Feasibility and safety of focused ultrasound-enabled liquid biopsy in the brain of a porcine model

Christopher Pham Pacia,Hong Chen,Michael R Talcott,Yimei Yue,H Michael Gach,Lifei Zhu,Eric C Leuthardt,Arash Nazeri,Yaoheng Yang

doi:10.1038/s41598-020-64440-3

Abstract

Although blood-based liquid biopsy is a promising noninvasive technique to acquire a comprehensive molecular tumor profile by detecting cancer-specific biomarkers (e.g. DNA, RNA, and proteins), there has been limited progress for brain tumor application partially because the low permeability of the blood-brain barrier (BBB) hinders the release of tumor biomarkers. We previously demonstrated focused ultrasound-enabled liquid biopsy (FUS-LBx) that uses FUS to increase BBB permeability in murine glioblastoma models and thus enhance the release of tumor-specific biomarkers into the bloodstream. The objective of this study was to evaluate the feasibility and safety of FUS-LBx in the normal brain tissue of a porcine model. Increased BBB permeability was confirmed by the significant increase (p = 0.0053) in Ktrans (the transfer coefficient from blood to brain extravascular extracellular space) when comparing the FUS-sonicated brain area with the contralateral non-sonicated area. Meanwhile, there was a significant increase in the blood concentrations of glial fibrillary acidic protein (GFAP, p = 0.0074) and myelin basic protein (MBP, p = 0.0039) after FUS sonication as compared with before FUS. There was no detectable tissue damage by T2*-weighted MRI and histological analysis. Findings from this study suggest that FUS-LBx is a promising technique for noninvasive and localized diagnosis of the molecular profiles of brain diseases with the potential to translate to the clinic.

Highlights

Blood-based liquid biopsy is a promising noninvasive technique to acquire a comprehensive molecular tumor profile by detecting cancer-specific biomarkers (e.g. DNA, RNA, and proteins), there has been limited progress for brain tumor application partially because the low permeability of the blood-brain barrier (BBB) hinders the release of tumor biomarkers
Successful BBB opening evidenced by contrast enhancement following Focused ultrasound (FUS) was achieved in 7 out of 8 pigs
This study demonstrated the feasibility and safety of FUS-mediated release of brain-specific biomarkers from the brain to the blood in a pig model

Summary

Introduction

Blood-based liquid biopsy is a promising noninvasive technique to acquire a comprehensive molecular tumor profile by detecting cancer-specific biomarkers (e.g. DNA, RNA, and proteins), there has been limited progress for brain tumor application partially because the low permeability of the blood-brain barrier (BBB) hinders the release of tumor biomarkers. Repeated tissue biopsies to assess treatment response and cancer recurrence are often not feasible given the increased risk for complications and morbidity These challenges limit the timely diagnosis and selection of treatment options, hinder a better understanding of the disease, and impair the development of effective treatment approaches. FUS can transiently disrupt the BBB and increase its permeability without causing vascular damage Successful applications of this technique have been demonstrated in various small animal models and large animal models, such as nonhuman primates[12,13,14,15], sheep[16], and pigs[17,18,19]. We proposed that FUS-induced BBB disruption enables a “two-way transfer” between the brain and blood circulation and introduced the FUS-enabled liquid biopsy technique (FUS-LBx)[23]

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Conclusion