Development of nanocapsules bearing doxorubicin for macrophage targeting through the phosphatidylserine ligand: a system for intervention in visceral leishmaniasis

The purpose of this study was to explore the applicability, targeting potential and drug delivery to specialized phagocytes via phosphatidylserine (PS)-specific ligand-anchored nanocapsules (NCs) bearing doxorubicin. The layer-by-layer method was utilized to prepare NCs having a nanoemulsion core loaded with doxorubicin (NCs-DOX), which was further grafted with PS. PS-coated NCs (PS-NCs-DOX) were compared with NCs-DOX for in vitro targeting ability by studying uptake by macrophages, intracellular localization, in vivo pharmacokinetics and organ distribution studies. The in vivo antileishmanial activity of free doxorubicin, NCs-DOX and PS-NCs-DOX was tested against visceral leishmaniasis in Leishmania donovani-infected hamsters. Flow cytometric data revealed 1.75-fold enhanced uptake of PS-NCs-DOX in J774A.1 macrophage cell lines compared with NCs-DOX. In vivo organ distribution studies in Wistar rats demonstrated a significantly higher extent of accumulation of PS-NCs-DOX compared with NCs-DOX in macrophage-rich organs, particularly in liver and spleen. Highly significant antileishmanial activity (P0.05 compared with NCs) was observed with PS-NCs-DOX, causing 85.234.49 inhibition of splenic parasitic burden. NCs-DOX and free doxorubicin caused only 72.883.87 and 42.852.11 parasite inhibition, respectively, in Leishmania-infected hamsters (P0.01 for PS-NCs-DOX versus free doxorubicin and NCs-DOX versus free doxorubicin). We conclude that the PS targeting moiety can provide a new insight for efficient drug delivery to specialized macrophages and thus may be developed for effective use in macrophage-specific delivery systems, especially for leishmaniasis.