Sustained Nitric Oxide Release Research Articles

Spatiotemporally responsive cascade bilayer microneedles integrating local glucose depletion and sustained nitric oxide release for accelerated diabetic wound healing

High glucose level, bacterial infection, and persistent inflammation within the microenvironment are key factors contributing to the delay of diabetic ulcers healing, while traditional therapeutic methods generally fail to address these issues simultaneously. Here, we present a spatiotemporally responsive cascade bilayer microneedle (MN) patch for accelerating diabetic wound healing via local glucose depletion and sustained nitric oxide (NO) release for long-term antibacterial and anti-inflammatory effects. The MN patch (G/AZ-MNs) possesses a degradable tip layer loading glucose oxidase (GOx), as well as a dissolvable base layer encapsulating l-arginine (Arg)-loaded nanoparticles (NPs). After wound administration, the base part rapidly dissolved, resulting in prompt separation of the MN tip within the wound tissue, which subsequently responded to the overexpressed matrix metalloproteinase-9 (MMP-9) in diabetic lesions, leading to the responsive release of GOx. The released enzyme catalyzed glucose into gluconic acid and hydrogen peroxide (H2O2), which not only reduced glucose level within the diabetic wound, but also initiated the cascade reaction between H2O2 with the Arg that was released from NPs, thereby achieving continuous production of NO for 7 days. Our findings demonstrate that a single administration of the MN patch could effectively heal non-infected or biofilm-infected diabetic wounds with the multifunctional properties.

Applications of nitric oxide-releasing nanomaterials in dermatology: Skin infections and wound healing

Nitric oxide (NO) is produced in most cells in the skin and is an important regulator of essential cutaneous functions, including responses to UV irradiation, microbial defense, wound healing, melanogenesis and epidermal permeability barrier homeostasis. Harnessing the physiological activities of NO for therapeutic use is difficult because the molecule is highly reactive and unstable. A variety of exogenous NO delivery platforms have been developed and evaluated; however, they have limited clinical applications in dermatology due to instability and poor cutaneous penetration. NO-releasing nanomaterials overcome these limitations, providing targeted tissue delivery, and sustained and controlled NO release. This review provides a comprehensive and up-to-date evaluation of the use of NO-releasing nanomaterials in dermatology for the treatment of skin and soft tissue infections and wound healing.

Nitric oxide releasing novel amino acid-derived polymeric nanotherapeutic with anti-inflammatory properties for rapid wound tissue regeneration.

Endogenous gasotransmitter nitric oxide (NO) is a central signalling molecule that modulates wound healing by maintaining homeostasis, collagen formation, wound contraction, anti-microbial action and accelerating tissue regeneration. The optimum delivery of NO using nanoparticles (NPs) is clinically challenging; hence, it is drawing significant attention in wound healing. Herein, a novel polymeric nanoplatform loaded with sodium nitroprusside (SP) NPs was prepared and used for wound healing to obtain the sustained release of NO in therapeutic quantities. SP NPs-induced excellent proliferation (∼300%) of mouse fibroblast (L929) cells was observed. With an increase in the SP NPs dose at 200 μg mL-1 concentration, a 200% upsurge in proliferation was observed along with enhanced migration, and only 17.09 h were required to fill the 50% gap compared to 37.85 h required by the control group. Further, SP NPs showed an insignificant impact on the coagulation cascade, revealing safe wound-healing treatment when tested in isolated rat RBCs. Additionally, SP NPs exhibited excellent angiogenic activity at a 10 μg mL-1 dose. Moreover, the formulated SP nanoformulation is non-irritant, non-toxic, and does not produce any skin sensitivity reaction on the rat's skin. Further, an in vivo wound healing study revealed that within 11 days of treatment with SP nanoformulation, 99.2 ± 1.0% of the wound was closed, while in the control group, only 45.5 ± 3.8% was repaired. These results indicate that owing to sustained NO release, the SP NP and SP nanoformulations are paramount with enormous clinical potential for the regeneration of wound tissues.

Anti-proliferative, -migratory and -clonogenic effects of long-lasting nitric oxide release in HepG2 cells.

