NanostructuredLipid Carrier for Intracellular Deliveryof a Bis(pyridine-2-carboxamidine) DNA Minor Groove Binder Activeagainst <i>Leishmania</i>

Two types of nanostructured lipid carrier (NLC) formulations of the antileishmanial DNA minor groove binding compound 4-(picolinimidamido)-<i>N</i>-(4-(picolinimidamido)phenyl)benzamide (<b>1</b>) were synthesized by the microemulsion method to evaluate their potential as a delivery system to intracellular forms of the <i>Leishmania</i> parasite. Compound <b>1</b>-loaded NLC formulations, functionalized with folic acid (FA) or not, showed good colloidal stability both during storage and after dilution in biologically relevant media. The drug release, which was not pH dependent, occurred efficiently at 37 °C. Compound <b>1</b> and its NLC formulations displayed a good selectivity index (SI > 40) and were active in the submicromolar range against promastigotes and metacyclic promastigotes of Leishmania major and in the low micromolar range (∼2 μM) against intramacrophage amastigotes. However, they were inactive against Leishmania mexicana. This proof-of-concept study showed that compound <b>1</b> could be loaded effectively in NLC and FA-coated NLC whose size and anionic nature (i.e., FA-NLC) are favorable for uptake into macrophages. NLC functionalization with FA had a beneficial effect on the antileishmanial activity of <b>1</b> compared with noncoated NLC formulations, which resulted in an increase in selectivity toward the parasite.