Evaluation of the in vitro antiplasmodial and toxicity profiles of novel drug delivery formulations for combination therapies

Abstract

While considerable progress has been made towards malaria elimination over the past several decades, it continues to inflict a heavy burden on socio-economically challenged countries. Artemisinin-based combination therapies, including a fast-acting artemisinin component such as dihydroartemisinin (DHA), have been highly effective in slowing down the rate of drug resistance development and remain the mainstay of control against the disease. However, the complexity of the P. falciparum life cycle combined with antimalarial resistance development has necessitated the development of alternative therapeutic options. As malaria control interventions move toward disease elimination, the focus has shifted towards developing compounds targeting transmissible, gametocyte stages, which remain in the human host long after the asexual stages are cleared. While the clinical candidate MMV390048 exhibits multistage antimalarial activity, inefficient pharmacokinetic and pharmacodynamic properties, poor patient compliance, and the requirement for long-term drug administration pose a challenge for developing dual-stage therapies incorporating this compound.

Here, the encapsulation of MMV390048 with the known clinically active DHA in a slow release, bio-functional 3D polymer drug delivery system using P. falciparum as a model organism, is interrogated for its ability to deliver novel combinations with therapeutic applications. This drug delivery system uses DHA- and MMV390048-loaded solid lipid nanoparticles (SLNs). SLNs can directly release DHA and MMV390048, ensuring an antimalarial therapeutic effect. The in vitro inhibitory activity of a novel, dual active drug combination, DHA and MMV390048, was evaluated against asexual blood stages and transmissible gametocyte stages. Evidence for the combinatorial treatment of asexual and gametocyte stages with DHA and MMV390048 is provided. This revealed that late-stage gametocytes are susceptible to inhibition by the combination, an attractive point for transmission-blocking treatment geared towards elimination. DHA- and MMV390048-loaded SLNs did not retain antimalarial activity compared to the unencapsulated drugs against asexual stages, with excessive haemolytic effects and cytotoxicity. Ultimately, this project presents informative and preliminary evidence of polymer drug delivery systems for administering antimalarials. This strategy may contribute to improved pharmacokinetic and pharmacodynamic properties of transmission-blocking drugs and eventual malaria elimination.