Nitric oxide (NO) holds promise as a cytotoxic agent against tumors, but its gaseous nature and short half-life hinder direct administration to tumor tissues. Herein, we present novel 6,9-disubstituted purine derivatives designed to ensure sustained NO release, followed by study of their significant anti-proliferative, anti-migratory, and anti-clonogenic effects on HepG2 cell lines, highlighting NO release as a potent effector for treating hepatocellular carcinoma.

Inhalable Nitric Oxide Delivery Systems for Pulmonary Arterial Hypertension Treatment.

Pulmonary arterial hypertension (PAH) is a severe medical condition characterized by elevated blood pressure in the pulmonary arteries. Nitric oxide (NO) is a gaseous signaling molecule with potent vasodilator effects; however, inhaled NO is limited in clinical practice because of the need for tracheal intubation and the toxicity of high NO concentrations. In this study, inhalable NO-releasing microspheres (NO inhalers) are fabricated to deliver nanomolar NO through a nebulizer. Two NO inhalers with distinct porous structures are prepared depending on the molecular weights of NO donors. It is confirmed that pore formation can be controlled by regulating the migration of water molecules from the external aqueous phase to the internal aqueous phase. Notably, open porous NO inhalers (OPNIs) can deliver NO deep into the lungs through a nebulizer. Furthermore, OPNIs exhibit vasodilatory and anti-inflammatory effects via sustained NO release. In conclusion, the findings suggest that OPNIs with highly porous structures have the potential to serve as tools for PAH treatment.

Photostimulated Extended Nitric Oxide (NO) Release from Water-Soluble Block Copolymer to Enhance Antibacterial Activity.

N-Nitrosamines are well established motifs to release nitric oxide (NO) under photoirradiation. Herein, a series of amphiphilic N-nitrosamine-based block copolymers (BCPx-NO) are developed to attain controlled NO release under photoirradiation (365 nm, 3.71 mW/cm2). The water-soluble BCPx-NO forms micellar architecture in aqueous medium and exhibits a sustained NO release of 92-160 μM within 11.5 h, which is 36.8-64.0% of the calculated value. To understand the NO release mechanism, a small molecular NO donor (NOD) resembling the NO releasing functional motif of BCPx-NO is synthesized, which displays a burst NO release in DMSO within 2.5 h. The radical nature of the released NO is confirmed by electron paramagnetic resonance (EPR) spectroscopy. The gradual NO release from micellar BCPx-NO enhances antibacterial activity over NOD and exhibits a superior bactericidal effect on Gram-positive Staphylococcus aureus. In relation to biomedical applications, this work offers a comprehensive insight into tuning light-triggered NO release to improve antibacterial activity.

In Situ Photo-crosslinkable Hyaluronic Acid/Gelatin Hydrogel for Local Nitric Oxide Delivery.

An increasing number of studies have shown that the local release of nitric oxide (NO) from hydrogels stimulates tissue regeneration by modulating cell proliferation, angiogenesis, and inflammation. The potential biomedical uses of NO-releasing hydrogels can be expanded by enabling their application in a fluid state, followed by controlled gelation triggered by an external factor. In this study, we engineered a hydrogel composed of methacrylated hyaluronic acid (HAGMA) and thiolated gelatin (GELSH) with the capacity for in situ photo-cross-linking, coupled with localized NO release. To ensure a gradual and sustained NO release, we charged the hydrogels with poly(l-lactic-co-glycolic acid) (PLGA) nanoparticles functionalized with S-nitrosoglutathione (GSNO), safeguarding SNO group integrity during photo-cross-linking. The formation of thiol-ene bonds via the reaction between GELSH's thiol groups and HAGMA's vinyl groups substantially accelerated gelation (by a factor of 6) and increased the elastic modulus of hydrated hydrogels (by 1.9-2.4 times). HAGMA/GELSH hydrogels consistently released NO over a 14 day duration, with the release of NO depending on the hydrogels' equilibrium swelling degree, determined by the GELSH-to-HAGMA ratio. Biocompatibility assessments confirmed the suitability of these hydrogels for biological applications as they display low cytotoxicity and stimulated fibroblast adhesion and proliferation. In conclusion, in situ photo-cross-linkable HAGMA/GELSH hydrogels, loaded with PLGA-GSNO nanoparticles, present a promising avenue for achieving localized and sustained NO delivery in tissue regeneration applications.

