Naltrexone blockade of OGFr enhances cutaneous wound closure in diabetic rats

Abstract

Aims: Non-healing wounds are a major complication for the 27 million individuals in the United States with diagnosed diabetes. This study investigated the efficacy of a novel formulation to treat diabetic foot ulcers by targeting an underlying pathophysiology of diabetes. Main methods: The proprietary GMP formulations utilized increasing dosages of naltrexone (NTX) to block the inhibitory peptide Opioid Growth Factor (OGF) from binding to the OGF receptor (OGFr). Efficacy of topical application was studied using male Sprague-Dawley rats with uncontrolled (T1D) or insulin-controlled (T1D-INS) diabetes. Wound closure time, tensile strength of healed skin, and angiogenesis were endpoints. Serum drug dispersion was assessed. Key findings: Residual wound areas were significantly reduced within 2 days of surgery in T1D rats receiving either 0.5% or 1% NTX. By day 10, NTX-treated wounds were 5-fold smaller than those measured on T1D rats receiving vehicle. Tensile strength measurements and morphology studies revealed that NTX treatment of cutaneous wounds on T1D or T1D-INS rats accelerated epithelialization, accelerated angiogenesis, and increased the integrity of healed skin. Topical application of NTX resulted in no visible toxicity, and the NTX was not detected in serum. Significance: Proprietary GMP formulations up to 1% NTX were found to be effective and safe for topical treatment of full-thickness cutaneous wounds in diabetic rats. The mechanism of action involves blockade of the OGF-OGFr axis, a pathway known to become dysregulated with diabetes. These data warrant proof-of-concept human clinical trials for treatment of diabetic foot ulcers.

Keywords

• GMP formulation
• Naltrexone
• Wound healing
• Diabetic foot ulcers
• Rats