For more than a century, pentavalent antimonial drugs have served as a standard frontline therapy for leishmaniasis, a deadly neglected tropical disease characterized by parasitic infection of host immune cells. Yet these drugs, and the limited arsenal of alternatives that has been developed, suffer from caveats that limit their utility. These Sb(V) compounds are believed to serve as prodrugs that, upon reduction to the trivalent state, inhibit regulation of trypanothione, a parasitic thiol essential for maintenance of redox balance. However, structural similarities between parasitic targets and mammalian analogues render host cells similarly susceptible to the toxic effects of the drugs, and their use is indeed associated with severe clinical side effects. An additional limitation of the currently available antileishmanial agents is their cost, which is frequently prohibitively high for affected populations. To circumvent these caveats, our laboratory is investigating the encapsulation of Sb compounds within nanoparticles formulated from chitosan, a nontoxic and biodegradable derivative of the naturally abundant biopolymer chitin. Chitosan is derivatized with chelators that bind the metalloid and the functionalized polymer is then combined with tripolyphosphate to produce nanoparticles via ionic gelation. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) indicate that electrostatically crosslinking chains of chitosan to which Sb has been covalently conjugated reproducibly yields monodisperse distributions of nanoparticles with biocompatible physicochemical properties. Inductively coupled plasma optical emission spectroscopy (ICP-OES) data indicate that these nanoparticles exhibit high encapsulation efficiency and stable drug release. In vitro assays demonstrate that nanoparticles are readily internalized by Leishmania infantum, Leishmania donovani, and differentiated human THP1 cells, but exhibit higher potency against parasite cell lines. We hypothesize that progression to in vivo models will demonstrate a reduction in off-target toxicity relative to traditional pentavalent antimonial drugs, as nanoencapsulation will limit concentrations of free drug in the body while efficiently delivering encapsulated compounds to sites of infection.

Exploring the nanodelivery of antimony-based antiparasitic agents

ACS Spring 2022

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