Ligand decorated nanostructure carrier systems for targeted delivery of antimalarials

Antimalarial chemotherapeutics, including artemisinin derivatives and their combination regimens, sustain clinical effectiveness against Plasmodium species, including resistant strains. However, these chemotherapeutics face challenges, including poor aqueous solubility and membrane permeability, a short elimination half-life, erratic oral bioavailability, and delayed parasite clearance. These formidable challenges have been widely addressed by developing new chemical entities, combining artemisinin-based combination therapies, exploring alternative routes of administration, or prolonging the dosing schedule. However, developmental costs, time, and translational obstacles that may exacerbate current treatment gaps. In recent years, nanostructured carrier systems (NSCs) have emerged as novel delivery platforms to overcome constraints of conventional delivery systems. NSCs such as liposomes, polymeric nanoparticles (NPs), metallic (Gold and ferrite) NPs, lipid-based NPs, nanoemulsions, self-emulsifying drug delivery systems, and micelles, can be further decorated employing ligands (Plasmodium recognizing antibodies, polymers, carbohydrates (glucose), aptamers, heparins) to recognize Plasmodium-infected red blood cells (piRBCs) specifically. This review provides in-depth insights into the ligand decorated nanostructured carrier systems (L-NSCs) capable of differentiating between piRBCs and normal RBCs based on specific ligand decoration, which are not only capable of targeting piRBCs but also the extracellular merozoite stage of Plasmodium. We have discussed in detail the ligands that recognize piRBCs, based on specific biophysical alterations, expression, and the transport of Plasmodium proteins on the surface of piRBCs. The RBCs are structurally simple, lacking organelles, with limited metabolic activity, and a uniform microenvironment, resulting in minimal differentiation between normal and piRBCs. Overexpression of Glucose transporter, appearance of P. falciparum erythrocyte membrane protein, and selective targeting to sialic acid residues on Glycophorin A on the cell membrane of piRBCs can act as potential recognition sites for L-NSCs. This review offers in-depth insight into emerging opportunities for selective recognition and targeted delivery of antimalarials to address challenges of poor pharmacokinetics, targeted delivery within piRBCs, and enhance the therapeutic efficiency of antimalarials against both susceptible and resistant Plasmodium strains that transmit human malaria.