Extracellular matrix modifications by oligoguluronates for cancer treatment
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Type I collagen is the main structural protein of the extracellular matrix, and isabnormally produced in many types of solid tumours. The presence of a thickand linearised collagen fibres constituting a dense network in a tumours microenvironmenthas been linked to high malignancy and chemoresistance of cancers.Rixova is a novel drug-candidate based on G-blocks that has demonstrated promisingresults in normalising the extracellular matrix, reducing tumour growth andenhancing drug delivery in preliminary clinical studies. This thesis investigates themodifications of collagen network structure and viscoelastic properties by treatmentwith G-blocks, which are highly defined and short, bioactive guluronateoligomers derived from alginate.The effect of G-blocks on the fibrillation of type I tropocollagen monomers wasinvestigated by simultaneous timelapse confocal reflectance microscopy visualisingthe structure of the collagen network, and by multiple-particle tracking with meansquaredisplacement- analysis measuring the microrheology of the solution. Thisnew method of monitoring the sol-gel transition combines two established techniquesand has provided accurate information about the relation between structureand viscoelasticity of the collagen network during gelation. This tool canpotentially 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 strongesteffect on collagen, accelerating the formation of initial aggregates in fibrillogenesis.The premature aggregation resulted in a final-network structure where fiberswith larger diameters were organised in a more intertwined and densely connectednetwork. Corresponding to the accelerated development of fibres, there was anaccelerated development of viscoelastic properties of the gel. With increasing Gblockconcentrations the suspended particles exhibited earlier sub-diffusive motionpatterns due to increasing viscosity of the fluid within pores of the network andincreasing confinement by the surrounding network-structures.In this thesis, G-blocks have been observed to interact with type 1 tropocollagenmonomers, modulating the network-structure forming a stiffer and less penetrablematrix. This does not fully explain the beneficial effects seen in clinical studiesof Rixova, so the mechanism behind the effect of G-blocks in vivo is yet to bedetermined. Further studies need to be performed to narrow down the knowledgegap between the results observed on in vivo and in vitro systems.