Final Report Summary - MRGFUS IN THE BRAIN (Focused ultrasound under magnetic resonance guidance for targeted drug delivery in the brain)
There are limited treatment options for patients with a tumour in the brain. One of the reasons is the presence of the blood brain barrier, which prevents most drugs from entering the brain. The blood brain barrier can be seen as the gatekeeper of the brain by preventing harmful molecules from leaving the vasculature to enter the brain. However, in this way also many therapeutics are blocked that have been proven to be effective for tumours outside the brain.
In this project ‘Focused ultrasound under magnetic resonance (MR) guidance for targeted drug delivery in the brain’ we aim to temporarily disrupt the blood brain barrier by using focused ultrasound in combination with microbubbles. With this technique we want to improve the delivery of therapeutics to brain metastasis from breast cancer. As ultrasound can be focused, the disruption will only be at the location of the tumour. For patients with breast cancer metastases, good antibody therapies are available when the metastases are outside the brain (extracranial tumours). But these therapies do not work for brain metastases, due to the presence of the blood-brain barrier. In this project, we study the response of rats with brain metastases from breast cancer to transient disruption of the blood-brain barrier in combination with two antibody therapies.
The first period of the project was dedicated to learning the technique to disrupt the blood-brain barrier using focused ultrasound and everything that was involved with these experiments, such as cell culturing and tumour implantation, animal handing, characterization of transducers, histological analyses, use of MR imaging and ultrasound systems.
It is anticipated that multiple treatments are needed for effective tumour treatment. Therefore, in our study, animals will receive six weekly treatments during which the blood-brain barrier is disrupted. To be sure that this can be performed safely, the effects of repeated blood-brain barrier disruption were studied in 15 healthy rats by analysis of histological brain sections after completion of six weekly sessions. Furthermore, MR images were obtained before and after each sonication session and evaluated for signs of damage. We demonstrated that the blood-brain barrier can be disrupted repeatedly without significant damage to the brain when low acoustic pressures are used.
The main part of project was dedicated to study the effects of two antibody therapies in combination with focused ultrasound-mediated blood-brain barrier disruption for the treatment of brain metastases from breast cancer. As these antibodies are relatively large, they normally do not cross the blood-brain barrier. Several antibody therapies are approved in humans for the treatment of extracranial metastases from HER2-positive breast cancer. By combining these therapies with blood-brain barrier disruption using focused ultrasound, we aim to improve the response of brain metastases to these antibodies. Therefore, we started with comparing two different tumour models and chose one human cell line from breast cancer brain metastasis for this project. We grew brain metastases in 30 nude rats and divided them in three different treatment groups, namely animals that did not receive any treatment (controls), animals that received only the two antibody treatments and animals that received the antibodies in combination with focused ultrasound-mediated blood-brain barrier disruption. The animals received six treatments and were imaged every two weeks in the MR-scanner to follow the growth of the tumour. When the tumours became too large, animals were sacrificed and their brains were processed for histological analysis. We showed that the combination of focused ultrasound and the antibody therapy resulted in growth inhibition during the treatment period in part of the animals. After the treatment period, the effect vanished. Furthermore, the response was only observed in part of the animals (4 out of 10). We could not explain based on our results why not all animals responded. This is topic for further research. By using a human tumour cell line in combination with therapies that have been approved for treatment of extracranial metastases, we hope that in the future this technique can be translated to humans.
This second part of the project was dedicated to implementing the technique at Radboudumc in the Netherlands. To this end, an upgrade dedicated to small animal brain treatments for the focused ultrasound system was bought. For this system, dedicated MR-coils were developed in-house, imaging protocols were optimized using phantoms and the first in vivo experiments to disrupt the blood-brain barrier in mice were successfully performed. With this set-up we will continue to investigate the possibilities for enhanced drug delivery using blood-brain barrier disruption with focused ultrasound.
In this project ‘Focused ultrasound under magnetic resonance (MR) guidance for targeted drug delivery in the brain’ we aim to temporarily disrupt the blood brain barrier by using focused ultrasound in combination with microbubbles. With this technique we want to improve the delivery of therapeutics to brain metastasis from breast cancer. As ultrasound can be focused, the disruption will only be at the location of the tumour. For patients with breast cancer metastases, good antibody therapies are available when the metastases are outside the brain (extracranial tumours). But these therapies do not work for brain metastases, due to the presence of the blood-brain barrier. In this project, we study the response of rats with brain metastases from breast cancer to transient disruption of the blood-brain barrier in combination with two antibody therapies.
The first period of the project was dedicated to learning the technique to disrupt the blood-brain barrier using focused ultrasound and everything that was involved with these experiments, such as cell culturing and tumour implantation, animal handing, characterization of transducers, histological analyses, use of MR imaging and ultrasound systems.
It is anticipated that multiple treatments are needed for effective tumour treatment. Therefore, in our study, animals will receive six weekly treatments during which the blood-brain barrier is disrupted. To be sure that this can be performed safely, the effects of repeated blood-brain barrier disruption were studied in 15 healthy rats by analysis of histological brain sections after completion of six weekly sessions. Furthermore, MR images were obtained before and after each sonication session and evaluated for signs of damage. We demonstrated that the blood-brain barrier can be disrupted repeatedly without significant damage to the brain when low acoustic pressures are used.
The main part of project was dedicated to study the effects of two antibody therapies in combination with focused ultrasound-mediated blood-brain barrier disruption for the treatment of brain metastases from breast cancer. As these antibodies are relatively large, they normally do not cross the blood-brain barrier. Several antibody therapies are approved in humans for the treatment of extracranial metastases from HER2-positive breast cancer. By combining these therapies with blood-brain barrier disruption using focused ultrasound, we aim to improve the response of brain metastases to these antibodies. Therefore, we started with comparing two different tumour models and chose one human cell line from breast cancer brain metastasis for this project. We grew brain metastases in 30 nude rats and divided them in three different treatment groups, namely animals that did not receive any treatment (controls), animals that received only the two antibody treatments and animals that received the antibodies in combination with focused ultrasound-mediated blood-brain barrier disruption. The animals received six treatments and were imaged every two weeks in the MR-scanner to follow the growth of the tumour. When the tumours became too large, animals were sacrificed and their brains were processed for histological analysis. We showed that the combination of focused ultrasound and the antibody therapy resulted in growth inhibition during the treatment period in part of the animals. After the treatment period, the effect vanished. Furthermore, the response was only observed in part of the animals (4 out of 10). We could not explain based on our results why not all animals responded. This is topic for further research. By using a human tumour cell line in combination with therapies that have been approved for treatment of extracranial metastases, we hope that in the future this technique can be translated to humans.
This second part of the project was dedicated to implementing the technique at Radboudumc in the Netherlands. To this end, an upgrade dedicated to small animal brain treatments for the focused ultrasound system was bought. For this system, dedicated MR-coils were developed in-house, imaging protocols were optimized using phantoms and the first in vivo experiments to disrupt the blood-brain barrier in mice were successfully performed. With this set-up we will continue to investigate the possibilities for enhanced drug delivery using blood-brain barrier disruption with focused ultrasound.