Local Delivery Of Nitric Oxide Research Articles

Hyaluronic Acid-Coated Silica Nanoparticles for Targeted Delivery of Nitric Oxide to Cancer Cells.

Drug resistance and off-target toxicity are two of the greatest challenges to chemotherapeutic melanoma treatments. Nitric oxide (NO) represents an attractive alternative to conventional therapeutics due to its numerous anticancer properties and low probability of engendering resistance. As NO is highly reactive, macromolecular NO donors are needed for the controlled and targeted delivery of NO for therapeutic applications. Herein, mesoporous silica nanoparticles (MSNs) coated with hyaluronic acid (HA) were developed as a NO delivery system to facilitate controlled delivery to cancer cells through both passive and active targeting via the enhanced permeation and retention effect and directed binding of HA with CD44 receptors, respectively. The aminosilane modification, HA concentration, and HA molecular weight were systematically evaluated to facilitate the MSN coating and NO loading. The hydrodynamic diameter and dispersity of the nanoparticles increased after HA coating due to the hydrophilic nature of HA, with greater increases observed at higher HA molecular weight. Lower starting concentrations of HA and aminosilanes with longer alkyl chains favored more efficient HA coating. Faster NO-release kinetics and lower NO payloads were observed for the HA-coated MSNs relative to uncoated MSNs. However, the localized delivery of NO to cancer cells through the active targeting conferred by HA increased levels of oxidative stress and induced mitochondria-mediated apoptosis in melanoma cells. Cytotoxicity was also evaluated against human dermal fibroblasts, with the use of 6 kDa HA-coated MSNs resulting in the greatest therapeutic indices. Enhanced internalization of HA-coated nanoparticles into melanoma cells versus uncoated nanoparticles was visualized with confocal microscopy and quantified by fluorescence spectroscopy. In total, HA-coated MSNs represent a promising NO delivery system for potential use as a chemotherapeutic for skin melanomas.

Injectable Polysaccharide Hydrogels as Localized Nitric Oxide Delivery Formulations

AbstractA series of injectable polysaccharide hydrogels are prepared with oxidized dextran and diethylenetriamine‐modified carboxymethylcellulose (CMC) or hyaluronic acid (HA). Rheological evaluation reveals that CMC‐based hydrogels achieve storage moduli >1 kPa when prepared from 5 wt% solutions, while storage moduli >100 Pa are achievable from solutions with concentrations as low as 2 wt%. HA‐based hydrogels demonstrate smaller storage moduli but have swelling ratios more than four‐fold that of CMC systems at equal concentrations. The incorporation of N‐diazeniumdiolate nitric oxide (NO) donors into the hydrogels results in reduced hydrogel storage moduli as a function of NO donor concentration. The impact of the hydrogel architecture on NO‐release kinetics proves dependent on the identity of the NO donor. Hydrogel degradation over 14 d indicates that HA‐based hydrogels degrade more rapidly than CMC hydrogels and that the addition of NO to the hydrogels increases the rate at which they degrade. In vitro cytotoxicity of hydrogel extracts is minimal, with toxicity observed only at high NO‐donor concentrations for select cell lines. The diverse properties, versatility, and nontoxic characteristics of these injectable hydrogels should facilitate local delivery of nitric oxide for a range of biomedical applications.

Bioactive Nanogels Mimicking the Antithrombogenic Nitric Oxide-Release Function of the Endothelium.

Nitric oxide (NO) plays a significant role in controlling the physiology and pathophysiology of the body, including the endothelial antiplatelet function and therefore, antithrombogenic property of the blood vessels. This property of NO can be exploited to prevent thrombus formation on artificial surfaces like extracorporeal membrane oxygenators, which when come into contact with blood lead to protein adsorption and thereby platelet activation causing thrombus formation. However, NO is extremely reactive and has a very short biological half-life in blood, so only endogenous generation of NO from the blood contacting material can result into a stable and kinetically controllable local delivery of NO. In this regards, highly hydrophilic bioactive nanogels are presented which can endogenously generate NO in blood plasma from endogenous NO-donors thereby maintaining a physiological NO flux.It is shown that NO releasing nanogels could initiate cGMP-dependent protein kinase signaling followed by phosphorylation of vasodilator-stimulated phosphoprotein in platelets. Thisprevents platelet activation and aggregation even in presence of highly potent platelet activators like thrombin, adenosine 5'-diphosphate, and U46619 (thromboxane A2 mimetic).

