ImmunoPEGliposomes for the targeted delivery of novel lipophilic drugs to red blood cells in a falciparum malaria murine model

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.

Micelle carriers based on dendritic macromolecules containing bis-MPA and glycine for antimalarial drug delivery

“…35,36 This scenario resulted in a significantly improved efficacy of drugs encapsulated inside liposomes targeted to both pRBCs and to non-parasitized red blood cells. 35,37 The modest binding of DHP-bMPA to early ring forms, where the parasite has not significantly modified the erythrocyte membrane, suggests that this polymer might interact predominantly with exported Plasmodium antigens, which are scarce in rings and completely absent from non-parasitized RBCs.…”

Coupling the Antimalarial Cell Penetrating Peptide TP10 to Classical Antimalarial Drugs Primaquine and Chloroquine Produces Strongly Hemolytic Conjugates

“…One of our main lines of research concerns the chemical modification of classical antimalarials such as PQ, CQ, or CQR, aimed at "masking" the drugs in such a way that their activity is preserved or even improved, while undesirable metabolic conversions and/or toxicity are decreased, and/or parasite resistance pathways are eluded [3][4][5][6][7][8][9][10]. Recently, we hypothesized that coupling cell-penetrating peptides (CPP) to classical antimalarials could both improve internalization into Plasmodium-infected cells and avoid resistance and pharmacokinetic liabilities.…”

The Multirole of Liposomes in Therapy and Prevention of Infectious Diseases

“…In the fight against malaria, the majority of drugs under development are lipophilic and characterized by poor plasma solubility and large biodistribution volumes with low accumulation in red blood cells (RBC). As a consequence, these drugs have shown limited therapeutic activity against intra-erythrocyte plasmodia ( 53 ). Rajendran et al developed lipid formulations of soy-PC Chol containing either stearylamine (SA) or phosphatidic acid (PA) and different densities of distearoyl phosphatidylethanolamine-methoxy-PEG 2000 as a delivery system to test the antimalarial activity of monensin.…”