Forsøksdyr: Using MRI guided focused ultrasound for delivery of non-targeted and targeted nanoparticles across the BBB in rats

Godkjenningsdato 21.06.2018

Currently there are only a few ways of treating most diseases associated to the brain. The main reason for the lack of effecient drug delivery and thus treatment of these diseases, is the blood-brain barrier (BBB). The BBB effectively hinders almost all drugs from entering the brain since the endothelial cells that the capillaries are composed of are very tightly packed and have abilities to pump out unwanted chemicals.

Focused ultrasound in the presence of microbubbles (MBs) is known to open the BBB and shows great potential as a way of surpassing the BBB. It is a relatively new technique and the first clinical trials in humans started.

Nanoparticles have been studied intensively for drug delivery purposes to tumors throughout the body and show promising results. However, just as for regular drugs, delivery of drugs for the treatment of brain disorders is limited, because the BBB hinders NPs from entering the brain. Opening the BBB with focused ultrasound and MBs will enable NPs to enter the brain, making it possible to use them for drug delivery purposes.

The main aim of this study is to investigate if the use of targeting nanoparticles in combination with focused ultrasound opening of the BBB can increase the amount of nanoparticles that enter the brain. This combination has not been studied before and the main idea behind this approach is that the nanoparticles will specifically target the brain endothelial cells resulting in an increased concentration of nanoparticles at the site of BBB opening. This approach could result in more nanoparticles crossing the BBB, making it an interesting strategy for several brain diseases.

The nanoparticles used will target a transferrin receptor which is only expressed on brain endothelial cells, making the targeting really specific. One type of targeting nanoparticles will be used and compared to two different negative control that both lack targeting properties. Opening of the BBB will take place at different timepoints after injecting of the nanoparticles.

In this study we have the following aims:
- Investigate if the use of nanoparticles with targeting properties towards the transferrin receptor on brain endothelial cells in combination with focused ultrasound mediated opening of the blood brain barrier results in increased extravasation of the nanoparticles.
- Study the effect of opening the BBB on the delivery of the nanoparticles at different timepoints after injection of the NPs.
- Gain time resolved understanding of the non-targeted and targeted nanoparticles when exposed to ultrasound in combination with microbubbles.
- Determine the blood circulation life time of the nanoparticles used.

To answer these research questions we will be using maximal 197 rats. We expect them to have minimal pain and distress, mainly because they will be fully anaesthetised during all the inventions and will receive pain medication post ultrasound treatment or will not regain consciousness at all in case of the more invasive intervention. In case they show signs of pain or discomfort, more pain medication will be administered or other measures will be taken to end the discomfort.