Local delivery of nitric oxide prevents endothelial dysfunction in periodontitis

AimsIncreased cardiovascular disease risk underlies elevated rates of mortality in individuals with periodontitis. A key characteristic of those with increased cardiovascular risk is endothelial dysfunction, a phenomenon synonymous with deficiencies of bioavailable nitric oxide (NO), and prominently expressed in patients with periodontitis. Also, inorganic nitrate can be reduced to NO in vivo to restore NO levels, leading us to hypothesise that its use may be beneficial in reducing periodontitis-associated endothelial dysfunction. Herein we sought to determine whether inorganic nitrate improves endothelial function in the setting of periodontitis and if so to determine the mechanisms underpinning any responses seen. Methods and resultsPeriodontitis was induced in mice by placement of a ligature for 14 days around the second molar. Treatment in vivo with potassium nitrate, either prior to or following establishment of experimental periodontitis, attenuated endothelial dysfunction, as determined by assessment of acetylcholine-induced relaxation of aortic rings, compared to control (potassium chloride treatment). These beneficial effects were associated with a suppression of vascular wall inflammatory pathways (assessed by quantitative-PCR), increases in the anti-inflammatory cytokine interleukin (IL)-10 and reduced tissue oxidative stress due to attenuation of xanthine oxidoreductase-dependent superoxide generation. In patients with periodontitis, plasma nitrite levels were not associated with endothelial function indicating dysfunction. ConclusionOur results suggest that inorganic nitrate protects against, and can partially reverse pre-existing, periodontitis-induced endothelial dysfunction through restoration of nitrite and thus NO levels. This research highlights the potential of dietary nitrate as adjunct therapy to target the associated negative cardiovascular outcomes in patients with periodontitis.

Red Light-Mediated Photoredox Catalysis Triggers Nitric Oxide Release for Treatment of Cutibacterium Acne Induced Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) has been known as a highly prevalent and disabling disease, which is one of the main causes of low back pain and disability. Unfortunately, there is no effective cure to treat this formidable disease, and surgical interventions are typically applied. Herein, we report that the local administration of nitric oxide (NO)-releasing micellar nanoparticles can efficiently treat IVDD associated with Modic changes in a rat model established by infection with Cutibacterium acnes (C. acnes). By covalent incorporation of palladium(II) meso-tetraphenyltetrabenzoporphyrin photocatalyst and coumarin-based NO donors into the core of micellar nanoparticles, we demonstrate that the activation of the UV-absorbing coumarin-based NO donors can be achieved under red light irradiation via photoredox catalysis, although it remains a great challenge to implement photoredox catalysis reactions in biological conditions due to the complex microenvironments. Notably, the local delivery of NO can not only efficiently eradicate C. acnes pathogens but also inhibit the inflammatory response and osteoclast differentiation in the intervertebral disc tissues, exerting antibacterial, anti-inflammatory, and antiosteoclastogenesis effects. This work provides a feasible means to efficiently treat IVDD by the local administration of NO signaling molecules without resorting to a surgical approach.

Nitric oxide improves regeneration and prevents calcification in bio-hybrid vascular grafts via regulation of vascular stem/progenitor cells.

