An ImmunoPEGliposome for Targeted Antimalarial Combination Therapy at the Nanoscale

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.

Promising nanomaterials in the fight against malaria

“…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.…”

“…[80][81][82] In addition, combination therapies contemplating the simultaneous administration of two or more active compounds have also been proposed. 60,79 The encapsulation efficiency in liposomes of many antimalarial drugs can be increased using active loading techniques based on pH gradients. 39,75,83 Drugs with amphiphilic nature such as CQ and PQ, which depending on the solution pH present different degrees of protonation, can be efficiently encapsulated using a pH gradient.…”

“…When tested in in vitro P. falciparum cultures, this strategy offered antiparasitic activities significantly higher than when the drugs were administered together in their free forms. 79 Despite the considerable therapeutic advantages of liposomes, their clinical translation to antimalarial treatments has not progressed as quickly as the encouraging positive preliminary results predicted. The main issues behind this delay are pharmaceutical manufacturing limitations, government regulations and intellectual property.…”

Porphyrin Derivative Nanoformulations for Therapy and Antiparasitic Agents

“…This strategy has shown to be very promising for treatment of several diseases [181][182][183][184][185], including malaria. More recently, Biosca et al [186] described an immunoliposomal nanosystem encapsulating the antimalarial drugs pyronaridine and atovaquone. The conjugation of these encapsulated antimalarials with antibodies against glycophorin The conjugation of specific ligands on the surface of nanosystems, including vitamins, glycoproteins, peptides, oligonucleotides, aptamers, and antibodies, has been explored to increase their selectivity by specific target cells and tissues [180].…”

“…More complex nanoformulations can be used to perform combination therapy, whereby two or more therapeutic agents are incorporated in the same particle [186,191,192]. One example for malaria treatment of P. berghei-infected mice was based on the administration of a liposomal formulation loaded with curcuminoids in combination with α/β arteether.…”