The bioeffects of focused ultrasound sonication on brain tumor in patients following focused ultrasound-enabled liquid biopsy sonobiopsy

Transcranial low intensity focused ultrasound in combination with intravenously injected microbubbles is a promising technique for noninvasive, spatially targeted, and reversible disruption of the BBB. We hypothesized that FUS induced BBB opening enables two-way trafficking between the brain and bloodstream. With FUS mediated BBB opening, agents in the bloodstream can enter the brain for the treatment of brain diseases, while brain tumor-derived biomarkers can be released into the bloodstream for diagnostic access. We term this FUS induced release of biomarkers into the bloodstream for blood-based liquid biopsy as sonobiopsy. Sonobiopsy opens the BBB at the spatially targeted brain location, releases tumor derived biomarkers from precisely defined tumor locations into the blood circulation, and enables timely detection of biomarkers in the blood to minimize clearance.A pilot prospective sonobiopsy clinical study was conducted on patients with high grade glioma to evaluate the feasibility and safety of sonobiopsy. Analysis of blood samples collected before and after FUS sonication showed that sonobiopsy enriched plasma circulating tumor DNA, including a maximum increase of 1.6-fold for the mononucleosome cell free DNA fragments, 1.9 fold for the patient specific tumor variant ctDNA level, and 5.6 fold for the TERT mutation ctDNA level. Histological analysis of surgically resected tumors confirmed the safety of sonobiopsy. Transcriptome analysis of sonicated and nonsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes. Sonobiopsy did not induce evident inflammation/immune responses within a short time period. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.The transcriptome analysis of sonicated and nonsonicated tumor provided an unprecedented opportunity to evaluate the bioeffects of FUS sonication on the tumor in brain tumor patients.