Vascular bypass surgery continues to use autologous grafts and often suffers from a shortage of donor grafts. Decellularized xenografts derived from porcine veins provide a promising candidate because of their abundant availability and low immunogenicity. Unfortunately, transplantation outcomes are far from satisfactory because of insufficient regeneration and adverse pathologic remodeling. Herein, a nitrate-functionalized prosthesis has been incorporated into a decellularized porcine vein graft to fabricate a bio-hybrid vascular graft with local delivery of nitric oxide (NO). Exogenous NO efficiently promotes vascular regeneration and attenuates intimal hyperplasia and vascular calcification in both rabbit and mouse models. The underlying mechanism was investigated using a Sca1 2A-CreER; Rosa-RFP genetic-lineage-tracing mouse model that reveals that Sca1+ stem/progenitor cells (SPCs) are major contributors to vascular regeneration and remodeling, and NO plays a critical role in regulating SPC fate. These results support the translational potential of this off-the-shelf vascular graft.

Nitric Oxide-Releasing Supramolecular Cellulose Nanocrystal/Silsesquioxane Foams.

Cellulose nanocrystals (CNC)-based foams are promising tissue engineering materials that may facilitate implant-tissue integration and allow localized and controlled drug delivery. Herein, hybrid CNC-based foams, which are ultralightweight (30-100mg cm-3 ), highly porous (>95%), ominiphilic and superabsorbent (1500-3000 wt% of water and/or toluene uptake) are obtained by the in situ condensation of poly(ethylene glycol) ditriethoxysilyl (TES-PEG-TES) into a 3D network, where silsesquioxane nanoparticles (SS-NP) are the crosslinking nodes, and CNC are entrapped forming ionic interactions, in a supramolecular structure. In a new approach, using 3-mercaptopropyltrimethoxysilane, sulfhydryl groups are inserted on the SS-NP periphery and S-nitrosated to enable the functionalization of SS-NP with S-nitrosothiol groups, which can nitric oxide (NO), in a process triggered by the hydration of the foams and modulated by their supramolecular structure. CNC-SS-PEG foams exhibit elevated thermal and structural stability, compressive strength compatible with various soft human tissues, and NO release rates (1-18pmol mg-1 min-1 ) within the range of the beneficial NO actions. Thus, the CNC-SS-PEG foams herein described represent a new platform of supramolecular hybrid materials for localized delivery of NO, with potential uses in tissue engineering and other biomedical applications.

Red-Light-Mediated Photoredox Catalysis Enables Self-Reporting Nitric Oxide Release for Efficient Antibacterial Treatment.

Nitric oxide (NO) serves as a key regulator of many physiological processes and as a potent therapeutic agent. The local delivery of NO is important to achieve target therapeutic outcomes due to the toxicity of NO at high concentrations. Although light stimulus represents a non-invasive tool with spatiotemporal precision to mediate NO release, many photoresponsive NO-releasing molecules can only respond to ultraviolet (UV) or near-UV visible light with low penetration and high phototoxicity. We report that coumarin-based NO donors with maximal absorbances at 328 nm can be activated under (deep) red-light (630 or 700 nm) irradiation in the presence of palladium(II) tetraphenyltetrabenzoporphyrin, enabling stoichiometric and self-reporting NO release with a photolysis quantum yield of 8 % via photoredox catalysis. This NO-releasing platform with ciprofloxacin loading can eradicate Pseudomonas aeruginosa biofilm in vitro and treat cutaneous abscesses in vivo.

Reducing Ischemia/Reperfusion Injury by the Targeted Delivery of Nitric Oxide from Magnetic-Field-Induced Localization of S-Nitrosothiol-Coated Paramagnetic Nanoparticles.

