Correlating tissue properties, particle size and acoustic pressure in ultrasound mediated delivery of nanoparticles
Using microbubbles in combination with focused ultrasound has been shown to enhance the delivery of nanoparticles to tumor, making it possible to delivery drugs encapsulated in the particles in a more safe and efficient manner. However, increased understanding of this treatment system is needed to exploit its full potential. In this study we will attempt to uncover any correlations between tumor tissue properties, acoustic pressure and nanoparticle size on the transport of nanoparticles through the extracellular matrix. We will use subcutaneous murine tumor models of pancreatic adenocarcinoma, mammary carcinoma and colorectal carcinoma as three representatives of different tumor microenvironments.
The expected benefit of the study will be to gain increased understanding of the role the tumor microenvironment has in mediating the delivery of nanoparticles with the use of microbubbles and focused ultrasound. The study will also serve as an input in the development and validation of a predictive mathematical model for ultrasound mediated nanoparticle delivery.
A total of 463 mice will be used in the study. In order to replace and reduce the number of animals, we are currently working with both in vitro models of the extracellular matrix, as well as the already mentioned model of delivery of nanoparticles using microbubbles and ultrasound. However, these activities cannot fully replace in vivo studies as it is difficult to mimic the complex tumor microenvironment. Furthermore, preliminary studies with few will also be used to optimize the experimental protocol before starting the main studies to ensure that we do not use more animals than needed or perform an experiment with a large number of animals. We expect the animals to be under mild stress for the duration of the experiment. The mice will be implanted with a small subcutaneous tumor on one of their hind legs, where the study will be terminated and the animal euthanized before we expect the animal to be in discomfort. The animals will then be subjected to non-invasive optical imaging and ultrasound treatment and imaging. They will not be subjected to ultrasound at a mechanical index above what is considered safe. All treatments, blood sampling and i.v. injections will be made under anesthesia.
The expected benefit of the study will be to gain increased understanding of the role the tumor microenvironment has in mediating the delivery of nanoparticles with the use of microbubbles and focused ultrasound. The study will also serve as an input in the development and validation of a predictive mathematical model for ultrasound mediated nanoparticle delivery.
A total of 463 mice will be used in the study. In order to replace and reduce the number of animals, we are currently working with both in vitro models of the extracellular matrix, as well as the already mentioned model of delivery of nanoparticles using microbubbles and ultrasound. However, these activities cannot fully replace in vivo studies as it is difficult to mimic the complex tumor microenvironment. Furthermore, preliminary studies with few will also be used to optimize the experimental protocol before starting the main studies to ensure that we do not use more animals than needed or perform an experiment with a large number of animals. We expect the animals to be under mild stress for the duration of the experiment. The mice will be implanted with a small subcutaneous tumor on one of their hind legs, where the study will be terminated and the animal euthanized before we expect the animal to be in discomfort. The animals will then be subjected to non-invasive optical imaging and ultrasound treatment and imaging. They will not be subjected to ultrasound at a mechanical index above what is considered safe. All treatments, blood sampling and i.v. injections will be made under anesthesia.