Treatment of mice with pancreatic ductal adenocarcinoma (PDAC) with chemotherapy combined with microbubbles (MB) and focused ultrasound (FUS). Safety study with rats.
Experiments at NTNU have shown that ultrasound (US) improves the therapeutic effect and delivery of nanoparticle-stabilized microbubbles (MBs) in breast cancer xenografts. Our research group has also experience with the use of the MBs SonoVue combined with nanoparticles and chemotherapy. Experience from these projects will be applied to experiments with mice with orthotopic PDAC.
This animal model experiment will mimic a planned clinical trial involving patients with inoperable pancreatic ductal adenocarcinoma (PDAC). The effect of focused ultrasound (FUS) and MBs on delivery of the combination regimen FOLFIRINOX will be studied by measuring chemically the uptake of drugs in tumors and by measuring tumor growth. FUS exposure parameters like frequency, pulse length, mechanical index/acoustic pressure and exposure time will be systematically explored. Results from this preclinical experiment will be used to optimize US exposure parameters for drug uptake. Ultimately, these parameters will be used to enhance uptake and improve local therapeutic effect of chemotherapy in humans. It is important to know the impact of the various US parameters and the threshold for possible negative effects.
A total of 200 mice will be included for 1 pilot study and 5 substudies. Impact on animals is expected to be moderate because of application of humane endpoints, anesthesia and analgesia.
To limit the number of mice, the research groups have also performed in vitro studies using organs-on-a-chip and gel-based phantoms. However, it is not possible to mimic the complex vascular system of human tumors in phantom studies. Therefore, mice models are necessary to better be able to predict tumor behavior in humans.
In a separate safety study we would like to examine the effect of US combined with MBs in a trial with 15 rats. In this study we will expose the animals to relevant US parameters in combination with MBs to explore the effect on vessel wall, bleeding, hemolysis and kindey function.
This animal model experiment will mimic a planned clinical trial involving patients with inoperable pancreatic ductal adenocarcinoma (PDAC). The effect of focused ultrasound (FUS) and MBs on delivery of the combination regimen FOLFIRINOX will be studied by measuring chemically the uptake of drugs in tumors and by measuring tumor growth. FUS exposure parameters like frequency, pulse length, mechanical index/acoustic pressure and exposure time will be systematically explored. Results from this preclinical experiment will be used to optimize US exposure parameters for drug uptake. Ultimately, these parameters will be used to enhance uptake and improve local therapeutic effect of chemotherapy in humans. It is important to know the impact of the various US parameters and the threshold for possible negative effects.
A total of 200 mice will be included for 1 pilot study and 5 substudies. Impact on animals is expected to be moderate because of application of humane endpoints, anesthesia and analgesia.
To limit the number of mice, the research groups have also performed in vitro studies using organs-on-a-chip and gel-based phantoms. However, it is not possible to mimic the complex vascular system of human tumors in phantom studies. Therefore, mice models are necessary to better be able to predict tumor behavior in humans.
In a separate safety study we would like to examine the effect of US combined with MBs in a trial with 15 rats. In this study we will expose the animals to relevant US parameters in combination with MBs to explore the effect on vessel wall, bleeding, hemolysis and kindey function.