Nitric oxide (NO) is an important factor during an ischemia/reperfusion (I/R) injury. Protective actions of NO during I/R are attributed to antioxidant and anti-inflammatory effects, as well as cell-signaling-based inhibition of nuclear proteins. The therapeutic potential of supplemented NO during I/R is nonetheless uncertain, since peroxynitrite formed from NO near superoxide can be potentially harmful due to NF-κB up-regulation and direct cytotoxicity. This study investigates new technology to provide the magnet-assisted delivery of therapeutic levels of localized NO to targeted I/R tissues using biocompatible gadolinium-oxide-based paramagnetic nanoparticles coated with S-nitrosothiols (SNO-PMNPs). Hamsters fitted with a window chamber were subjected to ischemia by application of a tourniquet at the periphery of the window chamber for 1 h. The SNO-PMNPs were intravenously infused (10 mg/kg) during the reperfusion phase, during which time a localized external magnetic field was either applied or not applied to the I/R area. The microvascular hemodynamics, functional capillary density (FCD), rolling and adherent leukocytes, reactive oxygen and nitrogen species, and tissue viability were assessed using intravital microscopy. Control animals did not receive SNO-PMNPs. Treatment with SNO-PMNPs plus a magnet but not without a magnet increased reflow, decreased leukocytes rolling and sticking in postcapillary venules, limited cell death, and restored the FCD. The absence of the magnet resulted in systemic changes in heart rate and mean arterial blood pressure, consistent with the systemic delivery of NO by the SNO-PMNP. These results indicate that the localized delivery of NO during reperfusion counters the deleterious consequences of peroxynitrite and other reactive species generated upon reperfusion as reflected in localized increases in blood flow and tissue viability, all with minimal systemic effects. This technology can provide the basis for a timely treatment of a localized ischemia-associated disease to prevent injury in different tissues and organs.

Radial artery access site complications during cardiac procedures, clinical implications and potential solutions: The role of nitric oxide.

Percutaneous coronary intervention for the treatment of coronary artery disease is most commonly performed in the UK through the radial artery, as this is safer than the femoral approach. However, despite improvements in technology and techniques, complications can occur. The most common complication, arterial spasm, can cause intense pain and, in some cases, procedural failure. The incidence of spasm is dependent on several variables, including operator experience, artery size, and equipment used. An anti-spasmolytic cocktail can be applied to reduce spasm, which usually includes an exogenous nitric oxide (NO) donor (glyceryl trinitrate). NO is an endogenous local vasodilator and therefore is a potential target for anti-spasm intervention. However, systemic administration can result in unwanted side-effects, such as hypotension. A method that adopts local delivery of NO might be advantageous. This review article describes the mechanisms involved in radial artery spasm, discusses the advantages and disadvantages of current strategies to reduce spasm, and highlight the potential of NO-loaded nanoporous materials for use in this setting.

S-Nitrosothiols as Platforms for Topical Nitric Oxide Delivery.

Nitric oxide (NO) is a small radical species involved in several fundamental physiological processes, including the control of vascular tone, the immune response and neuronal signalling. Endothelial dysfunction with the decreased NO bioavailability is the underlying cause of several diseases and has led to the development of a wide range of systemic NO donor compounds to lower the blood pressure and control hypertensive crises. However, several potential therapeutic actions of NO, not related to the cardiovascular system, demand exclusively local actions. Primary S-nitrosothiols (RSNOs) are endogenously found NO carriers and donors and have emerged as platforms for the localized delivery of NO in topical applications. Formulations for this purpose have evolved from low molecular weight RSNOs incorporated in polymeric films, hydrogels and viscous vehicles, to polymeric RSNOs where the SNO moiety is covalently bound to the polymer backbone. The biological actions displayed by these formulations include the increase in dermal vasodilation, the acceleration of wound healing, the killing of infectious microorganisms and an analgesic action against inflammatory pain. This MiniReview focuses on the state of the art of experimental topical formulations for NO delivery based on S-nitrosothiols and their potential therapeutic applications.

Origin of Long-Term Storage Stability and Nitric Oxide Release Behavior of CarboSil Polymer Doped with S-Nitroso-N-acetyl-D-penicillamine.

