Focused Ultrasound-enabled Brain Tumor Liquid Biopsy.
Authors: Zhu L, Cheng G, Ye D, Nazeri A, Yue Y, Liu W, Wang X, Dunn GP, Petti AA, Leuthardt EC, Chen H
Although blood-based liquid biopsies have emerged as a promising non-invasive method to detect biomarkers in various cancers, limited progress has been made for brain tumors. One major obstacle is the blood-brain barrier (BBB), which hinders efficient passage of tumor biomarkers into the peripheral circulation. The objective of this study was to determine whether FUS in combination with microbubbles can enhance the release of biomarkers from the brain tumor to the blood circulation. Two glioblastoma tumor models (U87 and GL261), developed by intracranial injection of respective enhanced green fluorescent protein (eGFP)-transduced glioblastoma cells, were treated by FUS in the presence of systemically injected microbubbles. Effect of FUS on plasma eGFP mRNA levels was determined using quantitative polymerase chain reaction. eGFP mRNA were only detectable in the FUS-treated U87 mice and undetectable in the untreated U87 mice (maximum cycle number set to 40). This finding was replicated in GL261 mice across three different acoustic pressures. The circulating levels of eGFP mRNA were 1,500-4,800 fold higher in the FUS-treated GL261 mice than that of the untreated mice for the three acoustic pressures. This study demonstrated the feasibility of FUS-enabled brain tumor liquid biopsies in two different murine glioma models across different acoustic pressures.
Introduction
Purpose
Sonobiopsy
Study Objective
To determine whether focused ultrasound (FUS) combined with microbubbles can enhance release of brain tumor biomarkers into the blood circulation.
Animal model / Human subject
Mus musculus (mouse); strain: not specified; age: not specified; sex: not specified
Disease model
glioblastoma
Cargo name and characteristics
Enhanced green fluorescent protein (eGFP) transgene expressed in intracranial glioblastoma cells; reporter protein transgene measured via circulating eGFP mRNA (nucleic acid biomarker)
Route of administration
Intracranial injection
Outcomes and Safety
Summary of Outcomes
Focused ultrasound (FUS) with systemically injected microbubbles enabled release of tumor-specific eGFP mRNA into the circulation (undetectable at baseline; 1,500–4,800× higher after FUS) in two orthotopic glioma mouse models. Treatments used ~1.5 MHz FUS (duty cycle 1%, PRF 1 Hz, 2 min) at acoustic pressures of ~1.52, 2.74 and 3.53 MPa (and 3.82 MPa in U87); all increased circulating eGFP but the lowest pressure (~1.52 MPa/~1.48 MPa) produced the largest biomarker release while higher pressures caused greater vascular hemorrhage.
Duration of biological effect
≈4 minutes (U87); ≈20 minutes (GL261)
Safety-related matter
Histology showed red blood cell extravasation (hemorrhage) in all FUS‑treated GL261 mice with more severe hemorrhage at higher acoustic pressures, indicating vascular damage; hemorrhage was not observed in the U87 mice (possibly due to the very short interval to sacrifice). The authors note these pressures were higher than those typically used for BBB opening, recommend optimizing acoustic/microbubble parameters to minimize tissue damage, and call for careful short‑ and long‑term safety and metastasis assessments in future studies.
Brain Region
Ultrasound Parameters
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
Treatment frequency
single
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