Co-delivery of simvastatin and microRNA-21 through liposome could accelerates the wound healing process

Abstract

The gene delivery approach, mainly microRNAs (miRNA) as key wound healing mediators, has recently received extensive attention. MicroRNA-21 (miR-21) has strongly impacted wound healing by affecting the inflammation and proliferation phases. Previous studies have also demonstrated the beneficial effect of simvastatin on wound healing. Therefore, we designed a dual-drug/gene delivery system using PEGylated liposomes that could simultaneously attain the co-encapsulation and co-delivery of miRNA and simvastatin (SIM) to explore the combined effect of this dual-drug delivery system on wound healing. The PEG-liposomes for simvastatin and miR-21 plasmid (miR-21-P/SIM/Liposomes) were prepared using the thin-film hydration method. The liposomes showed 85 % entrapment efficiency for SIM in the lipid bilayer and high physical entrapment of miR-21-P in the inner cavity. In vitro studies demonstrated no cytotoxicity for the carrier on normal human dermal fibroblast cells (NHDF) and 97 % cellular uptake over 2 h incubation. The scratch test revealed excellent cell proliferation and migration after treatment with miR-21-P/SIM/Liposomes. For the in vivo experiments, a full-thickness cutaneous wound model was used. The wound closure on day 8 was higher for Liposomal formulation containing miR-21-P promoting faster re-epithelialization. On day 12, all treated groups showed complete wound closure. However, following histological analysis, the miR-21-P/SIM/Liposomes revealed the best tissue regeneration, similar to normal functional skin, by reduced inflammation and increased re-epithelialization, collagen deposition and angiogenesis. In conclusion, the designed miR-21-P/SIM/Liposomes could significantly accelerate the process of wound healing, which provides a new strategy for the management of chronic wounds.

Keywords: Dual delivery; Liposome; Simvastatin; Wound healing; miR-21 plasmid.