Topical and Scaffold-Mediated Delivery of VCE-005.1 Enhances Diabetic Wound Healing Through Endothelial Protection and Vascular Regeneration

Abstract

Background/Objectives: Chronic diabetic wounds remain a major clinical challenge due to persistent inflammation, endothelial dysfunction, impaired angiogenesis, and defective tissue regeneration. Local therapies that restore vascular repair while providing sustained drug delivery are urgently needed. This study investigated the therapeutic efficacy of VCE-005.1, a hypoxia-mimetic betulinic acid derivative, administered topically or incorporated into a biocompatible and biodegradable polycaprolactone (PCL) scaffold, and examined the molecular mechanisms underlying its pro-regenerative activity. Methods: Endothelial protective activity was evaluated in endothelial cells exposed to hyperglycemic and oxidative stress by assessing cell viability, wound healing, senescence, and engagement of a B55α-associated signaling network involving AMPK, SIRT1, and HIF-1α. A VCE-005. 1-loaded PCL scaffold was fabricated and characterized for physicochemical properties, biological activity, and fibroblast adhesion. Therapeutic efficacy was then evaluated in excisional wound-healing models using diabetic (db/db) and non-diabetic (db/+) mice following topical or scaffold-mediated treatment. Results: VCE-005.1 protected endothelial cells against hyperglycemic and oxidative stress by enhancing AMPK phosphorylation, increasing SIRT1 expression and activity, stabilizing HIF-1α, and reducing endothelial senescence. The PCL scaffold preserved the biological activity of VCE-005.1 and enabled its local delivery. Both topical and scaffold-mediated administration significantly accelerated wound closure, improved histological wound architecture, enhanced angiogenesis and vascular maturation, restored endothelial SIRT1 expression in vivo, and reduced macrophage (F4/80+) and neutrophil (MPO+) infiltration. Conclusions: Topical and scaffold-mediated delivery of VCE-005.1 markedly improves wound repair through endothelial protection, vascular regeneration, and attenuation of local inflammation. These findings support VCE-005.1 as a promising local therapy for diabetic foot ulcers and support biodegradable scaffold-based delivery to enhance its therapeutic potential.