Improvement of diabetic wound healing using prostacyclin analoges encapsulated in lipid nanoparticles

Introduction Diabetes is associated with impairment of cutaneous wound healing and can lead to lower limb amputation. The cutaneous microcirculation in diabetes is impaired due to alterations of the nitric oxide and prostacyclin pathways that can be therapeutic targets. Topical application of lipid nanoparticles can increase drug delivery through improved stability and controlled delivery compared to classical formulations. Objective We tested the efficacy of topical delivery of the prostacyclin analogue treprostinil and the IP receptor agonist ACT-333679 (active metabolite of selexipag), encapsulated in lipid nanoparticles, on wound healing in a diabetic mice model. Method We used 80 nm cationic (C80) or neutral (N80) lipid nanoparticles. Cationic emulsions (EM) were also formulated. For the wound healing study, 12-week-old males db/db mice were used. Two 8 mm2 diameter ulcers were made on the back of each animal and protected using a transparent, occlusive dressing. Each treatment was evaluated on 12 mice with one ulcer treated with the treatment and the contralateral ulcer treated with the vehicle. Wounds were treated daily over 24 days and evaluated daily using planimetry (ImageJ, NIH). Area under the curve (AUC) of the wound surface (expressed as a % of day 0 size) was calculated and compared between treatments and their vehicles. Results Encapsulation of ACT-333679 was stable in C80 and N80 for 6 months at 4 °C. Encapsulation of ACT-333679 was stable for 3 months at 4 °C. Encapsulation of Treprostinil was stable for 3 months in C80 while encapsulation was not stable in EM (1 month stability). Both Treprostinil and ACT-333679 increased the rate of wound healing in the db/db mice model. There was no major difference between lipid nanoparticles and emulsions. Conclusion Stable lipid nanoparticles loaded with IP receptors agonists can be formulated in a topical gel, are stable over time and result in an improved wound healing in a diabetic mouse model.