The prolonged and localized delivery of nitric oxide (NO), a potent antithrombotic and antimicrobial agent, has many potential biomedical applications. In this work, the origin of the long-term storage stability and sustained NO release mechanism of S-nitroso-N-acetyl-d-penicillamine (SNAP)-doped CarboSil 20 80A polymer, a biomedical thermoplastic silicone-polycarbonate-urethane, is explored. Long-term (22 days) localized NO release is achieved by utilizing a cross-linked silicone rubber as topcoats, which can greatly reduce the amount of SNAP, NAP, and NAP disulfide leaching from the SNAP-doped CarboSil films, as measured by LC–MS. Raman spectroscopy and powder X-ray diffraction characterization of SNAP-doped CarboSil films demonstrate that a polymer–crystal composite is formed during the solvent evaporation process when SNAP exceeds its solubility in CarboSil (ca. 3.4–4.0 wt %). Further, when exceeding this solubility threshold, SNAP exists in an orthorhombic crystal form within the bulk of the polymer. The proposed mechanism of sustained NO release in SNAP-doped CarboSil is that the solubilized SNAP in the polymer matrix decomposes and releases NO, primarily in the water-rich regions near the polymer/solution interface, and the dissolved SNAP in the bulk polymeric phase becomes unsaturated, resulting in the dissolution of crystalline SNAP within the bulk of the polymer. This is a very slow process that ultimately leads to NO release at the physiological flux levels for >3 weeks. The increased stability of SNAP within CarboSil is attributed to the intermolecular hydrogen bonds between the SNAP molecules that crystallize. This crystallization also plays a key role in maintaining RSNO stability within the CarboSil polymer for >8 months at 37 °C (88.5% remains). Further, intravascular catheters fabricated with this new material are demonstrated to significantly decrease the formation of Staphylococcus aureus biofilm (a leading cause of nosocomial bloodstream infections) (in vitro) over a 7 day period, with 5 log units reduction of viable cell count on catheter surfaces. It is also shown that the NO release catheters can greatly reduce thrombus formation on the catheter surfaces during 7 h implantation in rabbit veins, when compared to the control catheters fabricated without SNAP. These results suggest that the SNAP-doped CarboSil system is a very attractive new composite material for creating long-term NO release medical devices with increased stability and biocompatibility.

Development and therapeutic applications of nitric oxide releasing materials to treat erectile dysfunction.

The role of nitric oxide (NO) in erectile physiology is well documented. NO activates relaxation of corporal cavernosal smooth muscle tissue resulting in increased blood flow into the penis resulting in an erection. At present, pharmacologic treatments for erectile dysfunction, such as the phosphodiesterase-5 inhibitors, potentiate the erectile response generated by NO. However, a new class of treatments at a preclinical stage may allow localized delivery of NO to the penis via cutaneous application. These treatments may be of particular value to patients with a neurogenic component to their erectile dysfunction, and may act synergistically with phosphodiesterase-5 inhibitors to increase their efficacy.

A Phase 1, Dose-Escalation Study of Topical Sodium Nitrite in Patients with Sickle Cell Anemia and Leg Ulcers

