Development of tailored artemether and lumefantrine nanocrystals for the management of cerebral malaria

Abstract

Malaria remains a global health crisis, causing an estimated 597,000 deaths in 2023, with cerebral malaria (CM) being the most lethal complication of Plasmodium (P.) falciparum infection. Current artemether-lumefantrine (ART-LUM) therapy is limited by poor oral bioavailability and inadequate blood-brain barrier (BBB) penetration. To address these challenges, this research developed nanocrystal (NC)-based delivery platforms, including dissolving microneedles (DMNs) and intranasal (IN) formulations, to enhance CNS-targeted drug delivery.

NC formulations were prepared by wet bead milling method and sequentially surface modified by chitosan (CS) and poly(ethylene glycol) (PEG), yielding colloidally stable particles (zeta potential: ± 5 mV) with enhanced mucopenetration. The optimised NC demonstrated exceptional drug loading capacity (~60 w/w) and uniform sub-200 nm diameters (PDI < 0.3), ensuring reproducible therapeutic delivery with high physical stability. As for transdermal delivery, NC-loaded DMNs exhibited robust mechanical strength and efficient skin penetration. In terms of IN delivery, EDC/NHS-coupled NC formulations functionalised with N-acetylcysteine (NAC) showed improved mucolytic properties, achieving 2.1-fold higher trans-epithelial transport (in the Calu-3 cell model) compared to unmodified NC. In vitro studies revealed their superior anti-inflammatory effects and safety profiles at 62.5 μg/mL. Specifically, ART NC formulations caused minimal metabolic disruption due to their robust antioxidant defences, while LUM NC induced metabolic inhibition via oxidative stress, reflecting complementary therapeutic potential. Despite these differences, both NC formulations effectively suppressed LPS- induced pro-inflammatory cytokine release while preserving bioactivity, independent of surface modifications.

Altogether, this research demonstrated the transformative potential of NC-based drug delivery systems in overcoming the solubility, stability, and transport barriers inherent to CNS-targeted therapies, establishing a solid foundation for future in vivo validation and clinical translation.

Thesis embargoed until 31 July 2026.

Date of Award	Jul 2025
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Alejandro Paredes (Supervisor) & Ryan Donnelly (Supervisor)