Costas Arvanitis
Georgia Institute of Technology

Popular version of paper 3aBA9 The role of U.S. thermal stress in modulating the vascular transport dynamics in the brain tumors
Presented Thursday morning, June 10, 2021
180th ASA Meeting, Acoustics in Focus

Local hyperthermia and stimuli-responsive delivery systems, such as thermosensitive liposomes, represent promising strategies to locally enhance drug delivery in brain tumors and improve treatment outcomes. However, a critical obstacle towards exploring their therapeutic potential in brain tumors is the limited ability to attain reliably and reproducibly the desired temperature in the brain.

Dr Costas Arvanitis at the Georgia Institute of Technology and Emory University, and his graduate student, Chulyong Kim, hypothesized that trans-skull focused ultrasound combined with closed-loop controlled methods can achieve this goal.

brain tumors
Figure 1. Graphical representation of  US mediated  thermal stress drug release and delivery from  thermosensitive drugs in brain tumors.

Attaining controlled thermal stress through the skull is not a trivial problem, especially in mice where every new treatment is tested for safety and efficacy. For example, although at low frequencies (< 1 MHz) most of the energy is transmitted through the skull, the resulting large focal region overlaps substantially with the skull, which due to its higher absorption leads to disproportionally high skull heating. On the other hand, at higher frequencies (> 2 MHz) skull reflections and aberrations become significant, and thus limit our ability to focus the beam in the brain through the skull. Using a physically accurate mathematical modeling, the investigations revealed that an optimal frequency (≈ 1.7 MHz) does exist for applying localized thermal stress in mice brain without overheating the skull.

Based on this knowledge, the investigators built a closed-loop trans-skull magnetic resonance imaging guided focused ultrasound (MRgFUS) prototype and demonstrated that it can attain reproducible experimentation and heating of the entire tumor at the desired temperature. Next, using semi-quantitative imaging, they revealed that localized thermal stress (41.5 oC for 10 minutes) in brain tumors in rodents promotes acute changes in the cerebrovascular transport dynamics in the brain tumor microenvironment. These changes can be important, as they can increase the amount of drug that reaches the tumor.

Subsequently, by combining the abilities of this system with those of thermosensitive liposomes loaded with doxorubicin, the most common chemotherapeutic agent, they were able to achieve a marked improvement in doxorubicin accumulation and uptake in preclinical glioma tumor models. Crucially, survival studies indicated that the proposed two-pronged strategy could lead to substantial improvement in the survival.

Overall, this work, in addition to refining our understanding on the role of thermal stress in modulating the transport dynamics in the brain tumor microenvironment, allowed to establish a new paradigm for noninvasive targeted drug delivery in glioblastomas. It may, thus, create new opportunities towards attaining clinically effective drug delivery in patients with aggressive brain tumors, such as glioblastoma, that currently have limited treatment options.

Acknowledgments: This study was supported by the National Institutes of Health grants R00 EB016971.


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