Browsing by Author "Reader, Paul William"

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    Anti-Malarial Polymer-Peptide Conjugates
    (Stellenbosch : Stellenbosch University, 2014-12) Reader, Paul William; Klumperman, Bert; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: The primary aim of this study was to investigate an amphiphilic polyvinylpyrrolidone (PVP)-based drug delivery system for the treatment of the Plasmodium falciparum strain of malaria, using a known anti-malarial cylic decapeptide, tyrothricin. A triazole-based reversible addition-fragmentation chain-transfer (RAFT) agent, comprising an acetal-based R-group and a xanthate-based Z-group was synthesised. α-Acetal, ω-xanthate heterotelechelic PVP was synthesised via RAFT polymerisation and it was shown that the polymerisation was adequately controlled. A one-pot orthogonal chain-end functionality deprotection strategy was developed and conditions were established to conjugate a model targeting ligand and a model drug linker to the α- and ω-chain-ends, respectively. A micellar drug delivery system was developed by conjugating the aggregation-prone tyrothricin to PVP, via its ω-chain-end functionality through an acid-labile linker. The α-chain-end functionality of the PVP was sparsely conjugated to a targeting ligand and to a fluorescent marker. In aqueous media, the conjugate exhibited self-assembly into micelles. The tyrothricin formed the core of the micelle, stabilised via the hydrophilic PVP, decorated with the targeting ligands and fluorescent marker. The conjugate was shown to inhibit chloroquine-resistant P. falciparum strains of malaria in picomolar concentrations with virtually no haemolysis observed; a 700-fold improvement of the IC50 over tyrothricin alone was observed. In addition, the conjugates were found to vaccinate the erythrocytes against re-infection. The drug delivery system appears to be a promising candidate for further investigation as a treatment against drug-resistant strains of malaria.