Improved drug delivery to metastatic breast tumors by combining ultrasound, microbubbles and chemotherapy
Cytotoxic drug treatment is one of the main strategies within cancer therapy. The systemic side effects experienced by cancer patients, caused by the drugs, are limiting factors when it comes to maximum doses that can be given. One strategy to overcome this is to encapsulate the drug in nanoparticles. Due to the leakiness in the fast growing blood vessels within tumor tissue, the nanoparticles may extravasate more efficiently from the blood stream and into the tumor tissue than in normal tissue, hence lowering the burden on the healthy tissue. To further improve the drug uptake in tumors, we will combine cytostatic drugs with the injection of microbubbles in the bloodstream and local sonication of ultrasound to the tumor. The oscillation and local disruption of microbubbles within the bloodstream have shown to cause extravasation of nanoparticles and model drugs in previous in-vivo studies. There is great potential of translation of the results from these experiments to patients with various forms of solid tumors. Already, a pilot study with the combination of gemcitabine, microbubbles and ultrasound treatment in patients with pancreatic cancer have been performed at the Haukeland University Hospital, with promising results.
In these experiments we will study the growth of PC3 prostate cancer xenografts on the hind leg of female Balb/c nude mice during various forms of treatment. The experimental groups will be given different combinations of Cabazitaxel, microbubbles and low frequency ultrasound treatment. We will compare the combination of free drug and commercially available microbubbles (the ultrasound contrast agent SonoVue) to drug-loaded nanoparticles given as microbubbles.
A total of 125 mice will be included in the experiments. 55 of them will be part of the phase 1 study where optimal dose and treatment schedule will be determined. In phase 2, we will use a total of 70 mice in 7 experimental groups. The inoculation of cancer cells, intravenous injections of drugs and microbubbles and ultrasound treatment will be done under general anesthesia. Body weight and tumor size will be registered 2-3 times a week and a pain score sheet will be used to monitor the general burden on animals. If needed the animals will be given analgesia. Humane endpoints are clearly described in the pain score sheet.
In order to minimize the burden on the animals, several in-vitro measurements have been performed:
• Acoustic characterization and ultrasound imaging of both SonoVue and SINTEF microbubbles have been done in-vitro.
• The pressure levels and sonication scheme will be determined based on in-vitro measurements and from the results produced in FOTS6803 and FOTS7586.
• Toxicity and biodegradation of SINTEF microbubbles have been studied in cell cultures and biodistribution and circulation time of the microbubbles have been studies in previously performed and ongoing experiments (FOTS6649 and FOTS7586, FOTS8121).
• The ultrasound treatment will be tested in-vitro (in chicken meat) to ensure that it will not lead to local heating causing tissue damage.
In these experiments we will study the growth of PC3 prostate cancer xenografts on the hind leg of female Balb/c nude mice during various forms of treatment. The experimental groups will be given different combinations of Cabazitaxel, microbubbles and low frequency ultrasound treatment. We will compare the combination of free drug and commercially available microbubbles (the ultrasound contrast agent SonoVue) to drug-loaded nanoparticles given as microbubbles.
A total of 125 mice will be included in the experiments. 55 of them will be part of the phase 1 study where optimal dose and treatment schedule will be determined. In phase 2, we will use a total of 70 mice in 7 experimental groups. The inoculation of cancer cells, intravenous injections of drugs and microbubbles and ultrasound treatment will be done under general anesthesia. Body weight and tumor size will be registered 2-3 times a week and a pain score sheet will be used to monitor the general burden on animals. If needed the animals will be given analgesia. Humane endpoints are clearly described in the pain score sheet.
In order to minimize the burden on the animals, several in-vitro measurements have been performed:
• Acoustic characterization and ultrasound imaging of both SonoVue and SINTEF microbubbles have been done in-vitro.
• The pressure levels and sonication scheme will be determined based on in-vitro measurements and from the results produced in FOTS6803 and FOTS7586.
• Toxicity and biodegradation of SINTEF microbubbles have been studied in cell cultures and biodistribution and circulation time of the microbubbles have been studies in previously performed and ongoing experiments (FOTS6649 and FOTS7586, FOTS8121).
• The ultrasound treatment will be tested in-vitro (in chicken meat) to ensure that it will not lead to local heating causing tissue damage.