There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
Most drugs currently entering the clinical pipeline for severe malaria therapeutics
are of lipophilic nature, with a relatively poor solubility in plasma and large biodistribution
volumes. Low amounts of these compounds do consequently accumulate in circulating
Plasmodium-infected red blood cells, exhibiting limited antiparasitic activity. These
drawbacks can in principle be satisfactorily dealt with by stably encapsulating drugs
in targeted nanocarriers. Here this approach has been adapted for its use in immunocompetent
mice infected by the Plasmodium yoelii 17XL lethal strain, selected as a model for
human blood infections by Plasmodium falciparum. Using immunoliposomes targeted against
a surface protein characteristic of the murine erythroid lineage, the protocol has
been applied to two novel antimalarial lipophilic drug candidates, an aminoquinoline
and an aminoalcohol. Large encapsulation yields of >90% were obtained using a citrate-buffered
pH gradient method and the resulting immunoliposomes reached in vivo erythrocyte targeting
and retention efficacies of >80%. In P. yoelii-infected mice, the immunoliposomized
aminoquinoline succeeded in decreasing blood parasitemia from severe to uncomplicated
malaria parasite densities (i.e. from ≥25% to ca. 5%), whereas the same amount of
drug encapsulated in non-targeted liposomes had no significant effect on parasite
growth. Pharmacokinetic analysis indicated that this good performance was obtained
with a rapid clearance of immunoliposomes from the circulation (blood half-life of
ca. 2 h), suggesting a potential for improvement of the proposed model.