AbstractAbstract 86▪▪This icon denotes a clinically relevant abstract Background:Leg ulcers are a common and debilitating complication of sickle cell anemia and other hemolytic disorders. Despite many advances in the care of SCD, there is still a clinical need for a well-tolerated, safe and effective therapy. Sodium nitrite may function as a reservoir for local delivery of nitric oxide, whose vasodilating, angiogenic, and antimicrobicidal activities make it an attractive novel therapy for chronic wounds. We describe the safety data and preliminary efficacy data of topical sodium nitrite in adults with sickle cell anemia. Design and Methods:This is a phase 1 dose-escalation, single institution, study of topical sodium nitrite (ClinicalTrials.gov NCT01316796). Eligibility criteria: > 18 years old, have a leg ulcer of > 4 weeks duration, between 2.5 and 100 cm2 in size, and not acutely infected. Patients were screened with medical history, physical exam and laboratory tests. Sodium nitrite cream was applied twice a week for 4 weeks on one leg ulcer (“study ulcer”) in four cohorts of three subjects each with escalating concentrations in each cohort of 0.5., 1, 1.5 and 2%. Safety, tolerability and pharmacokinetic data of plasma nitrite and nitrate were obtained during the first 48 hours of drug exposure and then weekly for four weeks. Leg ulcer healing was a secondary endpoint and was assessed by calculating the change in surface area from visible light photographs of the study leg ulcer obtained at week 1, 3, and end of study, using a digital camera at a distance of 0.25 – 0.5 m from the ulcer. Borders were traced using ENVI software and ulcer size was calculated by converting the pixel area of the ulcer to cm2 using a calibrated square for reference. Pain at the ulcer site was assessed both with a Brief Pain Inventory and Visual Analog Pain Scale at predetermined time points. Results:Sixteen subjects were screened and 12 enrolled. There were no serious adverse events associated with the drug. Possibly related, grade 1; adverse events occurred in 10 of the subjects, more frequently in the cohorts with the highest concentration, which included non-clinically significant decrease in diastolic blood pressure in two subjects of cohort 4. Adverse events resolved without clinical intervention. Methemoglobin levels did not exceed pre-established safety thresholds (max of 4.1 % in one subject in cohort 3). Tolerability was excellent, with short-lived stinging at the site of application reported by two subjects. Pharmacokinetics of plasma nitrite and nitrate indicated minimal systemic absorption of topically applied sodium nitrite (median plasma nitrite AUC: 0.311 (0.169–0.659) umol*h/L/umol nitrite dose), with high interpatient variability. There was no evidence of plasma nitrite and nitrate and methemoglobin accumulation during the 4- week study trial. All but one subject experienced a decrease in leg ulcer surface area, fig 1, (pretreatment 4.65 vs. post-treatment 2.78 cm2, p <.001) and improvement in pain scores (pretreatment 4.87 vs. 2.91, p=.024 ), which often preceded the decrease in size. Healing was most marked in cohort 4, the one treated with the highest strength of sodium nitrite cream, with 2 of 3 subjects experiencing complete closure of the ulcer. Conclusions:On the basis of these safety, pharmacokinetic and tolerability data, and promising efficacy results, topical sodium nitrite warrants further clinical evaluation in patients with sickle cell disease or other hemolytic disorders and leg ulcers. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Local delivery of nitric oxide: Targeted delivery of therapeutics to bone and connective tissues

Local delivery of nitric oxide: Targeted delivery of therapeutics to bone and connective tissues

Solid Films of Blended Poly(Vinyl Alcohol)/Poly(Vinyl Pyrrolidone) for Topical S-Nitrosoglutathione and Nitric Oxide Release

Nitric oxide (NO) is responsible for biological actions in mammals, ranging from the control of arterial pressure to immunological responses. In this study, S-nitrosoglutathione (GSNO), a spontaneous NO donor, was incorporated in solid films of blended poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) comprising a biomaterial with potential for the local delivery of NO. In dry conditions, the extinction of the absorption bands of GSNO was correlated with the increase of the absorption band of its dimmer, GS─SG, implying NO release through the homolytic cleavage of the S─N bond. Mass spectrometry was used to confirm and to monitor the release of free NO from solid PVA/PVP-GSNO films to the gas phase. Kinetic measurement based on the Griess reaction was used to show that solid PVA/PVP-GSNO films are also capable of releasing both NO and GSNO to aqueous solution trough diffusion. Storage experiments have shown that GSNO is highly stabilized in the dry PVA/PVP matrix. The results indicate that GSNO-containing PVA/PVP films may be used for delivering free NO and/or GSNO topically and controllably. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association

Current status of stroke prevention in patients with atrial fibrillation

Atrial fibrillation (AF) is a common dysrhythmia and increases the risk of stroke. Data from primary and secondary trials have shown that anticoagulation with vitamin K antagonists such as warfarin, for example, is the treatment of choice for preventing stroke and systemic cardioembolism. The recommended international normalized ratio is 2.0–3.0, which maintains the balance between risk of ischaemic stroke and bleeding. Anticoagulation with warfarin is more effective than aspirin monotherapy, but ongoing studies are assessing the role of dual antiplatelet therapy (combined aspirin and clopidogrel). Recently, fixed dose ximelagatran, an oral direct thrombin inhibitor, was shown to be as effective as warfarin and well-tolerated. Anticoagulation for patients with acute ischaemic stroke and AF has not resulted in significant improvements in functional outcome, whilst reductions in recurrent stroke were counterbalanced by an increase in intracerebral haemorrhage. Aspirin therefore remains the first line treatment for these patients. Lowering blood pressure and lipids provide additional benefits in reducing the rate of stroke in patients with AF. Other approaches are being assessed, including the local delivery of nitric oxide, and excision of the left atrial appendage, the source of most atrial embolic clots.

