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Extracellular matrix modifications by oligoguluronates for cancer treatment

Haug, Bente
Master thesis
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http://hdl.handle.net/11250/2507033
Utgivelsesdato
2018
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  • Institutt for bioteknologi og matvitenskap [901]
Sammendrag
Type I collagen is the main structural protein of the extracellular matrix, and is

abnormally produced in many types of solid tumours. The presence of a thick

and linearised collagen fibres constituting a dense network in a tumours microenvironment

has been linked to high malignancy and chemoresistance of cancers.

Rixova is a novel drug-candidate based on G-blocks that has demonstrated promising

results in normalising the extracellular matrix, reducing tumour growth and

enhancing drug delivery in preliminary clinical studies. This thesis investigates the

modifications of collagen network structure and viscoelastic properties by treatment

with G-blocks, which are highly defined and short, bioactive guluronate

oligomers derived from alginate.

The effect of G-blocks on the fibrillation of type I tropocollagen monomers was

investigated by simultaneous timelapse confocal reflectance microscopy visualising

the structure of the collagen network, and by multiple-particle tracking with meansquare

displacement- analysis measuring the microrheology of the solution. This

new method of monitoring the sol-gel transition combines two established techniques

and has provided accurate information about the relation between structure

and viscoelasticity of the collagen network during gelation. This tool can

potentially be used to study the sol-gel transition of other biopolymer-systems.

The study determined that short chained G-blocks with a DPn=12 had the strongest

effect on collagen, accelerating the formation of initial aggregates in fibrillogenesis.

The premature aggregation resulted in a final-network structure where fibers

with larger diameters were organised in a more intertwined and densely connected

network. Corresponding to the accelerated development of fibres, there was an

accelerated development of viscoelastic properties of the gel. With increasing Gblock

concentrations the suspended particles exhibited earlier sub-diffusive motion

patterns due to increasing viscosity of the fluid within pores of the network and

increasing confinement by the surrounding network-structures.

In this thesis, G-blocks have been observed to interact with type 1 tropocollagen

monomers, modulating the network-structure forming a stiffer and less penetrable

matrix. This does not fully explain the beneficial effects seen in clinical studies

of Rixova, so the mechanism behind the effect of G-blocks in vivo is yet to be

determined. Further studies need to be performed to narrow down the knowledge

gap between the results observed on in vivo and in vitro systems.
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