Mannosylated Imiquimod-Terbinafine Co-Loaded Transethosomes for Cutaneous Leishmaniasis; Assessment of Its Anti-Leishmanial Potential, in Vivo Safety and Immune Response Modulation.

Current treatment options for cutaneous leishmaniasis are associated with myriad limiting factors including low penetration, poor efficacy, and drug toxicities. Herein, we reported imiquimod and terbinafine co-loaded mannosylated transethosomes (IMQ-TER-MTES) with enhanced cutaneous retention, macrophage targeting, anti-leishmanial potential, and dermal immunomodulation. IMQ-TER-MTES were optimized using Design Expert® followed by their loading into chitosan gel. Moreover, the antileishmanial response against amastigotes-infected macrophages and Leishmania-infected BALB/c mice was evaluated. Finally, the safety and immunomodulation activity of IMQ-TER-MTES gel was performed using BALB/c mice. Optimized IMQ-TER-MTES showed nano-sized particles with low poly-dispersibility index (PDI) and high drug entrapment. Mannosylation has augmented macrophage targeting and the internalization capability of TES. IMQ-TER-MTES showed significantly reduced IC50 value (19.56 ± 3.62 μg/ml), higher selectivity index (29.24), and synergism against Leishmania major (L. major) amastigotes. In L. major infected BALB/c mice, the cutaneous lesion healing potential of IMQ-TER-MTES was also elevated with reduced lesion size (1.52 ± 0.43 mm). Superior safety of IMQ-TER-MTES was observed in BALB/c mice along with adequate stimulation of dermal immune cells, in contrast to the ALDARA®. Moreover, incremented Nuclear factor Kappa-β (NF-κβ) and nitric oxide (NO) biosynthesis were observed with IMQ-TER-MTES.