Synthesis, characterization and in vitro analyses of lumefantrine-based pharmacologically active polymer for the treatment of severe malaria

Abstract

Between 2000 and 2015, new malaria cases dropped by 27% globally. This reduction in the number of reported annual cases could be attributed to the United Nations’ Millennium Development Goals (MDGs) and other concerted national and international initiatives that set out to halt the spread of infectious diseases like malaria by the year 2015. Unfortunately, this positive trend has slowed and there are indications of a reversal of the gains made. The last two years of the global COVID-19 have also negatively impacted on the gains made during the MDGs period. At least half of the world’s population are still at risk of contracting the disease. To regain the lost ground of 2000-2015, the successor to the MDGs, the Sustainable Development Goals (SDGs), also includes the determination to manage malaria by 2030. Since the adoption of combination therapy in 2001 to treat malaria, treatment outcomes have been highly successful. There is however still a need to improve on the pharmacological properties of the antimalarials for the longevity of the regimen. Of the current World Health Organization (WHO) approved antimalarial chemotherapy, there are five artemisinin-based drug combinations (ACTs). The artemether/lumefantrine combination has been the most widely administered to treat uncomplicated cases of malaria. The current treatment option for the more complicated cases of malaria requires intravenous (IV) administration of a monotherapy preceding the ACT. This two-part treatment strategy has its disadvantages. The use of a monotherapy, which effectively alleviates the serious clinical symptoms of patients could increase the risk of failure to follow through on the additional full three-day course of ACT. This exposes the artemisinins to a higher risk of drug resistance from the malaria parasites. The partner drug in the ACT, lumefantrine, cannot be used in an IV combination as it is in the oral ACT because of its very low aqueous solubility. The aim of the project was to improve the aqueous solubility of lumefantrine using nanomedicine delivery systems. In this study, lumefantrine was chemically linked to water-soluble polymers via hydrolysable bonds (Scheme I). This nanomedicine technology of conjugating an active drug molecule to a water-soluble carrier polymer is referred to as polymer therapeutics. While it has been extensively used in improving cancer chemotherapeutics, the application to parasitic infectious diseases like malaria has been very limited. There has not been any report in the research literature of the conjugation of an antimalarial to a polymer to improve its solubility for the treatment of the disease.The two polymer types investigated in this project increased the aqueous solubility of the drug by three orders of magnitude. The polymer-lumefantrine conjugate investigated for antiplasmodial activity demonstrated efficacy against the parasite comparable to that of the free drug without introducing any new cytotoxicity. The objectives achieved in this research project pave the way for the potential development of a lumefantrine therapeutic that could be used in combination with artesunate in an IV formulation for the treatment of complicated malaria cases. Some of the findings and data from this project have been contributed to draft manuscripts under preparation for peer-reviewed publications and a conference presentation.