Nitric oxide-generating hydrogels inhibit neointima formation

This study evaluated the effects of localized delivery of nitric oxide (NO) from hydrogels covalently modified with S-nitrosocysteine (Cys-NO) on neoinitma formation, a key component of restenosis, in a rat balloon-injury model. Soluble Cys-NO was used in preliminary studies to identify dosage ranges that were able to simultaneously inhibit smooth muscle cell proliferation, enhance endothelial cell proliferation, and reduce platelet adhesion. Photo-cross-linked PEG-based hydrogels were formed with covalently immobilized Cys-NO. These materials release NO for approximately 24 h and can be applied to tissues and photo-cross-linked in situ to form local drug-delivery systems. Localized delivery of NO from hydrogels containing Cys-NO inhibited neointima formation in a rat balloon-injury model by approximately 75% at 14 days.

Thermal and photochemical nitric oxide release from S-nitrosothiols incorporated in Pluronic F127 gel: potential uses for local and controlled nitric oxide release

The local delivery of nitric oxide (nitrogen monoxide, NO) by thermal or photochemical means to target cells or organs has a great potential in several biomedical applications, especially if the NO donors are incorporated into non-toxic viscous matrices. In this work, we have shown that the NO donors S-nitrosoglutathione (GSNO) and S-nitroso- N-acetylcysteine (SNAC) can be incorporated into F127 hydrogels, from where NO can be released thermally or photochemically (with λ irr>480 nm). High sensitivity differential scanning calorimetry (HSDSC) and a new spectrophotometric method, were used to characterize the micellization and the reversal thermal gelation processes of the F127 hydrogels containing NO donors, and to modulate the gelation temperatures to the range 29–32°C. Spectral monitoring of the S–NO bond cleavage showed that the initial rates of thermal and photochemical NO release (ranging from 2 to 45 μmol l −1 min −1) are decreased in the hydrogel matrices, relative to those obtained in aqueous solutions. This stabilization effect was assigned to a cage recombination mechanism and offers an additional advantage for the storage and handling of S-nitrosothiols. These results indicate that F127 hydrogels might be used for the thermal and photochemical delivery of NO from S-nitrosothiols to target areas in biomedical applications.

Local delivery of nitric oxide from an eluting stent to inhibit neointimal thickening in a porcine coronary injury model.

To assess the effect of a NO-eluting stent on reducing neointimal thickening in a porcine coronary artery stent injury model, sodium nitroprusside (SNP), a NO donor, was incorporated into polyurethane (PU) polymer and coated onto metallic coil stents, and two types of stents with thin and thick barrier coatings were characterized. In vivo biological activity of the NO-eluting stents was assessed by measurement of coronary arterial cGMP levels in 32 pigs/64 arteries at days 1, 2, 7 and 14. Morphometric analyses were performed in 16 pigs to determine the effect of NO-eluting stents on neointimal hyperplasia 28 days following arterial injury. The SNP-coated stents released NO in a controlled manner for up to 4 weeks in the in vitro experiments and an increase in local tissue cGMP levels was demonstrated for up to 14 days. The neointimal area at 28 days was not diminished, however, by NO eluded from either stents of thin or thick barriers (control bare stent - 0.66 mm2, control PU stent - 0.68 mm2, SNP-PU thin coating stent - 0.78 mm2, SNP-PU thick coating stent - 0.85 mm2; all p=NS). In conclusion, the SNP-coated polymer stent exerted a local biological effect on the arterial wall, with sustained elevation of cGMP level. Although local delivery of NO from this device did not reduce neointimal hyperplasia in this porcine model, this polymer-coated stent might be a promising tool for administration of other agents that may modify the reparative tissue responses leading to restenosis.