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Modelling extravascular drug penetration using multilayered cell cultures Kyle, Alastair Hugh


This thesis describes experiments using multilayered cell cultures (MCCs) to examine the ability of anticancer drugs to penetrate the extravascular compartment of tumour tissue. An MCC consists of cells grown on a permeable plastic membrane to form a disc-like, threedimensional tissue culture 10-30 layers in thickness. MCCs are similar to the spheroidal cell culture model in that they rnirnic the cell environment of tumour tissue better than monolayer cultures in terms of cell contact effects, oxygen and nutrient gradients and the extracellular matrix content. The geometry of MCCs allows for simple experiments in which the cultures are used to separate two reservoirs of a diffusion apparatus and the flux of a drug from one reservoir, through the culture and into the second reservoir, is determined. When coupled with detailed knowledge of the tissue environment and drug-cell interactions, the analysis of flux data from such experiments provides quantitative information on the rate of diffusion and metabolism, or binding, of the drug within the tissue. Such information can be used as a comparative measure between analogues within a given family of drugs or be directly applied to predict the ability of a drug to distribute into tumour tissue. The flux of representative compounds from several classes of anticancer drugs including hypoxic cell radiosensitizers, hypoxic cell cytotoxins and anthracyclines was studied and results are reported in this thesis. In addition to drug flux studies, the cell environment of MCCs was characterised using electrical impedance spectroscopy as well as through experiments involving the use of radiolabeled inulin.

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