Review of the Current Landscape of the Potential of Nanotechnology for Future Malaria Diagnosis, Treatment, and Vaccination Strategies

Abstract

Malaria eradication has for decades been on the global health agenda, but the causative agents of the disease, several species of the protist parasite Plasmodium, have evolved mechanisms to evade vaccine-induced immunity and to rapidly acquire resistance against all drugs entering clinical use. Because classical antimalarial approaches have consistently failed, new strategies must be explored. One of these is nanomedicine, the application of manipulation and fabrication technology in the range of molecular dimensions between 1 and 100 nm, to the development of new medical solutions. Here we review the current state of the art in malaria diagnosis, prevention, and therapy and how nanotechnology is already having an incipient impact in improving them. In the second half of this review, the next generation of antimalarial drugs currently in the clinical pipeline is presented, with a definition of these drugs' target product profiles and an assessment of the potential role of nanotechnology in their development. Opinions extracted from interviews with experts in the fields of nanomedicine, clinical malaria, and the economic landscape of the disease are included to offer a wider scope of the current requirements to win the fight against malaria and of how nanoscience can contribute to achieve them.

Keywords: Plasmodium; antimalarial drugs; malaria diagnosis; malaria prophylaxis; malaria therapy; nanocarriers; nanomedicine; nanotechnology; targeted drug delivery.

Figure 1

The life cycle of Plasmodium falciparum. Reproduced with permission from [4], Cell Press, 2018.

Figure 2

Schematic representation of liposomes formulated using different strategies aiming at improving the therapeutic efficacy of encapsulated drugs and the presentation of vaccine antigens. Conventional liposomes are formed by phospholipids and cholesterol and can encapsulate hydrophilic drugs in their aqueous cores and hydrophobic compounds in their phospholipid bilayers. Active encapsulating liposomes hold a pH gradient that can improve the loading of drugs with amphiphilic nature, which, depending on the pH, are found either in their protonated or deprotonated forms. Targeted liposomes are developed using specific pRBC ligands such as antibodies or heparin and promote the delivery of high drug doses with few side effects. Long-circulating liposomes can be formulated by modifying their surfaces with poly(ethylene) glycol (PEG) to enhance the blood residence time. Reproduced with permission from [14], The Royal Society of Chemistry, 2020.

Figure 3

Chemical structures of the most advanced compounds in the current global antimalarial portfolio.

Figure 4

Confocal fluorescence microscopy analysis of the delivery of immunoliposome cargo to pRBCs. (A) Cartoon showing a quantum dot-containing liposome functionalized with half-antibodies. (B) Western blot analysis of the conjugation to liposomes (right lane) of the pRBC-targeting BM1234 antibody. Immunoliposomes were purified by ultracentrifugation prior to electrophoresis. (C) Graphical scheme of the expected performance of nanovectors when added to a P. falciparum culture containing both infected and noninfected cells. (D) Confocal fluorescence microscopy section of a suspension of RBCs containing ca. 5% pRBCs that had been treated, for 90 min and prior to fixation, with a preparation of immunoliposomes assembled as depicted in (A). The selected field contained a single pRBC among tens of noninfected cells, showing the fluorescence of RBC plasma membranes (red), antibody detection (green), quantum dots (white), and nuclei (blue). For easier visualization of the colocalization of quantum dots and antibodies only in pRBCs, the fluorescence signals for (E) antibodies, (F) nuclei, and (G) quantum dots are shown separately in white. Reproduced with permission from [87], Elsevier B. V., 2011.

Figure 5

Scheme of an immunoliposome designed for targeted antimalarial combination therapy. DOPC: 1,2-dioleoyl-sn-glycero-3-phosphocholine; POPC: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; DSPE: 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine; Mal: maleimide; GPA: glycophorin A. Reproduced with permission from [172], MDPI, 2019.

Figure 6

Confocal fluorescence microscopy analysis of the interaction of curcumin-containing, Cy3-labeled PBMA-SBMA and PBMA-MESBMA nanoparticles with RBCs and pRBCs. The arrowhead indicates an early trophozoite-stage parasite. Reproduced with permission from [173], Elsevier B. V., 2021.

Figure 7

High-sensitivity, single-molecule nanosensor for the detection of DXS inhibitors. (A) Single-molecule force spectroscopy analysis of the effect of soluble fluoropyruvate on the binding between immobilized DXS and pyruvate. Temporal sequence from top to bottom: no soluble fluoropyruvate, addition of 1 μM fluoropyruvate, addition of 10 μM fluoropyruvate, removal of soluble fluoropyruvate. (B) Configuration showing the interaction between DXS bound to a nanoscale sensor and pyruvate to mica surfaces. (C) A significant decrease in the binding of DXS to the pyruvate-functionalized surface indicated the presence of an inhibitor in solution. Reproduced with permission from [176], Federation of American Societies for Experimental Biology, 2010.