Table 1.
NO donors and delivery vehicles.
| Authors (PMID) | NO donor | Delivery vehicle | NO concentration | NO release half-life or duration | In vitro/ in vivo | Model system | Aim | Outcome |
|---|---|---|---|---|---|---|---|---|
| Zhu et al. (2007) | Sodium nitrite | Gel | 14.6 mM sodium nitrite mixed in equal amounts with maleic acid 14.6 mM + ascorbic acid 14.6 mM cream | Concentration of NO maintained at 10 mM for >1 h after application. | In vivo | Rats | Topical Gel-based NO donor effect on wound healing | Increased anti-inflammatory cell infiltration |
| Zhu et al. (2008) | Sodium nitrite | Gel | 14.6 mM sodium nitrite mixed in equal amounts with low pH acid gel | Concentration of NO maintained at 10 mM for >1 h after application. | In vivo | Mice | Topical NO gel on wound healing | Increased re-epithelization by 50%, hair follicle regeneration, angiogenesis, procollagen—expressing fibroblasts, promotion and infiltration of inflammatory cells in wound beds |
| Phillips et al. (2004) | Sodium nitrite | Cream | 6% wt/wt sodium nitrite mixed with 9.9% wt/wt citric acid cream | Not reported | In vivo | Human clinical trial | Topical nitrite cream effect on ulcer reduction | Reduction in surface area ulcers in Mycobacterium ulcerans wounds |
| Ormerod et al. (2011) | Sodium nitrite | Cream | 3% (w/v) sodium nitrite mixed in equal amounts with 4.5% (w/v) citric acid in aqueous cream | Not reported | In vivo | Human clinical trial | Topical NO cream effect on MRSA wound clearance | Acidified topical nitrites able to clear 60% MRSA wounds |
| Martinez et al. (2009) | Topical NO | Chitosan derived hydrogel/ glass composite |
100 nM peak, 50 nM steady state | Steady state reached after 6 h and maintained for 9 h, ongoing release occurred for ~24 h | In vivo | Mice | NO nanoparticle activity against MRSA wounds | Decreased eschar size, decreased bacterial burden, prevention of collagen degradation |
| Mihu et al. (2010) | Topical NO | Chitosan derived hydrogel/ glass composite |
2.5 mg/ml of NO-np: initial peak 37.5 nM, steady state 20 nM 5 mg/ml of NO-np: initial peak 75 nM, steady state 50 nM 10 mg/ml of NO-np: initial peak 150 nM, steady state 100 nM 20 mg/ml of NO-np: initial peak 300 nM, steady state 200 nM |
Not measured, reported in prior studies as ongoing release for ~24 h (Friedman et al., 2008; Martinez et al., 2009) | In vivo | Mice | NO-np activity on murine Acinetobacter baumannii wound model | Reduced suppurative infection, decreased microbial burden, reduced collagen degradation |
| Mancini et al. (2000) | SNP and 2,2' (hydroxynitrosohydrazino) bis-ethanamine (NOC-18) | SNP: 10μM, 50μM, 100μM NOC-18: 10μM, 50μM, 100μM |
Not reported | In vitro | Rat enriched osteoblast cultures | NO effect on osteoblast activity | Slow, moderate NO release with NOC-18 stimulated osteoblast replication and alkaline phosphatase activity. Rapid high-concentration NO release with SNP inhibited proliferation and induced apoptosis | |
| Abnosi and Pari (2019) | SNP | SNP 100 μM and 1,000 μM | Not reported | In vivo | Rats | Demonstrate possible effect of SNP as an NO-releasing agent on MSC differentiation to osteoblasts | SNP increased matrix deposition, promoted MSC differentiation to osteoblasts and may be useful in promotion of bone repair | |
| Chen et al. (2019) | Dinitrosyl iron complexes (DNIC-1 and DNIC-2) | Direct application of DNICs into wounds | Angiogenesis: 7.8 μM DNIC-1, DNIC-2 Diabetic hindlimb ischemia: 0.18 mg/kg DNIC- |
