Development And Evaluation Of the Antimalarial Potential Of Bioactive based Nanocarrier System

Abstract

Malaria is a potentially fatal parasitic disease transmitted by infected female newlineAnopheles mosquitoes. A recent report in 2022 by the World Health Organization newline(WHO) estimates that fifty percent of the world s population is at risk of malaria newlineinfection. Artemisinin and its derivatives have been commonly used to treat malaria. newlineHowever, the emergence of resistance against artemisinin derivatives has posed a newlinecritical challenge in malaria management. The present study aimed to explore the newlineantimalarial potential of phyto-lead molecules from Withania somnifera (W. newlinesomnifera), identify specific molecular targets within the malaria parasite, and engineer newlinea nanoformulation for precise drug delivery to infected red blood cells. Withaferin A newline(WS-3), a major steroidal withanoloids isolated from W. somnifera, shows a superior newlinemolecular interaction with the P. falciparum kelch-13 protein (one of the key proteins newlineinvolved in artemisinin resistance) in comparison with artesunate (Art). Flow newlinecytometry and computational-based model showed WS-3 possess a stronger inhibitory newlinemolecular interaction towards sugar (glucose) transporters (GLUT-1 and PfHT) newlineoverexpressed on the surface of parasite-infected RBCs. Low water solubility and short newlinebiological half-life are the two critical challenges faced by combination drug treatment newline(WS-3 and Art). To address the challenges, pH-responsive acetal-dextran nanoparticles newline(Ac-Dex NPs) are designed to co-delivery the payload (WS-3 and Art) to the newlineparasitophorous compartment. The optimized WS-3 and Art Ac-Dex NPs newlinedemonstrated enhanced pH-responsive release profiles under parasitophorous mimetic newlineconditions (pH 5.5). Computational molecular modelling reveals that Ac-Dex s newlinepolymeric backbone strongly interacts with merozoite surface protein-1 (MSP-1), newlinepreventing erythrocyte invasion. In-vitro antimalarial activity of drug-loaded Ac-Dex newlineNPs reveals a 1 1.5-fold reduction in IC50 values compared to pure drug against the newline3D7 strain of Plasmodium falciparum. Treatment with WS-3 Ac-Dex NPs (100mg/kg) newlineand Art