Potential of nanoformulations in malaria treatment

Abstract

Malaria is caused by the protozoan Plasmodium sp and affects millions of people worldwide. Its clinical form ranges from asymptomatic to potentially fatal and severe. Current treatments include single drugs such as chloroquine, lumefantrine, primaquine, or in combination with artemisinin or its derivatives. Resistance to antimalarial drugs has increased; therefore, there is an urgent need to diversify therapeutic approaches. The disease cycle is influenced by biological, social, and anthropological factors. This longevity and complexity contributes to the records of drug resistance, where further studies and proposals for new therapeutic formulations are needed for successful treatment of malaria. Nanotechnology is promising for drug development. Preclinical formulations with antimalarial agents have shown positive results, but only a few have progressed to clinical phase. Therefore, studies focusing on the development and evaluation of antimalarial formulations should be encouraged because of their enormous therapeutic potential.

Keywords: infectious disease; malaria; nanotechnology; pre-clinical study; treatment.

FIGURE 1

Life cycle of Plasmodium sp. The cycle can be divided into two stages: mosquito vector or sexual cycle and human host or asexual cycle. The mosquito ingests gametocytes while performing hematophagy. The zygote is formed from the union of gametocytes and generates oocyte. It crosses the intestinal wall and forms oocyst that releases sporozoites, which migrate to the mosquito’s salivary glands, completing the sexual cycle. The infected female Anopheles sp mosquito inoculates sporozoites, performs hematophagy, and begins the asexual cycle of Plasmodium sp in human. Sporozoites are transported to the liver through the blood, and asexual multiplication occurs in the hepatocytes, forming merozoites in the pre-erythrocytic cycle (Ashley et al., 2018). In P. vivax and P. ovale infections, some sporozoites differentiate in the liver to a latent form called hypnozoites. After rupture of the hepatocytes, merozoites are released into the bloodstream and penetrate the erythrocytes (erythrocyte phase), assuming a ring-shaped configuration (Coban et al., 2018). Proliferative schizogony occurs in infected erythrocytes, where merozoites multiply asexually, differentiating into schizonts and trophozoites. Erythrocytes rupture and release schizonts into the bloodstream, where one part differentiates into male and female gametocytes, and another part infects new erythrocytes (Phillips et al., 2017; Ashley et al., 2018). Image was created in BioRender.com.

FIGURE 2

Current drug targets for malaria treatment: I—Asexual cycle; II—Liver cycle, III, IV, VI—Erythrocytic cycle, V—Asexual and sexual cycles. Source: Artemisinin-based combination therapies (ACTs) are recommended by the World Health Organization (World malaria report, 2020; Wicht et al., 2020; World malaria report, 2021).

FIGURE 3

Classes of Nanoparticles. Nanoparticles can be divided into organic (lipid-based and polymeric) and inorganic. Each class embodies several NPs with the most relevant highlighted in the figure.

FIGURE 4

Nanocarriers. (A) Nanocarriers targeting. A schematic diagram represents the active and passive targeting of NPs. In passive targeting, NPs are carried by red blood cells and in the bloodstream to all tissues. During active targeting, NPs are conjugated with affinity ligands on their surface to enhance their uptake by the target site and cells. Different targeting moieties, such as antibodies, integrins, folate, glucose, or transferrin, can interact with molecules on the target cell surface. (B) Nanocarrier uptake mechanism. In the blood, nanocarriers can be targeted to recognize only parasitized red blood cells. These reduce the chances of resistant pathogen strains and side effects for the patient since the intake is considerably low compared to traditional treatments. In addition, Plasmodium induces new permeation pathways (NPPs) that confer increased permeability to the pRBC by changing the osmotic stability and enabling nanocarriers to enter the pRBC. In other tissues, intracellular uptake of nanocarriers follows different endocytosis pathways. When nanocarriers reach the cell surface, they are taken up by endocytosis depending on their shape, charge, size, or surface. Endocytosis can occur by macropinocytosis, driven by membrane ruffling and actin protrusions. After engulfment, they fuse with lysosomal compartments to content degradation. Clathrin-mediated endocytosis is based on clathrin-coated pits on the cytosolic side of the membrane forming clathrin-coated vesicles that undergo vesicular trafficking. Caveolae-mediated endocytosis undergoes the same dynamics. However, they fuse to caveosomes, avoiding lysosomal degradation.

FIGURE 5

Currently published articles on nano-formulated therapies against malaria. The illustration shows that data recorded from 2017 to 2022 were evaluated and retrieved from the National Library of Medicine USA databases (MEDLINE∕PUBMED—NLM), Scientific Electronic Library Online (SciELO), and Google Scholar (Google Scholar).