Development of nanovectors for the targeted drug delivery of antimalarials

Resumen

Malaria is arguably one of the main medical concerns worldwide because of the numbers of people affected, the severity of the disease, and the complexity of the life cycle of its causative agent, the protozoan Plasmodium sp. The clinical, social and economic burden of malaria has led for the last 100 years to several waves of serious efforts to reach its control and eventual eradication, without success to this day. At present, administration methods of antimalarial drugs release the free compound in the blood stream, from where it can be significantly removed by many tissues and organs, thus reducing its availability for Plasmodium-infected erythrocytes. Due to this lack of specificity regarding the target cells, current oral or intravenous delivery approaches for most antimalarial drugs require high doses. However, unspecificity of toxic drugs demands low concentrations to minimize undesirable side-effects, thus incurring the risk of sublethal doses favouring the appearance of resistant pathogen strains. Targeted nanovector systems can fulfill the objective of achieving the intake of total doses sufficiently low to be innocuous for the patient but that locally are high enough to be lethal for the malaria parasite. With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought-after magic bullet against malaria in the form of a nanovector for the targeted delivery of antimalarial drugs exclusively to Plasmodium-infected cells. We work on the development of antimalarial drug-carrying nanovectors specifically targeted to Plasmodium-infected red blood cells (pRBCs). Our first immunoliposomal prototype delivers its contents exclusively to pRBCs containing the P. falciparum late forms trophozoites and schizonts, and improves on average tenfold the efficacy of the antimalarial drugs chloroquine and fosmidomycin. Using chloroquine concentrations well below its IC50, and by modifying parameters such as liposome size, density of targeting antibodies on the liposome surface, targeted antigen, and intraliposomal drug concentration, we approach 100% of parasitemia reduction both in vitro and in vivo using a murine model for P. falciparum malaria. We are working in the improvement of the nanovector through modification of (i) the targeting element: better antibodies, non-protein molecules such as DNA aptamers and polysaccharides, (ii) the encapsulated drug(s), and (iii) the type of nanocapsule, making special emphasis on polymeric structures. Our objective in the short term is the design of a nanostructure adequate to enter the preclinical pipeline as an economically affordable new antimalarial therapy.