique has been used to demonstrate NO release from arteries, veins, and cultured arterial endothelial cells and has wide applications in biological research (Moncada et al., 1991).

Figure 1. Bioassay cascade procedure used to study the release and properties of EDRF. Physiological salt solution is perfused by a roller pump through a segment of endothelium (E)-intact blood vessel or a column of isolated endothelial cells. The perfusate is superfused over three strips of E-denuded artery or vein that are precontracted by agents added to a separate superfusion line. Strips are mounted in a series (cascade), separated from one another by 3 s of flow time. Changes in smooth muscle tension are measured by transducers and recorded on chart paper. EDRF release from blood vessels or endothelial cells results in decremental relaxation responses down the cascade of strips due to the short half-life (t _1/2) of EDRF. (Inset) Recordings of typical relaxant responses, downward deflections signifying a loss of muscle tone or relaxation.

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Inorganic Photochemistry

Zofia Stasicka , in Advances in Inorganic Chemistry, 2011

B.2 Ruthenium NO complexes

Complexes of other transition metals, such as Ru, Mn, Cr, Cu, Co, are also capable of regulating the level of NO in biological and environmental systems by the binding and chemical or photochemical release of gaseous NO. In recent years, various transition metal complexes have been synthesized to modulate NO concentrations in cellular environments and control physiological processes that are regulated by NO (33,46,54,75,96).

The high affinity of ruthenium for NO is well documented. Since ruthenium complexes are in general stable, various ruthenium nitrosyls have been isolated and studied in detail in terms of their NO donating capacities. Ruthenium compounds with readily available coordination sites can be used as NO scavengers, whereas ruthenium nitrosyl complexes are investigated as agents controlling the NO-release for medicinal applications, in particular for the control of high blood pressure, and as anti-tumor agents that might release cytotoxic NO within tumor cells, thus leading to cell death.

Modulation of NO release can be induced by one-electron reduction, which occurs at NO⁺ to yield coordinated NO^•, or by photolysis (41,46). Thus, the ruthenium complexes were studied in search for an ideal system for the site-directed NO delivery from thermally stable precursors which can release NO when triggered by light. A large number of [RuNO]⁶ nitrosyls release NO upon exposure to UV light and their potential as NO donors under the control of light has been surveyed. In general, the nitrosyls with nonporphyrin ligands (such as amines, Schiff bases, thiolates, and ligands with carboxamide groups) readily release NO upon illumination and generate Ru(III) photoproducts. In contrast, photolysis of ruthenium nitrosyls derived from porphyrins is followed by a rapid recombination that reduces the release of NO. To date, notable progress has been made in the area of [RuNO]⁶ species derived from polydentate ligands with strong absorption bands in the visible/NIR region that could be used for site-specific light induced NO delivery (75,97–101).

Dinuclear hydrotris(pyrazolyl)borate complexes of ruthenium were reported to be NN coupled by two nitrosyl ligands. These complexes undergo transformation of the NN bridged into the oxo-bridged dinuclear complexes with the release of N₂O. The NN bond is easily cleaved by oxidation and regenerated again by reduction. This observation would provide significant information regarding the mechanism of NO reduction to N₂O by nitrosyl complexes (102).

Similarly to the iron complexes, the nitrite ruthenium compounds might serve as photochemical NO delivery agents (103).

Also the triruthenium cluster, [Ru₃(μ₃-O)(μ-CH₃COO)₆(CO)(L₁)(L₂)] (where L₁  =   [(NC₅H₄)CH₂NHC(O)(CH₂)₁₀S⁻]₂, L₂  =   4-methylpyridine), which forms a self-assembled monolayer is able to coordinate NO. The NO ligand can be selectively introduced into the cluster to replace the originally bound CO ligand when the Ru₃ cluster is oxidized by one electron, and part of the coordinated NO can also be desorbed from the resultant NO-bound monolayer when the cluster is reduced by one-electron from its original oxidation state (104). These findings demonstrate also new prospects for the NO reactivity pathways in the interfacial environmental space.