DNIC-1 t1/2 = 27.4 ± 0.5 h at 25°C and 16.8 ± 1.8 h at 37°CDNIC-2 t1/2 = 1.7 ± 0.1 h at 25°C and 0.8 ± 0.1 h at 37°C | In vivo | Mice | Effect of DNICs on wound healing | DNIC-1 displays best pro-angiogenesis and restores impaired angiogenesis in ischemic hind limbs, increasing wound repair in diabetic mice |
| Shekhter et al. (2015) | Dinitrosyl iron complexes with glutathione (DNIC- GS) | Collagen matrix/ DNIC-GS composite spongy sheets | 4.0 μM DNIC-GS | Complete NO release from matrix in 1 h after submersion in distilled water | In vivo | Rats | DNIC on skin wound healing | Enhanced growth, maturation, and fibrous transformation of granulation tissue |
| Kim et al. (2015) | GSNO | CS/NO-releasing film | 0.625 mM GSNO (2.5, 10 and 20 wt%) in 20 g of chitosan solution | Ongoing NO release at 48 h for all concentrations | In vitro | Rats | CS/NO releasing films on wound healing | Increased wound healing and epithelialization compared to chitosan only films |
| Choi et al. (2020) | GSNO | CS/NO-releasing film | 0.26 μM NO/mg film | Continued NO release up to day 3 | In vitro | Mice | CS/NO releasing films on diabetic wound healing | Enhanced antibacterial activity against MRSA; Greater anti-biofilm activity; Faster biofilm dispersal, wound size reduction, epithelialization rates and collagen deposition than untreated and chitosan only groups |
| Baldik et al. (2002) | SNO-BSA | Demineralized bone matrix | 0.3 mM/L nitrosobovine serum albumin | Not reported | In vivo | Rats | Femoral bone healing defect recovery | Increased union, mineral density, cortex modeling |
| Storm et al. (2014) | NONO xerogels | Xerogel- coated glass slides | Total NO released, μM cm−2: 3.3 ± 0.4, 2.5 ± 0.6, 2.6 ± 0.3, 1.9 ± 0.3, 2.3 ± 0.3 (0, 6, 12, 18, 24 coating layers, respectively) | Apparent t1/2, h: 11.4 ± 0.7, 13.6 ± 1.4, 17.8 ± 4.3, 13.2 ± 0.6, 16.3 ± 2.4 (0, 6, 12, 18, 24 coating layers, respectively) | In vitro | Mice fibroblasts | NO-releasing superhydrophobic xerogel effect on Pseudomonas | Reduction in Pseudomonas aeruginosa compared to control |
| Diwan et al. (2000) | CBC-NO | Surgically implanted NO-releasing chitosan matrix | 200 mg CBC-NO (releases 250 nM NO per 5 mg of CBC-NO) | Duration of NO release = 185 min | In vivo | Rats | NO impact in femoral fracture repair | Day 17 post-fracture: 20% increase in cross-sectional area fracture callus compared to control; 30% |
| compared to NOS inhibition | ||||||||
| Differ et al. (2019) | Deta NONOate, SNAP, L-Arginine | Deta NONOate (10–1,000 μM) SNAP (1–100 μM) Arginine (0.1–7.5 mM) |
Deta NONOate t1/2 = 20 h SNAP t1/2 = 6 h |
In vitro | C2C12BRELuc reporter cell line | BMP2- induced signaling and osteogenic abilities | Enhanced BMP2 signaling and osteogenic induction with all NO donors studied | |
| Charville et al. (2008) | NO diazeniumdiolate-modified xerogels; PVC coated | Xerogel- coated glass slides | 10, 20, 30 and 40% AHAP3 xerogels (average NO flux, pM cm−2 s−1: 11, 18, 23, 30, respectively) | Not reported | In vitro | Bacterial adhesion to fibrinogen coated NO releasing surfaces | Reduced bacterial adhesion for Staphylococcus aureus, Escheria coli and, Staphylococcus epidermidis | |
| Hetrick and Schoenfisch (2007) | NO xerogels | Xerogel- coated glass slides | 10, 20, 30, and 40% AHAP3 xerogels | Low-level NO release up to 16 h at 25°C | In vitro | Pseudomonas adhesion | NO xerogels showed inhibition of Pseudomonas aeruginosa and killing of adhered bacterial cells | |
| Privett et al. (2010) | Surface generated NO using model xerogel surfaces (AHAP3 and BTMOS) | Xerogel- coated glass slides | 10, 20, 30, and 40% AHAP3 xerogels (NO release over 15 h at 37°C, μM cm−2: 0.049 ± 0.004, 0.324 ± 0.055, 0.852 ± 0.323, 2.077 ± 0.656, respectively) | t1/2, h (37°C): 2.450 ± 0.272, 2.853 ± 0.231, 2.358 ± 0.274, 3.9364 ±0.381, respectively | In vitro | Surface generated NO against Candida albicans using modified xerogel surfaces | Reduction in Candida growth | |
