The Effect of G-block on the Extracellular Matrix Barrier to Molecular Diffusion
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Changes in extracellular matrix (ECM) are one of the characteristics of solid tumours. Many types of cancers associated with high mortality rates develop solid tumours with an extensive fibrotic extracellular matrix. Over expression of ECM may result in an increased barrier to drug diffusion in the tumour interstitium, resulting in inefficient drug delivery. There is an increasing number of studies supporting ECM as a potential target of treatment to improve drug delivery in cancer treatment. RiXOVA is an anti-cancer drug candidate based on G-block technology, targeting extracellular matrix. Experimental in vivo data has shown reduction in tumour growth in a mouse model of pancreatic cancer with RiXOVA both as a single agent and in combination with the standard cytostatic gemcitabine. A hypothesis for the mode of action of RiXOVA is that G-block is able to reduce the extracellular matrix barrier to drug diffusion in tumours with an over expression of ECM, such as pancreatic cancer, resulting in improved drug and immune system access to the cancer cells. The aim of this master thesis was to investigate if G-block can reduce the extracellular matrix barrier to molecule diffusion. A method for studying diffusion of model compounds out of an extracellular matrix was developed and optimized with Matrigel as model for ECM and the dye tartrazine and Alexa Fluor® 488 IgG as model compounds. By utilizing the developed method, diffusion of the model compounds from Matrigel with and without the presence of G-block was investigated. In addition, the rheological profile of Matrigel with and without G-block was characterized to study the effect of G-block on the rheological properties of Matrigel. G-block demonstrated an increased diffusion rate of both tartrazine and IgG from Matrigel. From the rheological measurements, G-block did not demonstrate an effect on the rheological profile of Matrigel in the presence of saline and tartrazine. However, rheological data demonstrated a reduction in the elastic properties of Matrigel with G-block as the only added component. It was postulated that G-block reduces the extracellular matrix barrier to molecule diffusion by affecting a bound fraction of tartrazine and IgG in Matrigel. It was also suggested that G-block can reduce the steric hindrance by affecting the structure of the Matrigel network, including elastic properties. However, due to the complex nature of Matrigel, an explanation of the interactions between Matrigel and G-block is most likely multifactorial.