Key Points
- Research led by Kullervo Hynynen, PhD, showed sonodynamic therapy produced significant anti-tumor effects and increased survivability in glioblastoma models.
- In another of his studies, focused ultrasound–mediated delivery of stem cells improved behavioral outcomes in a Parkinson’s disease model.
Research teams led by Kullervo Hynynen, PhD, the Temerty Chair of Focused Ultrasound Research at Sunnybrook Research Institute, recently published preclinical studies investigating the effects of focused ultrasound for the treatment of brain tumors and Parkinson’s disease.
Glioblastoma is a highly aggressive cancer of the central nervous system with a very poor prognosis for survival. Although multiple treatment modalities, including surgical resection, radiotherapy, and chemotherapy, have been employed to treat this disease, new therapeutic regimens are still needed.
A collaborative team of researchers at the University Toronto, Sunnybrook Research Institute, Tri-Service General Hospital, and SonALAsense investigated whether 5-ALA sonodynamic therapy, an innovative therapeutic approach for cancer treatment, could show promise in mouse models of glioblastoma.
After intravenously injecting 5-ALA (a commonly used drug that is used for tumor visualization during brain surgery) and allowing it to accumulate in the tumor tissue, the team applied focused ultrasound to activate protoporphyin IX, an intermediate compound of created during the metabolization of 5-ALA. The activation causes the production of reactive oxygen species, leading to cell death within the tumors. While multiple clinical trials are ongoing for 5-ALA sonodynamic therapy, this study investigated the effect of different parameters to further improve efficacy and safety of the technology.
Using two different tumor models, the groups assessed the ultrasound exposure parameters and timing on tumor volume and survivability. Longer ultrasound burst lengths showed inhibition of tumor growth and increased survival outcomes when compared to shorter exposures. In addition, weekly repeated treatments of 5-ALA sonodynamic therapies resulted in tumor-free treated animals and significantly prolonged survival times when compared with control groups of focused ultrasound alone or 5-ALA alone. The treatment even had a benefit on late-stage tumors.
Future studies are necessary to further elucidate the mechanisms that induce the positive effects visualized using 5-ALA sonodynamic therapy. A key question to investigate is how the immune system is altered after treatment, as this is crucial for effective tumor treatment. In addition, future studies will explore different tumor locations to determine whether the optimal ultrasound pressure or intensity might vary depending on the area effected.
MRI-Guided Focused Ultrasound for Treating Parkinson’s Disease with Human Mesenchymal Stem Cells
Parkinson’s disease is a neurodegenerative disorder that causes regions of the brain to deteriorate, leading to debilitating symptoms such as resting tremors and muscle rigidity. Currently, therapies available are limited in such they cannot halt disease progression or are invasive with the risk of severe side effects.
To overcome the barriers of current therapies, researchers investigated the use of focused ultrasound–mediated delivery of mesenchymal stem cells (MSCs). Human bone marrow–derived MSCs can induce a range of biological effects, making them a promising treatment option for neurodegenerative diseases. However, MSCs are larger than the average blood-brain barrier (BBB) gap, making delivery challenging. With the use of focused ultrasound in the presence of microbubble contrast agents, the group led by Dr. Hynynen was able to transiently open the BBB and successfully deliver MSCs to the brain.
The group used a rat model of Parkinson’s disease to provide proof-of-concept validation and demonstrate safety and effectiveness of the therapy. The treatment was well tolerated by the animals, and no tissue damage was visualized. In addition, animals that underwent focused ultrasound–mediated delivery of MSCs showed significant improvements in two different behavioral tests as compared with control, focused ultrasound alone, or MSC alone.
MSC therapy in the central nervous system offers great potential but is limited due to delivery efficacy. Using focused ultrasound and microbubbles to overcome delivery challenges provides an important step toward clinical translation.