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Improving the hemocompatibility of catheters via NO release/generation

Y. Wo , ... M.E. Meyerhoff , in Hemocompatibility of Biomaterials for Clinical Applications, 2018

16.5.1 Chemical-based NO releasing catheters

Amoako et al. developed extruded trilaminar NO-releasing silicone catheters and tested their thrombogenicity in a 4   h rabbit model [189]. An extruded trilayer catheter configuration was used, with the base and top layer consisting of silicone resin and the active layer containing silicone resin with 15   wt% N-(6-aminohexyl)aminopropyl trimethoxysiloxane (DACA-6/SR) and 11   wt% potassium tetrakis (4-chlorophenyl) borate as additives. The catheters were exposed to high pressure of NO (80   psi) to form DACA/NONOate using a NO reactor. The catheters released NO at approximately 6   ±   0.92   ×   10^{−   10}  mol   cm^{−   2}  min^{−   1} under physiological conditions for the first 4   h of testing. However, after storing the catheters dry for 24   h at −   20°C the NO release rate dropped 66.7%, suggesting that this type of NO releasing catheter is not stable enough for long-term storage. Nonetheless, the catheters were implanted in rabbit veins for 4   h, and the average functioning time was 2.3   ±   0.7   h for control catheter (with 4 of 6 occluded), and 4   ±   0   h for the NO release catheters, which all catheters remained patent for this time period [189].

GSNO and SNAP are the two most commonly used RSNOs for therapeutic applications, and the stability of RSNO-based polymeric materials during storage is a very important factor for their further development into clinically useful catheter devices [151,210,211]. Recently, Brisbois et al. discovered that SNAP is exceptionally stable in several low water uptake biomedical grade PU-based copolymers, such as Elast-eon E2As [151] and CarboSil [174], with more than 80% of the initial SNAP remaining after 2 months of storage at 37°C [151]. Wo et al. used Raman spectroscopy and powder X-ray diffraction (PXRD) to further investigate the enhanced stability and NO release mechanism of SNAP-based polymers, such as SNAP-doped Carbosil [174]. A polymer-crystal composite forms during the solvent evaporation process if the SNAP exceeds its solubility in the polymer CarboSil (3.4–4.0   wt%). The SNAP that exceeds the solubility limit exists in stable orthorhombic crystal form within the bulk of the polymer. The proposed mechanism for sustained NO release comes from the slow dissolution process of the SNAP within the bulk of the polymer, initially in the water-rich regions of the polymer, which ultimately leads to stable, continuous NO release over a 3-week period in PBS buffer at 37°C.

Meyerhoff and coworkers have also conducted studies with SNAP [43] or lipophilic SNAP analogs [212] impregnated into existing commercial silicone catheter tubing. SNAP or the analogs were dissolved in organic solvents (e.g., tetrahydrofuran or chloroform), and the catheter tubing was soaked for a given time period to impregnate the SNAP species within the catheter wall at RT. This impregnation process is beneficial because many NO donors are not stable at the high temperatures used during the industrial catheter extrusion processes [43]. The NO released from these impregnated catheters can last for more than 30 days above 0.5   ×   10^{−   10}  mol   cm^{−   2}  min^{−   1}, which is at the lower end of physiological NO released from endothelial cells. These catheters exhibited exceptional antibacterial effects toward several microorganisms (e.g., S. epidermis and S. aureus) [43,212]. This approach provides an excitingly new opportunity of transforming existing commercial biomedical catheters into NO releasing devices with enhanced hemocompatibility, both with respect to decrease in thrombosis as well as microbial infection/biofilm formation.

SNAP-based polymers have been used to fabricate catheters that have already been evaluated in vivo for their hemocompatibility [151,174]. The SNAP/E2As catheters tested in vivo had a trilayer configuration, with plain E2As as base and top layer to reduce SNAP leaching and 10   wt% SNAP/E2As as a NO releasing layer in the middle. These catheters were prepared by a dip-coating method using a suitable mandrel, not the new solvent impregnation method described above. The SNAP/E2As catheters were able to continuously release NO for 20 days under physiological conditions above 0.5   ×   10^{−   10}  mol   cm^{−   2}  min^{−   1}. The SNAP/E2As catheters also retained 88.8   ±   1.7% of original SNAP after ethylene oxide sterilization. After 7 days of implantation within sheep veins, the SNAP/E2As catheters exhibited a significant reduction in thrombus formation when compared to the controls (1.56   ±   0.76 vs. 5.06   ±   1.44   cm² clot area per catheter). The viable bacteria count on the surfaces of SNAP/E2As catheters were also 90% less than on the controls [188]. Similarly, SNAP/CarboSil catheters were fabricated and evaluated for antimicrobial activity against S. aureus in a drip-flow bioreactor. After 7 days, a 5 logarithmic unit reduction in viable cell count was observed on the surfaces of the SNAP/Carbosil catheters when compared to the controls [174]. These studies demonstrate the potential of SNAP-doped biomedical grade polymeric material for improving the hemocompatibility and antibacterial properties of IV catheters.