| Holt et al. (2011) | Diazeniumdiolate NO donor-functionalized xerogels | Surgically implanted | 0.28 ± 0.11 μM cm−2 total NO released, 20 ± 7 pM cm−2 s−1 max NO flux |
t1/2 = 4 h No NO release detected after 7 days |
In vivo | Rats | Quantify incidence of bacterial infection in implanted xerogel coated titanium pins | Reduced infection incidence, decreased erythema and edema surrounding surgical wounds |
| Riccio et al. (2009) | Sol-gel derived silica nanoparticles: NO-releasing RSNO-modified xerogels | Incubated with fibroblasts | 20, 40, 60, and 80% MPTMS xerogels (Total NO released, μM mg−1: 0.47 ± 0.13, 0.68 ± 0.07, 0.81 ± 0.03, 1.31 ± 0.07 for, respectively) | NO flux > 0.4 pM cm−2 s−1 for up to 3 days with 20% MPTMS gel and up to 1–2 weeks with 40–80% MPTMS gel | In vitro | Mouse fibroblasts | Examine ability of xerogel coatings to resist bacterial and platelet adhesion | Reduction in Pseudomonas aeruginoasa and activated platelet adhesion in RSNO-modified xerogels, with maintenance of fibroblast viability |
| Hetrick et al. (2008) | NO- releasing silica nanoparticles | Incubation | ~3.8 μM·mg−1 total NO released, ~21,700 ppb·mg−1 max NO flux | t1/2 = 18 min | In vitro | Mouse fibroblasts | Examine NO-releasing silica nanoparticles bactericidal effectiveness | NO delivered from silica nanoparticles more effective at killing P. aeruginosa |
| Lu et al. (2013) | PAMAM dendrimers | Incubation | ~1 μM/mg total NO release | t1/2 ~ 1 h | In vitro | Mouse fibroblasts | Evaluation of PAMAM bactericidal properties | Size and exterior functionality crucial in dendrimer-bacteria association, NO delivery efficiency, bacteria membrane disruption, migration of biofilm and mammalian toxicity |
| Johnson et al. (2010) | Nitrosthiol | G4-SNAP scaffold |
2 μM SNAP with 0.5–10 mM GSH, 1.28 μM NO/mg max NO release |
Not reported | In vitro | Rat Heart (isolated, perfused) | Evaluation of G4-SNAP for reducing ischemia-reperfusion injury) | Dendrimer scaffold did not inhibit NO therapeutic activity |
| Lin et al. (2018) | In situ self-assembling NO-releasing micelle deposits | Subcutaneously implantation | 30 μM NONOate | t1/2 = 1298.3 ± 205.8 s w/ Hb at 37°C |
In vivo | Ovariectomized rats with osteoporosis | Examine ability of self-assembling micelles to release NO | Longer NO-released in OVX-induced osteoporosis rats reversing effects |
| Duong et al. (2014) | CCS Polymers | Incubation | 60 μM total NO release | Continuous NO release for 70 h | In vitro | Evaluate CCS controlled NO release | Decreased cell attachment and biofilm production of Pseudomonas aeruginosa with CCS polymers | |
| Pant et al. (2019) | SNAP | 3D bone scaffolds | 10 wt% SNAP, initial NO release rate 0.5 ± 0.06 ×10−10 mol/min/mg, NO release rate 0.23 ± 0.02 ×10−10 mol/min/mg after 24 h | Theoretical t1/2 extrapolated to 8.6 days | In vivo | Mice fibroblasts | Examination of 3D bone scaffold releasing SNAP anti-bacterial properties | Reduction in Staphylococcus aureus and Pseudomonas aeruginosa adherence |
| Friedman et al. (2011) | Sol-gel derived silica nanoparticles: NO-np generating GSNO | Incubation | ~300 μM GSNO release | Duration of NO release >24 h | In vitro | Human clinical isolates | Examine NO-np GSNO generating abilities | NO-np are able to generate and maintain GSNO formation over prolonged time period, where lower NO concentrations are more effective antimicrobial agents |