Nanocrystallization Effectively Improves the Oral Efficacy of an Antileishmanial Chalcone

Background/Objectives: Cutaneous leishmaniasis (CL) is a vector-borne neglected disease that can cause permanent deformities. Current chemotherapy based on injections with toxic drugs or oral miltefosine poses many drawbacks, urging the need for new oral therapies. Here, we proposed to increase the bioavailability of NAT22, an intralesionally but not orally active antileishmanial chalcone, through nanocrystallization to promote its oral use in CL. Methods/Results: NAT22 nanocrystals were produced using a solvent-free green process of dry and wet milling that reduced NAT22 crystal sizes by around 1500-fold to 257 nm (nanoNAT22). Such reduction in size increased water solubility by 15-fold to 4.3 µg/mL and ensured stability in the absence of stabilizers for at least one month. Of note, nanoNAT22 in aqueous medium was more selective for parasites (SI = 35.2) than NAT22 in 1% DMSO (SI = 7.6). Leishmania amazonensis-infected mice treated with oral nanoNAT22 had lesion sizes and parasite loads similar to those achieved with intralesional Glucantime^®, and significantly smaller than NAT22. Conclusions: Together, these results indicate that nanocrystallization is an effective process to render NAT22 chalcone also orally active against CL.