Sustained Release of Nitric Oxide-Mediated Angiogenesis And Nerve Repair by Mussel-Inspired Adaptable Microreservoirs for Brain Traumatic Injury Therapy.

Traumatic brain injury (TBI) triggers inflammatory response and glial scarring, thus substantially hindering brain tissue repair. This process is exacerbated by the accumulation of activated immunocytes at the injury site, which contributes to scar formation and impedes tissue repair. In this study, a mussel-inspired nitric oxide-release microreservoir (MINOR) that combines the features of reactive oxygen species (ROS) scavengers and sustained NO release to promote angiogenesis and neurogenesis is developed for TBI therapy. The injectable MINOR fabricated using a microfluidic device exhibits excellent monodispersity and gel-like self-healing properties, thus allowing the maintenance of its structural integrity and functionality upon injection. Furthermore, polydopamine in the MINOR enhances cell adhesion, significantly reduces ROS levels, and suppresses inflammation. Moreover, a nitric oxide (NO) donor embedded into the MINOR enables the sustained release of NO, thus facilitating angiogenesis and mitigating inflammatory responses. By harnessing these synergistic effects, the biocompatible MINOR demonstrates remarkable efficacy in enhancing recovery in mice. These findings benefit future therapeutic interventions for patients with TBI. This article is protected by copyright. All rights reserved.

A multi-targeting bionanomatrix coating to reduce capsular contracture development on silicone implants

BackgroundCapsular contracture is a critical complication of silicone implantation caused by fibrotic tissue formation from excessive foreign body responses. Various approaches have been applied, but targeting the mechanisms of capsule formation has not been completely solved. Myofibroblast differentiation through the transforming growth factor beta (TGF-β)/p-SMADs signaling is one of the key factors for capsular contracture development. In addition, biofilm formation on implants may result chronic inflammation promoting capsular fibrosis formation with subsequent contraction. To date, there have been no approaches targeting multi-facted mechanisms of capsular contracture development.MethodsIn this study, we developed a multi-targeting nitric oxide (NO) releasing bionanomatrix coating to reduce capsular contracture formation by targeting myofibroblast differentiation, inflammatory responses, and infections. First, we characterized the bionanomatrix coating on silicon implants by conducting rheology test, scanning electron microcsopy analysis, nanoindentation analysis, and NO release kinetics evaluation. In addition, differentiated monocyte adhesion and S. epidermidis biofilm formation on bionanomatrix coated silicone implants were evaluated in vitro. Bionanomatrix coated silicone and uncoated silicone groups were subcutaneously implanted into a mouse model for evaluation of capsular contracture development for a month. Fibrosis formation, capsule thickness, TGF-β/SMAD 2/3 signaling cascade, NO production, and inflammatory cytokine production were evaluated using histology, immunofluorescent imaging analysis, and gene and protein expression assays.ResultsThe bionanomatrix coating maintained a uniform and smooth surface on the silicone even after mechanical stress conditions. In addition, the bionanomatrix coating showed sustained NO release for at least one month and reduction of differentiated monocyte adhesion and S. epidermidis biofilm formation on the silicone implants in vitro. In in vivo implantation studies, the bionanomatrix coated groups demonstrated significant reduction of capsule thickness surrounding the implants. This result was due to a decrease of myofibroblast differentiation and fibrous extracellular matrix production through inhibition of the TGF-β/p-SMADs signaling. Also, the bionanomatrix coated groups reduced gene expression of M1 macrophage markers and promoted M2 macrophage markers which indicated the bionanomatrix could reduce inflammation but promote healing process.ConclusionsIn conclusion, the bionanomatrix coating significantly reduced capsular contracture formation and promoted healing process on silicone implants by reducing myfibroblast differentiation, fibrotic tissue formation, and inflammation.Graphical A multi-targeting nitric oxide releasing bionanomatrix coating for silicone implant can reduce capsular contracture and improve healing process. The bionanomatrix coating reduces capsule thickness, α-smooth muscle actin and collagen synthesis, and myofibroblast differentiation through inhibition of TGF-β/SMADs signaling cascades in the subcutaneous mouse models for a month.

