Mechanisms of drug delivery to brain- and solid tumors with Acoustic Cluster Therapy (ACT)
1 Formål
The purpose of these experiments is to unveil the underlying mechanisms behind the improved therapeutic effect of drugs that are combined with acoustic cluster therapy (ACT). Especially we will study the effect of ACT on the blood vessel wall, extravasation of nanoparticles and drugs across the capillary wall and through the interstitium.
2 Skadevirkninger
In this experiments mice will be implanted either with tumors subcutaneously on the hind leg, orthotopically in the pancreas by intra-pancreatic injection and orthotopically in the brain by intra-cranial injection. Also subsets of the animals will be mounted with an intracranial window for imaging of drug delivery in the brain. Other animals will have their tumor imaged by the skin flap method (see ref.1). The two latter procedures will be performed under complete anaesthesia and the animals euthanized while still under anaesthesia.
3 Forventet nytteverdi
Ultrasound-mediated drug delivery (sonopermeation) has in previous clinical trials proven the ability to double the life expectancy of pancreatic cancer patients treated with gemcitabine (see ref.2). ACT is an advanced evolutionary step of sonopermeation that is entering clinical trials in July 2019. Further understanding the biological and biomechanical effect of ACT will greatly advance its clinical application and be important in optimizing cancer treatment. We will use two tumor models, pancreatic tumors and gliomas, both being tumors with extremely poor prognosis. Thus, new strategies for treating such types of cancer are highly needed. Our preclinical experiments are done in close collaboration with the company Phoenix Solutions who has developed the ACT concept and now is stating clinical trials together with medical doctors at Royal Marsden Hospital in London. Thus our results will have a direct impact on future clinical studies.
4 Antall dyr og art
A total of 340 animals are applied for and divided into 4 substudies as listed below.
Exp1: Activation, and biomechanical effect of ACT in various types of blood vessels. (N=90)
Exp2: Penetration of molecular and nano drugs in brain parenchyma with ACT. (N=70)
Exp3: Penetration of molecular and nano drugs in tumor extravascular space with ACT. (N=90)
Exp4: Cell migration and penetration in tumor tissue with ACT. (N=90)
5 Hvordan etterleve 3R
We are currently evaluating ACT both in micro channels and in the chicken chorioallantoic model (CAM) which are both measures to reduce the number of animals needed. This has made it possible to evaluate various ultrasound parameters in relation to ACT in vitro. However, delivery science is challenging to perform satisfactory without animal models because we need the complexity of blood vessels, circulation, extravascular space, cancer cells and immune cells to progress in the our understanding of ACT. However we have taking extensive measures to refine the experimental setup by having experienced researchers handling the animals in the experiments and receiving training on the experimental setup by experienced partners.
The purpose of these experiments is to unveil the underlying mechanisms behind the improved therapeutic effect of drugs that are combined with acoustic cluster therapy (ACT). Especially we will study the effect of ACT on the blood vessel wall, extravasation of nanoparticles and drugs across the capillary wall and through the interstitium.
2 Skadevirkninger
In this experiments mice will be implanted either with tumors subcutaneously on the hind leg, orthotopically in the pancreas by intra-pancreatic injection and orthotopically in the brain by intra-cranial injection. Also subsets of the animals will be mounted with an intracranial window for imaging of drug delivery in the brain. Other animals will have their tumor imaged by the skin flap method (see ref.1). The two latter procedures will be performed under complete anaesthesia and the animals euthanized while still under anaesthesia.
3 Forventet nytteverdi
Ultrasound-mediated drug delivery (sonopermeation) has in previous clinical trials proven the ability to double the life expectancy of pancreatic cancer patients treated with gemcitabine (see ref.2). ACT is an advanced evolutionary step of sonopermeation that is entering clinical trials in July 2019. Further understanding the biological and biomechanical effect of ACT will greatly advance its clinical application and be important in optimizing cancer treatment. We will use two tumor models, pancreatic tumors and gliomas, both being tumors with extremely poor prognosis. Thus, new strategies for treating such types of cancer are highly needed. Our preclinical experiments are done in close collaboration with the company Phoenix Solutions who has developed the ACT concept and now is stating clinical trials together with medical doctors at Royal Marsden Hospital in London. Thus our results will have a direct impact on future clinical studies.
4 Antall dyr og art
A total of 340 animals are applied for and divided into 4 substudies as listed below.
Exp1: Activation, and biomechanical effect of ACT in various types of blood vessels. (N=90)
Exp2: Penetration of molecular and nano drugs in brain parenchyma with ACT. (N=70)
Exp3: Penetration of molecular and nano drugs in tumor extravascular space with ACT. (N=90)
Exp4: Cell migration and penetration in tumor tissue with ACT. (N=90)
5 Hvordan etterleve 3R
We are currently evaluating ACT both in micro channels and in the chicken chorioallantoic model (CAM) which are both measures to reduce the number of animals needed. This has made it possible to evaluate various ultrasound parameters in relation to ACT in vitro. However, delivery science is challenging to perform satisfactory without animal models because we need the complexity of blood vessels, circulation, extravascular space, cancer cells and immune cells to progress in the our understanding of ACT. However we have taking extensive measures to refine the experimental setup by having experienced researchers handling the animals in the experiments and receiving training on the experimental setup by experienced partners.