Topical Wound Treatment with a Nitric Oxide-Releasing PDE5 Inhibitor Formulation Enhances Blood Perfusion and Promotes Healing in Mice

Abstract

Chronic, non-healing wounds constitute a major health problem, and the current therapeutic options are limited. Therefore, pharmaceuticals that can be locally applied to complicated wounds are urgently needed. Such treatments should directly target the underlying causes, which include diabetes mellitus, chronic local pressure and/or vascular insufficiency. A common consequence of these disorders is impaired wound angiogenesis. Here, we investigated the effect of topical application of a nitric oxide-releasing phosphodiesterase 5 inhibitor (TOP-N53)-containing liquid hydrogel on wound repair in mice. The drug-loaded hydrogel promoted re-epithelialization and angiogenesis in wounds of healthy and healing-impaired diabetic mice. Using a non-invasive label-free optoacoustic microscopy approach combined with automated vessel analysis, we show that the topical application of TOP-N53 formulation increases the microvascular network density and promotes the functionality of the newly formed blood vessels, resulting in enhanced blood perfusion of the wounds. These results demonstrate a remarkable healing-stimulating activity of topically applied TOP-N53 formulation, supporting its further development as a wound therapeutic.

Bifunctional Sildenafil Diazeniumdiolates Acting as Phosphodiesterase 5 Inhibitors and Nitric Oxide Donors− Towards Wound Healing

“…We hypothesized that incorporating an NO‐donating group into the sildenafil scaffold could render the resulting bifunctional compounds potentially promising candidates for wound healing. Recent studies using nitrate esters as NO donors have shown promising results for this dual approach [28–30] . However, our focus shifted to nitrogen‐bound diazeniumdiolates ( N ‐diazeniumdiolates) as the NO‐donating group (Figure 1C).…”

“…Recent studies using nitrate esters as NO donors have shown promising results for this dual approach. [28][29][30] However, our focus shifted to nitrogen-bound diazeniumdiolates (Ndiazeniumdiolates) as the NO-donating group (Figure 1C). Ndiazeniumdiolates are particularly attractive NO donors, which spontaneously release two molecules of NO under physiological conditions.…”