The synthesis and release studies of polyethylene glycol-lumefantrine conjugates with varying length linkers

Abstract

Malaria remains a global burden, specifically affecting developing countries in sub-Saharan Africa, East Asia and Oceania. To address the high mortality rates associated with severe malaria, researchers at the Council of Scientific and Industrial Research (CSIR) aim to utilise the technique of polymer therapeutics to develop a water-soluble, injectable antimalarial combination treatment. A crucial function of the treatment is the release of the drug through a linker at the necessary site of action. This thesis focuses on the development of water-soluble polyethylene glycol (PEG)-lumefantrine conjugates with varying linker lengths to investigate the effect of linker length on drug release rate.

To this end, lumefantrine (Lume) was covalently bonded to homobifunctional linkers of varying lengths, specifically 4, 5, 6 and 12-carbon dicarboxylic acids. This synthesis was achieved by reacting the linkers in their cyclic anhydride form to ensure reaction specificity. Characterisation of the four Lume-homobifunctional linker compounds proved challenging, with difficulties in visualising diagnostic peaks through NMR analysis. Mass spectrometry aided in confirming the successful conjugation of Lume to the homobifunctional linkers. A heterobifunctional linker, glycine, was also investigated as a potential linker candidate. However, the conjugation of the drug to the glycine linker proved to be challenging and was unsuccessful.

Four novel polyethylene glycol-Lume conjugates were then synthesised by conjugating the Lume-homobifunctional linker compounds to a carrier polymer. To promote the preferential release of the drug from the conjugate system, Lume was rationally covalently attached to the linker via a more readily hydrolysable ester bond while the polymer was connected to the linker through an amide bond to yield pH-responsive linkages. The polymer-drug conjugates were synthesised using different coupling reagents and characterised using specialised analytical techniques routine for polymer conjugates.

A critical function of the pro-drug system is the release of the drug at the relevant site of action and hence the release studies of the conjugate systems were investigated in an acidic environment of pH 5.5. A reliable release method was developed and validated to ensure accurate results from the release studies due to the extreme lipophilicity of Lume.

Release studies at pH 5.5 revealed that the length of the linker significantly influenced the drug release kinetics. The longest linker exhibited the slowest and lowest drug release (10%), while the shortest linker resulted in the fastest and highest drug release (90%) over 7 days. The released product was investigated and confirmed to be Lume, which revealed the stability of the drug throughout the rigorous release method which involves being subjected to an acidic environment, contact with silica and days spent in the solvent. The glutaric and adipic acid linkers exhibited sustained release profiles and are potential candidates for further investigation.

This research demonstrates the tunability of release kinetics in polyethylene glycol-Lume conjugates using pH-responsive linkers. The linker length had a significant effect on the release rate of the drug from the conjugate system. The findings provide insights to inform the development of an effective antimalarial treatment and indicate the potential application of polymer therapeutics to malaria.