Localized delivery of Roxadustat via cubosomes-based thermosensitive in-situ hydrogel enhances diabetic wound healing by stabilizing HIF-1α α in rats

Chronic non-healing wounds are a major complication among diabetic patients, significantly affecting their quality of life. The dysfunction of HIF-1, a crucial regulator of wound healing, contributes to impaired wound repair in diabetes. Roxadustat (ROX), an HIF-1 alpha stabilizer, has emerged as a promising therapeutic candidate for addressing chronic wounds. Accordingly, a few studies have investigated the systemic administration of ROX for wound healing. However, concerns have arisen about potential side effects. Our study aimed to address these limitations by developing a localized delivery approach using ROX-loaded cubosomes (ROX-CUs) incorporated into a thermosensitive hydrogel. ROX-CUs were prepared and evaluated for particle size (125.6 f 3.11 nm), zeta potential (-26.60 f 2.08 mV), and entrapment efficiency (94.23 f 2.93 %). ROX-CUs were then integrated into a poloxamer-based thermosensitive hydrogel with varying ratios of poloxamers 188 and 407. The selected formulation (F13) showed a phase transition temperature of 36.5 f 0.4 degrees C and a drug content of 97.80 f 1.60 %. In vitro drug release studies demonstrated a biphasic release for F13: an initial burst after 3 h (15.25 %) followed by sustained release up to 48 h (52.13 %), offering sustained release advantages. In vivo studies on diabetic rats revealed that F13 significantly accelerated wound closure (93 % reduction), with enhanced tissue characteristics, including neovascularization and increased collagen deposition. Additionally, F13 upregulated the HIF-1 alpha and other tissue remodeling factors, creating an optimal environment for tissue repair. Consequently, ROX-CUs incorporated into a thermosensitive hydrogel hold significant promise as a novel therapeutic strategy for promoting wound healing in clinical settings.