Abstract
Combination therapies, where two drugs acting through different mechanisms are administered simultaneously, are one of the most efficient approaches currently used to treat malaria infections. However, the different pharmacokinetic profiles often exhibited by the combined drugs tend to decrease treatment efficacy as the compounds are usually eliminated from the circulation at different rates. To circumvent this obstacle, we have engineered an immunoliposomal nanovector encapsulating hydrophilic and lipophilic compounds in its lumen and lipid bilayer, respectively. The antimalarial domiphen bromide has been encapsulated in the liposome membrane with good efficiency, although its high IC50 of ca. 1 µM for living parasites complicates its use as immunoliposomal therapy due to erythrocyte agglutination. The conjugation of antibodies against glycophorin A targeted the nanocarriers to Plasmodium-infected red blood cells and to gametocytes, the sole malaria parasite stage responsible for the transmission from the human to the mosquito vector. The antimalarials pyronaridine and atovaquone, which block the development of gametocytes, have been co-encapsulated in glycophorin A-targeted immunoliposomes. The co-immunoliposomized drugs have activities significantly higher than their free forms when tested in in vitro Plasmodium falciparum cultures: Pyronaridine and atovaquone concentrations that, when encapsulated in immunoliposomes, resulted in a 50% inhibition of parasite growth had no effect on the viability of the pathogen when used as free drugs.
Highlights
Despite the undeniable importance of malaria elimination on the global research agenda, current vaccines in development do not offer prospects of complete protection [1] and the available drugs are rapidly losing efficacy, with resistance already evolved to the front-line drug artemisinin [2]
The drug fosmidomycin inhibits the recombinant DOXP reductoisomerase (DXR) from Plasmodium falciparum with an IC50 value of ~28 nM and shows activity on the intact parasite, both in in vitro P. falciparum cultures (IC50 between 290 and 370 nM depending on the parasite strain) and in in vivo assays with mice infected with the rodent malaria species Plasmodium vinckei [16]
In an in vivo study with the murine malaria species Plasmodium berghei, curcumin-artesunate co-entrapped in poly(D,L-lactic-co-glycolic acid) nanoparticles resulted in significant parasitemia reduction and increased mice survival when compared with the free compounds [49]
Summary
Despite the undeniable importance of malaria elimination on the global research agenda, current vaccines in development do not offer prospects of complete protection [1] and the available drugs are rapidly losing efficacy, with resistance already evolved to the front-line drug artemisinin [2]. Whereas the MEP pathway is absent in mammals, it is essential for many human pathogens, including Plasmodium [14], its enzymes are attractive targets for the development of novel antimalarials. A (GPA) as an immunoliposomal target present in both non-parasitized red blood cells (RBCs) and in pRBCs, the efficacy of drugs encapsulated in LPs could be significantly improved due to the prophylactic effect of loading antimalarial compounds into RBCs when these have not yet been infected by Plasmodium [32,33,34]. We have integrated the strategies outlined above into the design of a GPA-targeted immunoliposome (iLP, Figure 1) encapsulating in its aqueous lumen pyronaridine and in its lipid bilayer DB or the lipophilic antimalarial drug atovaquone (whose site of action is complex III of the mitochondrial respiratory chain [35]), with the objective of exploring the capacity of nanocarriers to be developed into new antimalarial combination therapies at the nanoscale
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