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

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.

Grant Number: 4R37CA239039-06
NIH Institute/Center: NIH
Principal Investigator: Konstantinos-Costas Arvanitis