N-vinylpyrrolidone-vinyl acetate block copolymers as drug delivery vehicles

[摘要] ENGLISH ABSTRACT: The primary aim of this study was to investigate the feasibility of the amphiphilic blockcopolymer poly((vinylpyrrolidone)-b-poly(vinyl acetate)) (PVP-b-PVAc) as a vehicle forhydrophobic anti-cancer drugs.PVP-b-PVAc block copolymers of constant hydrophilic PVP block length and varyinghydrophobic PVAc block lengths were synthesized via xanthate-mediated controlled radicalpolymerization (CRP). The methodology consisted of growing the PVAc chain from a xanthateend-functional PVP. In an aqueous environment the amphiphilic block copolymers selfassembledinto spherical vesicle-like structures consisting of a hydrophobic PVAc bilayermembrane, a hydrophilic PVP corona and an aqueous core. The self-assembly behaviour and thephysicochemical properties of the self-assembled structures were investigated by 1H NMRspectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamicand static light scattering.Drug loading studies were performed using a model hydrophobic drug, clofazimine, and acommon anti-cancer drug paclitaxel (PTX) to evaluate the potential of the PVP-b-PVAc blockcopolymers for drug delivery,. Clofazimine and PTX were physically entrapped into thehydrophobic domain of the self-assembled PVP-b-PVAc block copolymers via the dialysismethod. The drug-loaded PVP-b-PVAc block copolymers were characterized regarding particlesize, morphology, stability and drug loading capacity in order to assess their feasibility as a drugvehicle. The polymer vesicles had a relatively high drug loading capacity of 20 wt %. The effectof the hydrophobic PVAc block length on the drug loading capacity and encapsulation efficiencywere 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 andencapsulation efficiency were also investigated. The optimal formulation for the drug-loadedPVP-b-PVAc was determined and further investigated in vitro. The size stability of the drugloadedPVP-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-resistanthuman breast epithelial cancer cells and normal MCF12A breast epithelial cells to provideevidence of their antitumor efficacy. In vitro cell culture studies revealed that the PVP-b-PVAcdrug carrier exhibited no cytotoxicity towards MDA-MB-231 and MCF12A cells, confirming thebiocompatibility 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 internalizationof the PVP-b-PVAc drug carrier was demonstrated by fluorescent labeling of the PVP-b-PVAccarrier. 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 promisingcandidates for the delivery of hydrophobic anti-cancer drugs.

[发布机构] Stellenbosch University