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Antibacterial polyurethanes

L.-C. Xu , C.A. Siedlecki , in Advances in Polyurethane Biomaterials, 2016

9.3.2.3 Nitric oxide-releasing polyurethanes

Nitric oxide (NO), a diatomic free radical, naturally produced in the body by endothelial cells, is well known as an antithrombogenic mediator and its continuous release from the surface of endothelial cells effectively prevents the adhesion/activation of platelets on normal blood vessel walls. ¹⁶⁸ Hence, materials that release or generate NO locally at the surface to inhibit thrombus formation have been developed with great potential applications in blood-contacting medical devices with improved biocompatibility. ^169,170

Nitric oxide also plays an important role in the immune response as an antimicrobial agent and host defense against pathogenic bacteria. As a free radical, nitric oxide can cross the membranes to enter the microbial cell readily and kill the microbe by directly nitrosating DNA, proteins, and lipids or by combining with reactive oxygen species (e.g., superoxide, peroxide) and oxidizing the same targets. ^171,172 Nitric oxide has been identified as a key mediator of biofilm dispersal and provides an unprecedented opportunity for developing novel treatments to induce biofilm dispersal and improved treatment for chronic infection. ¹⁷³ Nitric oxide is very reactive and has a short lifetime in the order of seconds in the body. Once it enters the body it quickly finds a target. The rapid reduction of microbial loads reduces the pressure for the evolution and spreading of variant bacteria and limits the possibility of promoting nitric oxide-resistant strains.

NO-releasing biomaterials have been developed for antibacterial applications including polymeric materials, ^174,175 xerogel, ^176,177 sol gel, ^178,179 and silica nanoparticles. ¹⁸⁰ Two different classes of NO donors, diazeniumdiolates and nitrosothiols, are commonly used. The diazeniumdiolates, also called as NONOates, are synthesized by reaction of amines with NO gas to form relatively stable compounds that spontaneously release NO on contact with bodily fluids.

The S-nitrosothiols are generally formed by reaction of nitrous acid with the parent thiol and are reported to require copper-mediated decomposition, reaction with ascorbate, or cleavage by light to release NO. ¹⁸¹ NO donors are incorporated into materials either by blending discrete NO donors within polymeric films or covalently attached to polymer backbones and/or to the inorganic polymeric filler particles that are often employed to enhance the strength of biomedical polymers (e.g., fumed silica or titanium dioxide). ¹⁶⁹

A variety of strategies for synthesizing NO-releasing polyurethanes by diazeniumdiolates NO donors have been reported. Jun et al. ¹⁸² synthesized a diazeniumdiolate peptide using standard fluorenylmethoxycarbonyl chemistry from a lysine-containing peptide by reaction with NO, in which the amine groups in lysine residues were converted to diazeniumdiolates and the hydroxyl groups in serine residues are allowed to incorporate the peptide into a polyurethane chain. A polyurethane polymer was obtained by reacting MDI and PTMO and then a combination of BD (1,4-butanediol) and diazeniumdiolate peptide was added as the chain extender. The obtained polyurethane showed two-phase kinetics of NO release: an initial burst within 48   h and a much slower sustained release over 2   months. The platelet adhesion to this NO-releasing polyurethane was dramatically decreased compared to control polyurethane. Reynolds et al. ¹⁸³ reported two novel strategies for synthesizing stable nitric oxide-releasing polyurethanes with covalently attached diazeniumdiolate groups onto secondary amines in a polymer chain. The first approach was to attach diazeniumdiolate groups to secondary amino nitrogen of alkane diamines inserted within the diol chain extender of a polyurethane material, and the second strategy involved ω-haloalkylating the urethane nitrogens and then displacing the halide from the resulting polymer with a nucleophilic polyamine to form a polyurethane with pendant amino groups suitable for diazeniumdiolation. Both were successful in preparing NO-releasing polyurethanes. The flux of molecular NO from the polyurethane by the former strategy reached levels as high as 19   pmol/cm²/s with a total recovery of 21   nmol of NO/mg of polyurethane on immersion in physiological buffer, and the released NO flux was at 14   pmol/cm²/s and a total recovery of 17   nmol/mg from the polyurethanes synthesized by the secondary strategy. Polyurethane films containing polyethyleneimine can also be directly exposed to NO gas to form diazeniumdiolate in situ under pressure of 5   atm and in Ar gas environment. ¹⁸⁴ The NO release capacity increased with increasing polydimethylsiloxane content in the soft segment of the polyurethane, and the NO releasing rates were maintained above the value of quiescent endothelial cells (0.83   pmol/cm²/s) for 5–10   days.

