Loading Antimalarial Drugs into Noninfected Red Blood Cells: An Undesirable Roommate for Plasmodium

Promising nanomaterials in the fight against malaria

“…Erythrocyte drug transporters limit extravasation, in addition to being biocompatible and safely removed from the body through natural mechanisms. [38][39][40] As shown by Wilson et al, RBCs pretreated with the antimalarials halofantrine, lumefantrine, piperaquine, amodiaquine and mefloquine retained them inside, inhibiting the growth of the parasites that were invading drug-containing RBCs. 38…”

“…six hours after invasion. 40,41 To reach their molecular targets inside pRBCs, antimalarial drugs must cross at least 3 membranes (the erythrocyte membrane, the parasitophorous vacuole and the parasite membrane), 42 plus one extra lipid bilayer for those compounds having their target inside organelles such as the food vacuole or the apicoplast. Lipophilic drugs are able to cross these membranes through passive diffusion, whereas other compounds are carried inside the parasite by available channels or transporters.…”

“…39 Since only after around 24 h post-invasion will Plasmodium export a substantial number of receptors and transporters to the host cell plasma membrane, the design of liposomes specifically targeted to early blood stages has remained remarkably elusive. 40 Most published studies report the development of liposomes for delivering an active compound to late parasite stages, 26,39,43,60,[73][74][75][76][79][80][81][82][83][84] when significant alterations in the structural and functional characteristics of RBCs are observed. 43,44 These liposomes have been formulated to deliver a high amount of drug to the targeted site to compensate for the short time available to kill the parasite before its egress.…”

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

“…As we have shown before, delivering antimalarial compounds to non-infected erythrocytes might represent an interesting therapeutic approach whereby Plasmodium would encounter a hostile environment since the very first moment after RBC inva- sion. 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.…”

“…In vivo, HDLDBC-bGMPA-CQ worked better than DHP-bMPA-CQ, possibly because the former targets all RBCs. The loading of antimalarial drugs into non-parasitized red blood cells has been described as an efficient approach to significantly reduce parasite survival, 35,36 as long as neither nanocarriers nor drugs affect the natural role of erythrocytes as O 2 and CO 2 transporters. Both dendrimeric structures studied in this work lack significant in vitro cytotoxicity and hemolytic activity, suggesting that they will not interfere with the red blood cell physiology.…”