Nitric oxide-releasing emulsion with hyaluronic acid and vitamin E

Abstract

S-Nitrosoglutathione (GSNO) is a naturally available S-nitrosothiol that can be incorporated into non-toxic formulations intended for topical use. The value of nitric oxide (NO) delivered topically relates to its wellstudied physiological functions such as vasodilation, angiogenesis, cell proliferation and broad-spectrum antibacterial activity. Previously reported topical NO-releasing substrates include polymeric materials that exhibit non-toxic behaviors on dermal tissue such as polyethylene glycol. However, they do not serve as humectants nor provide vitamins to the skin. In this study, GSNO was added to an emulsion that was fortified with a-tocopheryl acetate (vitamin E) and hyaluronic acid. The average total NO content for the NO-releasing emulsion was 58 AE 8 mmol g À1 at 150 C and the cumulative NO release over 53 h at physiological temperature (37.4 C) was 46 AE 4 mmol g À1 . The GSNO concentration in the lotion was optimized in order to reach a pH value similar to that of human skin (pH 5.5). The viscosity was analyzed using a rotational viscometer for the S-nitrosated and the non-nitrosated emulsions to obtain a material that can be readily spread on dermal tissue. The viscosity values obtained ranged from 7.88 AE 0.99 to 8.50 AE 0.36 Pa s. Previous studies have determined that the viscosity maximum for lotions is 100 Pa s. A low viscosity increases the diffusion coefficient of active ingredients to the skin given that they are inversely proportional as described by the Einstein-Smoluchowski equation. The effect of the Snitrosated and non-nitrosated emulsions on adult human dermal fibroblasts (HDFs) was assessed in comparison to untreated HDFs using Colorimetric Cell Viability Kit I-WST-8. The findings indicate that neither the S-nitrosated nor non-nitrosated emulsions induced cytotoxicity in HDFs. † Electronic supplementary information (ESI) available: Nitric oxide release proles using a chemiluminescence-based detection method are shown (n ¼ 3). See

Therapeutic Delivery of Nitric Oxide Utilizing Saccharide-Based Materials

“…The Reynolds group developed a formulation of the topically applied hydrogel by blending GSNO, α-tocopheryl acetate (vitamin E), and hyaluronic acid. 133 The total NO release from the hydrogel was found to be 46 ± 4 μmol g −1 with a total NO load of 58 ± 8 μmol g −1 . This gel was nontoxic to human dermal fibroblast, and the combination of NO and vitamin E provided photoprotection against harmful radiations, as well as anti-inflammatory and antibacterial effects for enhanced wound healing.…”

“…The Reynolds group developed a formulation of the topically applied hydrogel by blending GSNO, α-tocopheryl acetate (vitamin E), and hyaluronic acid . The total NO release from the hydrogel was found to be 46 ± 4 μmol g –1 with a total NO load of 58 ± 8 μmol g –1 .…”

Roles and current applications of S-nitrosoglutathione in anti-infective biomaterials

“… P.aeruginosa/ATCC 27853 HUVEC Rolim, W. R. [ 95 ] 2019 Infection and tumor AgNPs-containing PVA/PEG Films Solvent casting 2.5 ​wt% 4-7 ​μmol NO/cm 2 E.coli/ATCC 25922 Human prostate cancer cell/PC3 NA GSNO-containing PVA/PEG films demonstrated toxicity toward tumor cells but had no antibacterial effect. S.aureus/ATCC 29213 K.pneumoniae/ATCC 700603 human foreskin fibroblast cell/HFF-1 P.aeruginosa/ATCC-27853 Yapor, J. P. [ 14 ] 2019 Infection Emulsion containing HA and vitamin E Mixing 1.72 w/w % 46 ​± ​4 ​μmol ​g −1 NA HDFs NA GSNO-containing emulsion was produced and showed no cytotoxicity to HDFs Hopkins, S. P. [ 44 ] 2020 NA Fibers comprising PCL and gelatin Electrospinning 20 ​wt % 3.91 ​± ​0.96 ​× ​10 −10 ​mol ​mg −1 min −1 S.aureus/ATCC 5538 Mouse fibroblast cells/ATCC 1658 NA PCL/gelatin fiber containing GSNO demonstrated antibacterial activity and no cytotoxic response. Li, W. [ 8 ] 2021 Devices-associated inflammation and infection Silicone 3D printing 2 ​wt % >10 ​× ​10 −10 ​mol ​cm −2 min −1 P.mirabilis/ATCC 29906 Murine fibroblast cell/L929 NA GSNO embedded in the printed silicone matrix released NO about one month.…”

“…Nitric oxide (NO) is an endogenous gaseous molecule produced from arginine by nitric oxide synthase (eNOS, nNOS, or iNOS) [ 1 ]. NO is involved in multiple physiological processes, including angiogenesis [ 2 ], antiapoptosis, anti-inflammation [ [3] , [4] , [5] ], platelet activation [ 6 , 7 ], antithrombosis [ 8 ], vasodilation [ [9] , [10] , [11] ], and immune response [ [12] , [13] , [14] ]. Additionally, NO exhibits broad-spectrum antibacterial activities via the formation of reactive nitrogen species (RNS), including, but not limited to, peroxynitrile, dinitrogen trioxide, and nitrogen dioxide.…”

Nitric Oxide-Releasing Hyaluronic Acid as an Antibacterial Agent for Wound Therapy

“…For example, wounded diabetic mice systemically injected with high-molecular weight HA (e.g., 4 MDa) demonstrated improved healing and improved mechanical properties of the healed skin . Topical treatment with HA oligosaccharides (e.g., 1–7 kDa) in mice and rats has been found to increase wound-healing rates, angiogenesis, collagen deposition, and endothelial cell proliferation. − Wound dressings, ointments, and hydrogels containing HA have demonstrated enhanced wound-healing properties, such as increased fibroblast proliferation, alleviated inflammation, increased moisture, and improved skin regeneration. − In addition to the native state benefits of HA, the biopolymer backbone also allows for versatile chemical modification at available carboxylic acid and primary and secondary alcohol functional groups. Given HA’s unique properties in tissue repair and the potential to add NO donor functionality to leverage NO’s multifaceted roles in wound healing, NO-releasing HA represents a favorable antibacterial therapeutic for chronic wounds.…”