TRANSCRANIAL FUS THERAPY WITH CLOSED-LOOP US IMAGE GUIDANCE AND CIRCULATING

Georgia Institute Of Technology, Atlanta GA

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Abstract

Project summary A major obstacle towards attaining sufficient accumulation of blood-borne therapeutics in the brain and brain tumors is posed by the blood-brain barrier. Circulating microbubbles upon ultrasound exposure can exert mechanical stress in brain vessels to trigger a range of responses pertinent to key regulatory processes of the blood brain barrier, including local increase in the blood brain barrier permeability and activation of inflammatory signaling and phenotypes. While these transient phenotypic changes have led to novel and highly potent therapeutic and, more recently, diagnostic interventions against brain tumors, they also raised major safety concerns, which may hinder their effective translation to the clinic. Although, recent developments in microbubble emissions based closed-loop controllers have shown that it is possible to fine-tune the ultrasound excitation amplitude and mitigate major safety concerns, these methods can only control the relative strength of the observed biological responses and not the type of the responses, which inevitably leads to a very narrow treatment window. The central hypothesis of this proposal is that microbubbles resonant effects in brain capillaries can offer new ways to modulate the blood brain barrier signaling and function, thereby allowing to establish tumor-specific therapeutic windows (spatial, temporal, and molecular) to increase drug efficacy with minimal side effects. To test this hypothesis and understand the impact of microbubble resonant effects on blood- brain barrier signaling and function this research will combine high fidelity mathematical modeling of microbubbles dynamics in vessels with prospective experimental investigations. First, the microbubble resonance effects and exerted stress in brain vessels will be analyzed using mathematical modeling. Then, in prospective investigations the impact of ultrasound frequency-controlled microbubble-induced mechanical stress on the blood-brain barrier signaling and function in healthy rodents will be assessed. Subsequently, the potential of the proposed research to promote safer and more effective targeted drug delivery along with the abilities of cancer soluble biomarkers, such as cell free tumor DNA, to support the longitudinal monitoring of the treatment will be evaluated in brain tumor-bearing rodents. Moreover, to be able to excite and control the microbubble dynamics over a broad range of amplitudes and frequencies, this proposal will investigate the combined transmit and receive capabilities of capacitive micromachined ultrasound technology for implementing the proposed ultrasound frequency-controlled methods of microbubble dynamics. If successful, the proposed research will develop novel technologies and create unique opportunities for safer and more effective diagnosis, treatment, and treatment monitoring of brain cancer.