Nitric oxide-loaded nano- and microparticle platforms serving as potential new antifungal therapeutics

Fungal diseases are a leading threat to human health, especially in individuals with compromised immunity. Although there have been recent important advances in antifungal drug development, antifungal resistance, drug–drug interactions and difficulties in delivery remain major challenges. Among its pleiotropic actions, nitric oxide (NO) is a key molecule in host defense. We have developed a flexible nanoparticle platform that delivers sustained release of NO and have demonstrated the platform's efficacy against diverse bacteria as well as some fungal species. In this work, we investigate the effects of two NO-releasing particles against a panel of important human yeast. Our results demonstrate that the compounds are both effective against diverse yeast, including ascomycota and basidiomycota species, and that NO-releasing particles may be a potent addition to our armamentarium for the treatment of focal and disseminated mycoses.

Enhancement of mitochondrial function using NO releasing nanoparticles; a potential approach for therapy of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common type of dementia. Increasing evidence is showing the important role of mitochondrial dysfunction in AD. Mitochondria based oxidative stress, decrease in respiratory chain activity and ATP production are all associated with AD, hence indicating that the enhancement of mitochondrial function and biogenesis present a promising therapeutic approach for AD. Nitric oxide (NO) is an initiator of mitochondrial biogenesis. However, its gaseous nature and very short half-life limit the realization of its therapeutic potential. Additionally, its uncontrolled in-vivo distribution results in generalized vasodilation, hypotension among other off-target effects. Diazeniumdiolates (NONOates) are NO donors that release NO in physiological temperature and pH. Their encapsulation within a hydrophobic matrix carrier system could control the release of NO, and at the same time enable its delivery to the brain. In this work, PAPANONOate (PN) a NO donor was encapsulated in small (92 ± 7 nm) poly (lactic-co-glycolic acid) (PLGA) NPs. These NPs did not induce hemolysis upon intravenous administration and were able to accumulate in the brains of lipopolysaccharides (LPS) induced neurodegeneration mouse models. The encapsulation of PN within a hydrophobic PLGA matrix enabled the sustained release of NO from NPs (≈ 3 folds slower relative to free PN) and successfully delivered PN to brain. As a result, PN-NPs but not free PN resulted in an enhancement in memory and cognition in animals with neurodegeneration as determined by the Y-maze test. The enhancement in cognition was a result of increased mitochondria function as indicated by the increased production of ATP and Cytochrome C oxidase enzyme activity.

Thiol-Disulfide Exchange Coordinates the Release of Nitric Oxide and Dexamethasone for Synergistic Regulation of Intestinal Microenvironment in Colitis.

The cell-specific functions of nitric oxide (NO) in the intestinal microenvironment orchestrate its therapeutic effects in ulcerative colitis. While most biomaterials show promise by eliciting the characteristics of NO, the insufficient storage, burst release, and pro-inflammatory side effects of NO remain as challenges. Herein, we report the development of thiol-disulfide hybrid mesoporous organosilica nanoparticles (MONs) that improve the storage and sustained release of NO, broadening the therapeutic window of NO-based therapy against colitis. The tailored NO-storing nanomaterials coordinated the release of NO and the immunoregulator dexamethasone (Dex) in the intestinal microenvironment, specifically integrating the alleviation of oxidative stress in enterocytes and the reversal of NO-exacerbated macrophage activation. Mechanistically, such a synchronous operation was achieved by a self-motivated process wherein the thiyl radicals produced by NO release cleaved the disulfide bonds to degrade the matrix and release Dex via thiol-disulfide exchange. Specifically, the MON-mediated combination of NO and Dex greatly ameliorated intractable colitis compared with 5-aminosalicylic acid, even after delayed treatment. Together, our results reveal a key contribution of synergistic modulation of the intestinal microenvironment in NO-based colitis therapy and introduce thiol-disulfide hybrid nanotherapeutics for the management of inflammatory diseases and cancer.

Inclusion Complexation of S-Nitrosoglutathione for Sustained Nitric Oxide Release from Catheter Surfaces: A Strategy to Prevent and Treat Device-Associated Infections.

