Re-purposing of linagliptin for enhanced wound healing and skin rejuvenation via chitosan- modified PLGA nanoplatforms

Abstract

Dipeptidyl peptidase IV (DPP IV) is a multifunctional glycoprotein implicated in the exacerbation of various inflammatory skin conditions, including wounds. Therefore, topical delivery of Linagliptin (LNG)-a DPP IV inhibitor- augmented with Lavender Oil (LO) could offer an excellent repurposed tool for the treatment of inflammatory skin diseases. LNG/ LO loaded chitosan (Cs) -modified Poly (Lactide co-Glycolic Acid) (PLGA) nanoparticles (LNG/LO-Cs/PLGA NPs) were prepared by solvent emulsification-evaporation technique. D-optimal design explored the impact of independent factors namely; ratio of LO: PLGA, percentage of surfactant, and type of PLGA on; particle size, zeta potential, and entrapment efficiency of NPs. The optimized formulation displayed positively charged, homogeneous small-sized particles (159.34 nm), with high entrapment efficiency (89.30 %w/w). The in vitro release profile of the optimized NPs showed an initial burst release (16.6 %) after one hour, followed by an extended-release pattern for three days. Transmission electron microscopy showed spherical matrix particles with a slightly denser coat. An ex-vivo skin permeation study revealed notable LNG deposition in rat skin (51 % w/w after 24 h). Confocal laser scanning microscopy confirmed the time-dependent enhanced penetration of nanocarriers into the skin. In-vivo study done on induced-wound model revealed accelerated wound healing in NPs-treated group with 86.49 % wound contraction. Biochemical analysis of the impacted skin showed lower oxidative stress, with a 2.5-fold rise in reduced glutathione, a 3.2-fold boost in total antioxidant capacity, a 3.3-fold drop in malondialdehyde, and a 4.5-fold decrease in TNF-α levels versus the positive control. Therefore,This nanosystem could stand as a novel gateway and repurposed tool for accelerated wound healing and tissue regeneration.