The mechanism of focused ultrasound in the treatment of brain tumors
It is expected to help drugs cross the blood-brain barrier and penetrate abnormal tumor tissue and blood vessels
A study led by a team at Massachusetts general hospital (MGH) has for the first time analyzed the mechanism of using focused ultrasound to enhance the delivery of anti-cancer drugs across the blood-brain barrier into brain tumors. Their report, published in the proceedings of the national academy of sciences (PNAS), used advanced microscopic replication techniques and mathematical models to track the potential of this promising minimally invasive treatment in animal models of breast cancer brain metastases. The team also included investigators from Georgia tech, the university of Edinburgh, brigham and women's hospital."" the blood-brain barrier is a challenge in the treatment of brain malignancies because it can impede drug delivery," "said co-corresponding author Dr Costas Arvanitis. "Even when drugs enter the brain's circulation, abnormal blood vessels in and around the tumor can lead to uneven drug delivery, with low concentrations in some parts of the tumor." If the drug reaches an area of the tumor and passes through the abnormal blood vessel walls, it will encounter dense tissue within the tumor that may block the entry of malignant cells. We are trying to use a new method to improve these abnormal transmission characteristics to improve drug delivery and efficacy across brain tumors. Arvanitis, an assistant professor at Georgia tech, conducted the study at Edwin l. Steele's tumor biology laboratory in the department of radiation oncology at MGH and his new biomedical acoustics and image-guided treatment laboratory at Georgia tech.
Focused ultrasound focuses the energy of multiple beams of ultrasound at a point in the body. Microvesicles injected with blood circulation - tiny lipid bubbles that vibrate under the action of ultrasound signals - can temporarily breach the blood-brain barrier at the target site. Although the method has been studied in animal models with promising results - a phase 1 clinical trial in conditions including primary brain tumors such as glioblastoma - the mechanisms behind it have not been well understood. To further understand the nature of focused ultrasound therapy for brain tumors, the team used advanced microscopic techniques to implant her2-positive breast cancer cells in the brains of living mice.
In their experiment, the researchers explored the ability of focused ultrasound to enhance two anticancer drugs, commonly used chemotherapy drug doxorubicin and targeted drug t-dm1. This method not only improved the delivery of the two drugs on the blood vessel wall, but also improved the low-dose doxorubicin molecules, as well as the distribution of the two drugs in tumor tissues. The MGH team's experiment showed for the first time that focused ultrasound enhanced the permeability of tumor vascular endothelial cells, causing those cells to absorb doxorubicin.
Dr Vasileios Askoxylakis of MGH Steele laboratory said: "" the evidence that focused ultrasound increases cell transmembrane transport and uptake of adriamycin is not yet clear." " "Although focused ultrasound with microvesicles also increased the infiltration of the antibody-drug binding t-dm1 into the tumor, this improvement was attenuated five days after administration, supporting the hypothesis that t-dm1 accumulation is a transient increase in tumor vascular permeability."
High-resolution imaging allows researchers to demonstrate increased interstitial fluid flow between tumor cells after ultrasound application and reveal its role in improving drug delivery. The mathematical model allows researchers to quantify changes in tissue and cell transport characteristics induced by centralized ultrasound and determine the best conditions for improving drug delivery. These results can provide a framework for the development of new strategies and the design of clinical trials that combine promising treatments with focused ultrasound.
Explaining and highlighting the potential focused ultrasound combined with different drugs to treat brain metastases, our results provide the best clinical use of important scientific principles, "" said senior author Rakesh Jain, Ph.D., director of cancer biology and chef of the Steele lab and professor of radiation oncology at harvard medical school. "In particular, they may allow identification of specific drug delivery regimens to improve drug uptake - such as slow infusion rather than administration - and support the assumption that the method requires separate testing for different drugs." By laying the groundwork for a more rational design and a deeper understanding of focused ultrasound therapy, our work can help improve the treatment of any brain tumor - primary or metastatic - as well as revolutionize tumor immunotherapy by improving the local delivery of tumor killing immune cells.