S-Nitrosoglutathione (GSNO) is a nontoxic nitric oxide (NO)-donating compound that occurs naturally in the human body. The use of GSNO to deliver exogenous NO for therapeutic and protective applications is limited by the high lability of dissolved GSNO in aqueous formulations. In this paper, we report a host-guest chemistry-based strategy to modulate the GSNO reactivity and NO release kinetics for the design of anti-infective catheters and hydrogels. Cyclodextrins (CDs) are host molecules that are typically used to encapsulate hydrophobic guest molecules into their hydrophobic cavities. However, we found that CDs form inclusion complexes with GSNO, an extremely hydrophilic molecule with a solubility of over 1 M at physiological pH. More interestingly, the host-guest complexation reduces the decomposition reactivity of GSNO in the order of αCD > γCD > hydroxypropyl βCD. The lifetime of 0.1 M GSNO is increased to up to 15 days in the presence of CDs at 37 °C, which is more than twice the lifetime of free GSNO. Quantum chemistry calculations indicate that GSNO in αCD undergoes a conformational change that significantly reduces the S-NO bond distance and increases its stability. The calculated S-NO bond dissociation enthalpies of free and complexed GSNO well agree with the experimentally observed GSNO decomposition kinetics. The NO release from GSNO-CD solutions, compared to GSNO solutions, has suppressed initial bursts and extended durations, enhancing the safety and efficacy of NO-based therapies and device protections. In an example application as an anti-infective lock solution for intravascular catheters, the GSNO-αCD solution exhibits potent antibacterial activities for both planktonic and biofilm bacteria, both intraluminal and extraluminal environments, both prevention and treatment of infections, and against multiple bacterial strains, including a multidrug-resistant strain. In addition to solutions, the inclusion complexation also enables the preparation of GSNO hydrogels with enhanced stability and improved antibacterial efficacy. Since methods to suppress and control the GSNO decomposition rate are rare, this supramolecular strategy provides new opportunities for the formulation and application of this natural NO donor.

Cytotoxicity towards Breast Cancer Cells of Pluronic F-127/Hyaluronic Acid Hydrogel Containing Nitric Oxide Donor and Silica Nanoparticles Loaded with Cisplatin.

The incorporation of both nitric oxide (NO) donor (S-nitrosoglutathione, GSNO) and silica nanoparticles loaded with cisplatin (SiO2@CisPt NPs) into a polymeric matrix represents a suitable approach to creating a drug-delivery system with sustained and localized drug release against tumor cells. Herein, we report the synthesis, characterization, and cytotoxicity evaluation of Pluronic F-127/hyaluronic acid hydrogel containing GSNO and SiO2@CisPt NPs against breast cancer cells. SiO2@CisPt NPs were successfully synthesized, revealing a spherical morphology with an average size of 158 ± 20 nm. Both GSNO and SiO2@CisPt NPs were incorporated into the thermoresponsive Pluronic/hyaluronic hydrogel for sustained and localized release of both NO and cisplatin. The kinetics of NO release from a hydrogel matrix revealed spontaneous and sustained release of NO at the millimolar range for 24 h. The MTT assay showed concentration-dependent cytotoxicity of the hydrogel. The combination of GSNO and SiO2@CisPt incorporated into a polymeric matrix decreased the cell viability 20% more than the hydrogel containing only GSNO or SiO2@CisPt. At 200 µg/mL, this combination led to a critical cell viability of 30%, indicating a synergistic effect between GSNO and SiO2@CisPt NPs in the hydrogel matrix, and, therefore, highlighting the potential application of this drug-delivery system in the field of biomedicine.