NO-releasing polyurethane can also be synthesized from alternative NO donors, S-nitrosothiols, which are endogenous compounds involved in NO storage and transport in blood. Coneski and Schoenfisch ¹⁸⁵ synthesized a polyurethane incorporating active S-nitrosothiol functionalities into hard and soft segment domains using thiol group protection and postpolymerization modification, respectively, and the polyurethanes were capable of releasing NO up to 0.20   μmol/cm². The total NO release and release kinetics were affected by the nitrosothiol position in hard and soft segment domains of the polyurethanes. Thiol modification on soft segments was the most promising avenue for NO donor incorporation due to the retention of surface restructuring and microphase separation, and high thiol to nitrosothiol conversion efficiencies related to the solution accessibility of the thiols. The decomposition of S-nitrosothiols can be facilitated by copper (II) complex to release NO. Therefore, NO-releasing polyurethanes from S-nitrosothiols are often tethered with a copper (II) complex such as copper (II)–cyclen moieties. ^186,187 Puiu et al. ¹⁸⁸ modified Pellethane^® and Tecophilic^® polyurethanes via covalently linked cyclen/Cu(II) moieties onto structural polymer backbones. Both derivatized polyurethanes were found to produce NO at levels at or above those of endothelial cells. The promising behaviors in prevention of platelet adhesion and blood coagulation make NO-generating polyurethane materials that are able to be used in a wide variety of long-term biomedical applications such as a coating material for catheters, vascular grafts, and other blood-contacting devices.

Since most uses of NO-releasing polyurethanes are still concentrated on the purpose of resistance to thrombosis, reports of NO-releasing polyurethanes for antibacterial application are few. Seabra et al. ¹⁷⁴ reported on the synthesis of NO-releasing polyester for the coating of a polyurethane intravascular catheter. The catheter coated with polymers was shown to release NO in PBS solution at 37   °C at a rate of 4.6   nmol/cm²/h in the first 6   h and 0.8   nmol/cm²/h over the next 12   h, and exerted a potent dose- and time-dependent antimicrobial activity against S. aureus and P. aeruginosa strains. Heilman et al. ¹⁸⁹ synthesized a light-sensitive polyurethane-based composite material entrapped with silica xerogel particles and embedded with the photoactive NO donor manganese nitrosyls. This biocompatible material can readily release NO when exposed to visible light. The polymer film is durable and maintains its NO-releasing capacity for over 3   months of storage and exhibits antibiotic effects against a broad spectrum of bacteria including methicillin-resistant S. aureus, Acinetobacter baumannii, P. aureginosa, and E. coli. It is feasible to use these polymer films for the treatment of infected wounds.

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NOx Related Chemistry

Roberto Santana da Silva , ... Sérgio de Paula Machado , in Advances in Inorganic Chemistry, 2015

11 Trinuclear Oxo-Centered Ruthenium Carboxylates

The study of trinuclear ruthenium carboxylates of general formula [Ru₃O(RCOO)₆(L)₃] ⁿ (L   =   H₂O or N-heterocyclic ligands; n varies from −   1 to +   2) is a consolidated research theme in the literature. Studies began in the early 1970s with the work of Spencer and Wilkinson ( 58 ), but these complexes gained prominence with the classic work of Baumamm and collaborators ( 59 ), who first explored the redox properties of these carboxylates. Within this class of compounds, colloquially called "clusters", those in which the bridge between the metal centers consists of acetate ions are undoubtedly the most representative. The formation of these complexes constitutes an example of self-organization: RuCl₃∙ nH₂O reacts with RCOO and the corresponding carboxylic acid in ethanolic solution. The metal ions spontaneously organize themselves in a trigonal arrangement, bridged by the central oxygen atom and the carboxylate groups. Their typical spectroscopic and electrochemical properties result from the strong electronic interaction between the three Ru ions promoted by oxygen bridges and, to a lesser extent, acetate bridges.

