Abstract:
The multistage life cycle of malaria-causing P. falciparum is complex, making prevention and treatment difficult. As a result of resistance to many antimalarial drugs, novel compounds with unexplored targets are constantly sought after for the purpose of treating the symptoms of malaria. Here, novel compounds were screened for antiplasmodial activity against the symptom-causing asexual intraerythrocytic malaria-causing parasites. Unfortunately, many novel compounds in the drug discovery pipeline and drugs in clinical use possess underlying pharmacological issues that makes administration challenging. These include low aqueous solubility and short half-life which negatively impact bioavailability resulting in toxicity. This, in turn, increases patient non-compliance and the emergence of drug-resistant strains.
Nanoparticles (NP) have the ability to mask drugs from the external environment while increasing circulation time and often alleviate many issues at once. Furthermore, the selected drugs do not need to be modified. Drug conjugation NPs with a targeting ligand and stimuli-responsive linkers have been extensively researched in many diseases, however, none have been reported for malaria clinically. Here, the first acid-labile targeted NP (tNP) that exploits the biology of infected erythrocytes and the specialised food vacuole (FV) of P. falciparum is interrogated for ability to decrease toxicity while retaining antimalarial activity.
This dissertation describes the effect of tNPs on the efficacy and toxicity of selected compounds. In vitro haemolysis and cytotoxicity assays revealed that the tNPs are biocompatible to erythrocytes and HepG2 cells. The data also shows that tNPs decrease the toxicity of drugs and the chosen novel compound against human cells. A decrease in antiplasmodial activity was observed in vitro for the tNPs when compared to the novel compound and drugs on their own. However, this was due to the biogenesis of the FV and a shortened window of release. Nonetheless, the NP backbone was not active against P. falciparum intraerythrocytic parasites whereas tNPs were, showing activity due to released drug. The targeting ligand was also not specific for antiplasmodial activity.
Although a significant loss in activity is observed, the results presented here suggests that these novel acid-labile tNPs serve as an attractive starting point for targeted treatment of malaria with an improved patient tolerance. Furthermore, novel compounds with issues can be selected without having to be modified or completely discarded. Therefore, increasing the chances of finding a variety of compounds that can be used to treat malaria while keeping patients safe.
