Forsøksdyr: Evaluation of the combined effect of ACT and Losartan, on the delivery of model-drug/dye loaded-NPs in pancreatic cancer.

Godkjenningsdato 23.06.2020

Godkjenningsperiode 23.06.2020-22.06.2024

Acoustic Cluster Therapy (ACT) is a technology for improved delivery of drugs and nanoparticles (NPs) to tumours. The aim of this project is to evaluate the effect of the combined use of ACT and Losartan, a molecule which is shown to reduce the production of collagen and glycosaminoglycans and enhance uptake of drugs in tumours. Both ACT and Losartan is now in clinical testing, and we want to study to what extent combining these two strategies improve the delivery of drugs and NPs to tumours through the Extracellular Matrix (ECM). Furthermore, we aim to investigate the underlying mechanism for the therapeutic response by performing intravital microscopy.
Infiltrating ductal adenocarcinoma of the pancreas (PDAC) will be used as this is a clinically relevant tumour model, with very poor prognosis, characterized by a dense ECM and hypoxic areas where the access of therapeutic drugs is very limited. Losartan decreases the synthesis of growth factors and reduce the presence of collagen and hyaluronic acid, thereby reducing the ECM density. Thus, it is an appropriate model to investigate the effect of ACT combined with Losartan, with the aim of improving the low drug delivery typical of this malignancy. Losartan combined with chemotherapy (FOLFIRINOX) is used in clinical studies to treat PDAC, and treating PDAC with ACT and chemotherapy is planned. Furthermore, we aim to investigate the underlying mechanisms for the therapeutic response by performing intravital microscopy.

We have previously performed similar studies using ACT alone, and we expect that the mice will have moderate distress, and the severity classification is moderate. The animals will receive intraperitoneal, subcutaneous and intravenous injections. The mice will have cancer, but they will not have to suffer and the 3Rs principles will be taking into consideration constantly, humane endpoints will be applied as early as possible and we will continuously use both anaesthesia and analgesia, are a way to apply the Refinement principle. Animals are monitored daily.

Expected benefit
The study should evaluate the possibility of improving the low access of NPs and drugs into the PDAC tumour model, through the combined effect of ACT and Losartan. The preclinical experiments and intravital microscopy are essential to optimize and understand the mechanism of ongoing and planed clinical studies.

Number of animals, and what kind
A total of 287 B6-albino mice will be used over a total of 3 sub-studies.

How to adhere to 3R
Proper anaesthetic during subcutaneous tumour cell inoculation, all injections, imaging, and ACT treatment.
Proper anaesthetic during surgery and analgesia during and after surgery, both in the case of the laparotomy as well as in the dorsal window chamber implantation.
Ultrasound imaging is non-invasive and therefore tumour growth rate can be monitored for a several weeks.
The mice are kept at a heated pad at 37°C to maintain the body temperature.
During interventions the respiration will be monitored visually, and the anaesthesia will be tested by regularly checking the reflexes. The mice will be euthanized by cervical dislocation, this method is fast and ensures death.