Works on the coordination of NO to the [Ru₃O] center are still scarce in the literature. Spencer and Wilkinson ( 58 ) were the first to attempt the synthesis of a nitrosyl cluster by bubbling NO_(g) in a solution of the [Ru₃O(CH₃COO)₆(CH₃OH)₃]⁺ complex. However, these authors failed to isolate the pure species. In the past years, some authors have taken an interest in studying intramolecular electron transfer reactions in mixed-valence dimers in which the NO ligand acts as a probe to monitor such a reaction by IR spectroscopy ( 60 ). Also, Abe and colleagues have explored the subject of photoinduced NO release; they focused on bioinorganic aspects, but aimed to develop functional surfaces based on monolayers self-assembled on electrodes ( 61 ).

More recently, Brazilian researchers have described that two nitrosyl triruthenium complexes, namely [Ru₃O(CH₃COO)₆(NO)(L)₂]PF₆ (L   =   pyridine and 4-picoline) ( 62,63 ), can release NO and may find potential biological application, as extensively studied by Nikolaou et al. ( 65 ) Direct reaction of the precursor [Ru₃O(CH₃COO)₆(L)₂S]^{1   +} (S   =   solvent) with gaseous NO produces quite stable complexes. This stability stems from the strong interaction between the π* unpaired electron of NO⁰ and the unpaired electron of the [Ru₃O]^{1   +} unit (Ru^III,III,III ₃O), giving rise to interesting spectroscopic properties.

¹H NMR measurements have shown that these nitrosyl complexes display average behavior between those of reduced ([Ru₃O]⁰, diamagnetic species) and oxidized ([Ru₃O]^{1   +}, paramagnetic species) trinuclear complexes. This explains the significant increase in the electron density of the [Ru₃O]^{1   +} unit, a result of the extensive orbital mixing of the metallic and NO⁰ levels and of the consequent interaction between their unpaired electrons. This mixing also impacts the ν(NO) frequencies observed in the infrared spectrum, which apparently does not display the typical correlation with the coligands pK _a.

In chemical terms, these complexes have advantages over other classical NO-releasing molecules such as SNP: they are highly stable in the dark (with respect to NO release), given the large electronic interaction between the [Ru₃O]^{+   1} core and the NO ligand; they display broad absorption band in the visible region, which expands into the therapeutic window; and they contain NO⁰ species rather than NO₂ ⁻ coordinated to the metal center in physiological pH, which does not constitute a site of nucleophilic attack and provides more control over the actual species in solution.

Irradiation of aqueous solutions of these clusters (at physiological pH) with visible light attests to their significant photochemical sensitivity. More interestingly, NO release occurs (albeit with low yields) upon irradiation with 660-nm light, a wavelength within the therapeutic window.

In terms of biological activity, compounds of this class emerge as strong candidates for metallo-drugs, potentially acting as NO-releasing prodrugs. The nitrosyl cluster [(Ru₃O)(CH₃COO)₆(4-pic)₂(NO)]PF₆ remarkably lowers the viability of B16F10 melanoma cells upon irradiation with visible light, although some activity also exists in the dark. Control experiments have shown that NO is the actual active species, because a reduction reaction can release this molecule even in the dark. The solvated [(Ru₃O)(CH₃COO)₆(4-pic)₂(CH₃OH)]PF₆ species has no activity toward this cell line.

As for the ability of the [(Ru₃O)(CH₃COO)₆(3-pic)₂(NO)]PF₆ complex to induce vasodilation under a reducing environment, our results demonstrated that the compound induced 89% vasodilatation of denuded rat aortic rings precontracted with phenylephrin under ambient light. Some dark activity also occurred; however, it was about 3   × smaller (25%) than the activity detected in the presence of light ( 64,65 ).

In the cases mentioned above, it is worth bearing in mind that NO release in the dark may act synergistically with the photoinduced release, increasing the desired effects and opening the possibility of using this kind of compound in therapies other than those mediated by light induction.

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