Browsing by Author "Pfukwa, Rueben"

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    Facile route to targeted, biodegradable polymeric prodrugs for the delivery of combination therapy for Malaria
    (American Chemical Society, 2020-06) Fortuin, Lisa; Leshabane, Meta; Pfukwa, Rueben; Coertzen, Dina; Birkholtz, Lyn-Marie; Klumperman, Bert
    A facile synthetic methodology has been developed to prepare multifaceted polymeric prodrugs that are targeted, biodegradable, and nontoxic, and used for the delivery of combination therapy. This is the first instance of the delivery of the WHO recommended antimalarial combination of lumefantrine (LUM, drug 1) and artemether (AM, drug 2) via a polymeric prodrug. To achieve this, reversible addition-fragmentation chain transfer (RAFT)-mediated polymerization of N-vinylpyrrolidone (NVP) was conducted using a hydroxy-functional RAFT agent, and the resulting polymer was used as the macroinitiator in the ring-opening polymerization (ROP) of α-allylvalerolactone (AVL) to synthesize the biodegradable block copolymer of poly(N-vinylpyrrolidone) and poly(α-allylvalerolactone) (PVP-b-PAVL). The ω-end thiol group of PVP was protected using 2,2′-pyridyldisulfide prior to the ROP, and was conveniently used to bioconjugate a peptidic targeting ligand. To attach LUM, the allyl groups of PVP-b-PAVL underwent oxidation to introduce carboxylic acid groups, which were then esterified with ethylene glycol vinyl ether. Finally, LUM was conjugated to the block copolymer via an acid-labile acetal linkage in a “click”-type reaction, and AM was entrapped within the hydrophobic core of the self-assembled aggregates to render biodegradable multidrug-loaded micelles with targeting ability for combination therapy.
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    Hierarchical self‐assembly of novel para‐aryltriazole helical foldamers
    (Stellenbosch : Stellenbosch University, 2012-03) Pfukwa, Rueben; Klumperman, Bert; Rowan, Alan E.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Hierarchical information transfer is investigated as a tool to prepare well‐defined nanostructures with high aspect ratios, via the self‐assembly of helically folding poly(paraaryltriazole) (P(p‐AT)) foldamers. A novel ‘helicity codon’ based on the 1,4‐linkage geometry in 1,4‐aryl‐disubstituted‐1,2,3‐ triazoles is developed. Helical folding is induced exclusively by directing all triazole moieties into a cisoid configuration. By linking the triazole rings in a para fashion about the aryl moiety, this helicity codon codes for a helix with a large internal cavity of ~ 3 nm. One turn of the putative helical conformation requires 14 repeat units and the helical pitch is ~ 0.38 nm. The aryltriazole backbone is appended with amphiphilic oligo(ethylene glycol) (oEG) units which have the dual roles of imparting solubility as well as instigating a solvophobic helical folding in solvents which poorly solvate the hydrophobic arytriazole backbone but, solvate the side chains fully. The helix interior is hydrophobic and the exterior is amphiphilic. A true polymer synthesis approach to the foldamer synthesis, based on the copper catalysed azide‐alkyne cycloaddition (CuAAC) AB step growth polymerization system, is developed. This is preceded by a facile synthetic protocol for the AB monomers. The subsequent P(p‐ AT)s have high molecular weights ensuring several turns in the helical foldamer. A DMF/H2O good solvent/bad solvent system is established. Twist sense bias in the helical foldamers is successfully imparted by installing enantiopure chiral oEG side chains. Spectroscopic signatures for the solvent dependent coil to helix transition are established enabling the tracking of the conformational transitions from primary to secondary and finally tertiary structure. Conclusive evidence for the formation of stable, long stacked helical columns, in the solution state, is provided via cryo‐TEM. The helical stacks are several microns long, but of random lengths and do not intertwine but rather run parallel to each other. The helical stacks, however, have indeterminate lengths. Control over the length and chirality of the self‐assembled helical stacks is successfully imparted by using a template which mimics the role of ribonucleic acid (RNA) in tobacco mosaic virus (TMV). The template used