Doctoral Degrees (Chemistry and Polymer Science)

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Browsing Doctoral Degrees (Chemistry and Polymer Science) by Author "Bailly, Nathalie"

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    N-vinylpyrrolidone-vinyl acetate block copolymers as drug delivery vehicles
    (Stellenbosch : Stellenbosch University, 2012-03) Bailly, Nathalie; Klumperman, Bert; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: The primary aim of this study was to investigate the feasibility of the amphiphilic block copolymer poly((vinylpyrrolidone)-b-poly(vinyl acetate)) (PVP-b-PVAc) as a vehicle for hydrophobic anti-cancer drugs. PVP-b-PVAc block copolymers of constant hydrophilic PVP block length and varying hydrophobic PVAc block lengths were synthesized via xanthate-mediated controlled radical polymerization (CRP). The methodology consisted of growing the PVAc chain from a xanthate end-functional PVP. In an aqueous environment the amphiphilic block copolymers selfassembled into spherical vesicle-like structures consisting of a hydrophobic PVAc bilayer membrane, a hydrophilic PVP corona and an aqueous core. The self-assembly behaviour and the physicochemical properties of the self-assembled structures were investigated by 1H NMR spectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic and static light scattering. Drug loading studies were performed using a model hydrophobic drug, clofazimine, and a common anti-cancer drug paclitaxel (PTX) to evaluate the potential of the PVP-b-PVAc block copolymers for drug delivery,. Clofazimine and PTX were physically entrapped into the hydrophobic domain of the self-assembled PVP-b-PVAc block copolymers via the dialysis method. The drug-loaded PVP-b-PVAc block copolymers were characterized regarding particle size, morphology, stability and drug loading capacity in order to assess their feasibility as a drug vehicle. The polymer vesicles had a relatively high drug loading capacity of 20 wt %. The effect of the hydrophobic PVAc block length on the drug loading capacity and encapsulation efficiency were also studied. Drug loading increased with increasing the hydrophobic PVAc block length. The effect of the drug feed ratio of clofazimine and PTX on the drug loading capacity and encapsulation efficiency were also investigated. The optimal formulation for the drug-loaded PVP-b-PVAc was determined and further investigated in vitro. The size stability of the drugloaded PVP-b-PVAc block copolymers was also assessed under physiological conditions (PBS, pH 7.4, 37 °C) and were stable in the absence and presence of serum. PVP-b-PVAc block copolymers were tested in vitro on MDA-MB-231 multi-drug-resistant human breast epithelial cancer cells and normal MCF12A breast epithelial cells to provide evidence of their antitumor efficacy. In vitro cell culture studies revealed that the PVP-b-PVAc drug carrier exhibited no cytotoxicity towards MDA-MB-231 and MCF12A cells, confirming the biocompatibility of the PVP-b-PVAc carrier. In vitro cytotoxicity assays using clofazimine-PVPb- PVAc formulations showed that when MDA-MB-231 cells were exposed to the formulations, an enhanced therapeutic effect was observed compared to the free drug. Cellular internalization of the PVP-b-PVAc drug carrier was demonstrated by fluorescent labeling of the PVP-b-PVAc carrier. Fluorescence microscopy results showed that the carrier was internalized by the MDAMB- 231 cells after 3 hours and localized in the cytoplasm and the perinuclear region. Overall, it was demonstrated that PVP-b-PVAc block copolymers appear to be promising candidates for the delivery of hydrophobic anti-cancer drugs.