Enhancement of wound healing in diabetic mice by topical use of a peptide-ionic liquid conjugate

Abstract

Diabetic foot ulcers (DFU) are one of the most devastating complications of diabetes, with high impact on patient’s quality of life. In worst scenarios, DFU can lead to severe amputation or even death. DFUs are an easy target for microbial pathogens and their effective healing is hampered by the galloping increase of microbial resistance to antibiotics, including from the most prevalent pathogens in DFU, e.g. Staphylococcus aureus. As such, available antibiotics show poor efficacy in the treatment of DFU, leading to a chronic condition that is exacerbated by poor healing rates due to the persistent inflammation, poor oxygenation and low angiogenesis, leading to high risk of ischemia, among other conditions that typically affect patients with diabetes. Our group has recently designed new peptide-based strategies towards the topical treatment of DFU, whereby peptide-ionic liquid conjugates emerged as highly promising agents. One of the best such conjugates, C₁₆-Im-PP4, results from coupling an imidazolium-based ionic liquid with intrinsic antimicrobial activity to the N-terminus of a collagen boosting peptide used in cosmetics, the pentapeptide-4. C₁₆-Im-PP4 showed excellent in vitro properties, namely, wide-spectrum antimicrobial action and collagen-boosting effect on human dermal fibroblasts, prompting the in vivo study here reported. The peptide-ionic liquid conjugate was applied topically on wounds of mice with diabetes. The results show multitargeted actions, at a dose of 1 µg/wound including: i) anti-inflammatory; ii) antioxidant; iii) pro-collagenic; vi) pro-angiogenic; v) antimicrobial; and vi) improved wound maturation effects. Altogether, these results identify this technology as a novel topical treatment for DFU.