is the hydrophobic α‐helical polypeptide poly(γ‐ benzyl‐L‐glutamate) (PBLG). Self‐assembly is driven by solvophobicity in a DMF/H2O system, the PBLG template being encapsulated inside the hydrophobic cavities of the stacked/selfassembled helical foldamers. Information from the template, i.e. length and chirality, is used to control the length and the chirality of the stacked/self‐assembled construct. The templated self‐assembly process is solvent dependent. When carried out in the solvent regime at the coil to helix transition mid‐point of the foldamer host, system operates under a dynamic equilibrium. Under these conditions, the self‐assembly process is shown to take place between two distinct states, the foldamer helices and the helical template, the template threading through the foldamer helices. The resulting self‐assembled construct has a pseudo‐rotaxane architecture. Under dynamic equilibrium conditions, temperature induced dis‐assembly of the templated assembled construct, is shown to be a cooperative process, whilst re‐assembly is characterized by a large hysteresis. By increasing the volume fraction of water, the solvophobic character of the system is increased and template assembled construct is better stabilised. The assembly system, however, loses its dynamic equilibrium character and falls into kinetic traps. Temperature induced de‐threading, of the foldamer helices, becomes less favourable and loses its cooperative character although the hysteresis loop is reduced.
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    Synthesis and characterization of telechelic hydroxyl functional poly (N-vinylpyrrolidone)
    (Stellenbosch : Stellenbosch University, 2008-03) Pfukwa, Rueben; Klumperman, Bert; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    Reversible addition fragmentation chain transfer (RAFT)-mediated polymerization has emerged as a versatile method for preparing polymers with control over molecular weight and polydispersity. Inherent in its mechanism is the retention of the chain transfer agent, the RAFT agent, at the polymer chain ends. Typically RAFT agents are made up of two parts, the so called R (leaving) and Z (thiocarbonyl thio, stabilizing) groups. These are retained as the a-and the w-end groups of the final polymer, respectively. RAFT polymerization offers a ready method for preparing polymers with well defined end functionalities. The a-end functionality can easily be built into the R group. The Z group, however, is thermally unstable and can impart color and smell to the polymer. Hence, two new methods for Z end group removal were introduced. Both methods take advantage of the facile reaction between thiocarbonyl thio compounds and radicals. By matching the functionalities of the R group (a-end group) with that of the end modified w-chain end, both methods offer an easy route to accessing telechelic functional polymers. End functional polymers have many important uses in industry and in the biomedical field. An alcohol functional xanthate RAFT agent was synthesized and successfully used to conduct the RAFT-mediated polymerization of N-vinylpyrrolidone (NVP). Characterization by NMR and MALDI ToF MS confirmed that a-hydroxyl-w-xanthate-functional PVP was easily produced. In the first end group modification method radicals were generated as in atom transfer radical addition (ATRA). A hydroxyl functional a-haloester was used as the ATRA initiator with a Cu catalyst system. The alkyl radical produced by this ATRA initiator then replaced the Z group giving a telechelic hydroxyl functional polymer. NMR analysis showed that the thiocarbonyl thio end group was completely removed. The hydroxyl functionality was quantified by derivatizing with trichloro acetyl isocyanate and subsequent analysis by NMR. MALDI ToF MS analysis, however, was inconclusive. In the second method the thiocarbonyl thio end group was removed by simply heating the polymer with hydrogen peroxide, thereby replacing the Z group with a hydroxyl end group at the w-chain end, giving a telechelic functional polymer. The telechelic hydroxyl functional polymer was subsequently crosslinked with a trifunctional isocyanate to make a PVP hydrogel. This confirmed that the end-modified polymer was indeed telechelic. The swelling kinetics of this hydrogel were determined in water at 37 oC.