Author:
|
Moles Meler, Ernest; Galiano, Silvia; Gomes, Ana; Quiliano, Miguel; Teixeira, Catia Marlene; Aldana, Ignacio; Gomes, Paula; Fernàndez Busquets, Xavier
|
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. |