Forsøksdyr: Effect of collagene and solid stress in tumors

Godkjenningsdato 22.01.2018

Godkjenningsperiode 01.02.2018-31.03.2019

Drug delivery to solid tumors is a major challenge. Multiple biological barriers hinders effective transport of drugs, both of classical small molecules and of the more novel approach of macromolecules and nanoparticles. One important hinder for both functional perfusion, extravasation and intra-tumoral transport is the dense stromal compartment found in many tumors, consisting of a.o hyaluron and collagen fibers. These macromolecules along with high cell density is known to create a high solid stress in tumors.

In previous experiments (eg. Snipstad et al. 2017, Ultrasound in Medicine and Biology), it has been shown that drug delivery aided by microbubbles and ultrasound can increase the delivery of therapeutic agents. However, the exact mechanism remains unknown.

In this experiment, we aim to look at the effect of ultrasound and microbubbles on the density and structure of collagen and on the solid stress. This will be done by growing two very different tumors, namely Prostate carcinoma (PC3) and Osteosarcoma (OHS). These models have in other experiments been shown to exhibit different stiffness, and also different accumulation of nanoparticles. The animals carrying one of the 2 tumors will be treated with ultrasound and microbubbles, and fluorescently labelled nanoparticles will be injected. Subsequently, the animals will be killed and the tumors harvested for analysis of solid stress, stiffness and collagen/nanoparticle content.

These experiments could greatly improve the understanding of ultrasound-mediated drug delivery and of the tumor microenvironment in general. This in term can lead to more educated treatment strategies and in the end better outcomes for cancer patients.

In the application, a total of 60 animals is applied for. The animals will be injected subcutaneously on the hind leg with tumor cells, and carry the tumor for up to a maximum of 5 weeks or until the tumor is at most 15mm in the longest axis. Both tumor models are thoroughly characterised in our lab, and adverse effects on the animals such as metastatic spread has not been observed. The three R's are have been sought by studying the presens of collagen in samples from old experiments, hence reducing the number of animals needed in this round. The experiment is refined by using tumor models that have been extensivly studied by our group and by having experienced scientists performing the experiments. No satisfactory alternativ for replacement has been found.