Nitrosothiol-functionalized silicate bioceramic scaffolds with enhanced antibacterial property for bone repair

Bacterial infection is a challenge in the field of bone tissue engineering. Antibiotics are often used to combat infection, but the abuse of antibiotics causes nonselective cytotoxicity and induces bacterial drug resistance. Therefore, it is of great clinical significance to develop bone tissue engineering scaffolds with antibacterial properties for bone repair. In this study, polymer-derived β-Ca2SiO4 (C2S) scaffolds were functionalized with nitric oxide (NO) precursors to repair infected bone defects due to their synergistic antibacterial properties by combining a photothermal effect and NO gas therapy. The results showed that the functionalization of C2S scaffolds with NO precursors not only maintained the initial macropore structure and photothermal effect of the scaffolds, but also endowed the scaffolds with sustained NO release ability. Importantly, the NO precursor-functionalized C2S (C2S–SNO) scaffolds improved the proliferation and alkaline phosphatase (ALP) activity of bone marrow mesenchymal stem cells (rBMSCs), as well as the expression of related osteogenic genes. Furthermore, the photothermal effect of the C2S–SNO scaffolds and the NO release induced by near-infrared (NIR) laser irradiation contributed to enhanced antibacterial efficacy, and the inhibition efficiencies of the C2S–SNO scaffolds against Staphylococcus aureus and Escherichia coli were estimated to be approximately 83.3% and 87.5%, respectively. Therefore, the C2S–SNO scaffolds are promising for repairing infected bone defects.

Mechanisms of Foreign Body Response Mitigation by Nitric Oxide Release.

Implantable glucose biosensors provide real-time information about blood glucose fluctuations, but their utility and accuracy are time-limited due to the foreign body response (FBR) following their insertion beneath the skin. The slow release of nitric oxide (NO), a gasotransmitter with inflammation regulatory properties, from a sensor surface has been shown to dramatically improve sensors’ analytical biocompatibility by reducing the overall FBR response. Indeed, work in a porcine model suggests that as long as the implants (sensors) continue to release NO, even at low levels, the inflammatory cell infiltration and resulting collagen density are lessened. While these studies strongly support the benefits of NO release in mitigating the FBR, the mechanisms through which exogenous NO acts on the surrounding tissue, especially under the condition of hyperglycemia, remain vague. Such knowledge would inform strategies to refine appropriate NO dosage and release kinetics for optimal therapeutic activity. In this study, we evaluated mediator, immune cell, and mRNA expression profiles in the local tissue microenvironment surrounding implanted sensors as a function of NO release, diabetes, and implantation duration. A custom porcine wound healing-centric multiplex gene array was developed for nanoString barcoding analysis. Tissues adjacent to sensors with sustained NO release abrogated the implant-induced acute and chronic FBR through modulation of the tissue-specific immune chemokine and cytokine microenvironment, resulting in decreased cellular recruitment, proliferation, and activation at both the acute (7-d) and chronic (14-d) phases of the FBR. Further, we found that sustained NO release abrogated the implant-induced acute and chronic foreign body response through modulation of mRNA encoding for key immunological signaling molecules and pathways, including STAT1 and multiple STAT1 targets including MAPK14, IRAK4, MMP2, and CXCL10. The condition of diabetes promoted a more robust FBR to the implants, which was also controlled by sustained NO release.

Sustained Release of Nitric Oxide and Cascade Generation of Reactive Nitrogen/Oxygen Species via an Injectable Hydrogel for Tumor Synergistic Therapy (Adv. Funct. Mater. 36/2022)

Injectable Hydrogels In article number 2206554, Lin Yu and co-workers develop an injectable and thermosensitive hydrogel with inherent long-acting NO-releasing capacity. The hydrogel system loaded with β-lapachone and CuCys nanoparticles can synchronously boost intracellular reactive oxygen species and reactive nitrogen species levels, thereby synergistically enhancing the anti-tumor efficacy. This hydrogel is suitable as a platform for extending NO-associated medical applications.

Sustained Release of Nitric Oxide and Cascade Generation of Reactive Nitrogen/Oxygen Species via an Injectable Hydrogel for Tumor Synergistic Therapy

AbstractReactive nitrogen species (RNS) generated via the reaction of nitric oxide (NO) with reactive oxygen species (ROS) are more lethal than ROS, and thus RNS‐mediated therapy has great potential in cancer treatment, yet it is still largely unexploited. Herein, a novel, injectable and NO‐releasing hydrogel (NO‐Gel) composed of α‐(nitrate ester) acetic acid‐modified amphiphilic copolymers is developed. To further convert released NO to RNS, glutathione (GSH)‐sensitive CuCys nanoparticles (NPs) and β‐lapachone (Lapa) are co‐loaded into the NO‐Gel. This hydrogel system possesses a temperature‐induced sol‐gel transition and can continuously liberate Lapa, CuCys NPs, and NO in vitro for up to 3 weeks. The sustained supply of Lapa can efficiently boost hydrogen peroxide (H2O2) concentration in cancer cells, and intracellular GSH can induce the rapid release of NO and the reduction of CuCys NPs. With elevating H2O2 levels and producing highly reactive Cu(I), the Cu(I)‐catalyzed Fenton‐like reaction is dramatically enhanced, resulting in the generation of abundant hydroxyl radicals (·OH), and the subsequent cascade reactions among ·OH, H2O2, and NO cause more lethal RNS pool. After a single peritumoral injection of the hydrogel system, the cascade generation of ROS and RNS plus the substantial depletion of GSH can significantly suppress tumor growth.

Alginate/Polyethyleneimine-Based Nitric Oxide-Releasing Hydrogel As a Potential Platform to Study the Effects of NO on Carcinogenesis

Numerous biological functions are affected by the functions of nitric oxide (NO), such as cell proliferation and programmed cell death. NOis a ubiquitous free radical gas that exerts a wide range of biological effects and acts as a signaling molecule in the body. Recent studies have indicated that nitric oxide regulates multiple cancer-related processes, such as angiogenesis, apoptosis, cell cycle, invasion, and metastasis. Alternatively, it is also emerging as a potential anti-oncogenic agent under other conditions. Nitric oxide is synthesized by a complex family of nitric oxide synthase (NOS) enzymes. There is encouraging interest in developing NO-releasing materials as potent tumoricidal agents in which high and localized concentrations of NO may be directly released in a sustained manner to the tumor site. The goal of this project is to develop a hydrogel that incorporates inducible nitric oxide synthase (iNOS) using a layer-by-layer building strategy to form layers of polyethyleneimine (PEI) and iNOSoxy as NO-releasing coatings on alginate hydrogel. When the hydrogel coated with PEI/iNOSoxy films are exposed to arginine, a source of reducing equivalents, and other required ingredients, nitric oxide is formed and released. In this work, FTIR spectroscopy was employed to characterize the functional groups of pristine sodium alginate (SA), polyethyleneimine (PEI) and SA/PEI composite hydrogels. We also used scanning electron microscopy (SEM) for surface characterization. Cyclic voltammetry was used to determine the amount of electroactive heme-enzyme adsorbed on the modified surfaces. We examine how the electroactive heme enzyme in the thin films correlates with the enzymatic NOS activity in terms of NO release fluxes from PEI/NOS-coated hydrogels. After the structural characterization of the NOS/hydrogel films using spectroscopy, we examined their function in terms of NO release profiles. We observed an initial “burst” of NO release during the first 4 hours of activity, followed by a decline and then stable NO release for up to 144 hours possibility to interrogate the role of NO on the balance of cell proliferation and cell death in these cell lines. The measured fluxes are higher than what have been reported in the literature for other inorganic NO-releasing systems. This data will allow us to build NOS-alginate hydrogels with defined NO release profiles for application in cell biology to test the effect of sustained NO release on cell proliferation and cell death on specific cancer cell lines.

Recent Advances in Hydrogel-Mediated Nitric Oxide Delivery Systems Targeted for Wound Healing Applications.

Despite the noticeable evolution in wound treatment over the centuries, a functional material that promotes correct and swift wound healing is important, considering the relative weight of chronic wounds in healthcare. Difficult to heal in a fashionable time, chronic wounds are more prone to infections and complications thereof. Nitric oxide (NO) has been explored for wound healing applications due to its appealing properties, which in the wound healing context include vasodilation, angiogenesis promotion, cell proliferation, and antimicrobial activity. NO delivery is facilitated by molecules that release NO when prompted, whose stability is ensured using carriers. Hydrogels, popular materials for wound dressings, have been studied as scaffolds for NO storage and delivery, showing promising results such as enhanced wound healing, controlled and sustained NO release, and bactericidal properties. Systems reported so far regarding NO delivery by hydrogels are reviewed.