2. Academic Validation
  3. Dynamic release of extracellular particles after opening of the blood-brain barrier predicts glioblastoma susceptibility to paclitaxel

Dynamic release of extracellular particles after opening of the blood-brain barrier predicts glioblastoma susceptibility to paclitaxel

  • Nat Commun. 2025 Dec 16;16(1):11045. doi: 10.1038/s41467-025-65681-4.
Mark W Youngblood # 1 2,  Abha Kumari # 3 4,  Yoon-Tae Kang 3 4,  Andrew Gould 1 2,  Karl Habashy 1 2,  Mateo Gomez 1 2,  Harika Lingamarla 5,  Trevor Morey 3 4,  Li Chen 1 2,  Harrshavasan Congivaram 1 2,  Rachel Ward 1 2,  Hui Zhang 6,  Thomas K Sears 1 2,  Kathleen McCortney 1 2,  Katarzyna C Pituch 1 2,  Elena M Torres Ponce 1 2,  Ashkan Zarrieneh 1 2,  Mariana Nieves 1 2,  Sarah Vandermolen 1 2,  Ditte Primdahl 2 7,  Karan Dixit 2 7,  Rimas V Lukas 2 7,  Priya Kumthekar 2 7,  Crismita Dmello 1 2,  Guillaume Bouchoux 8,  Michael Canney 8,  Christina Amidei 1 2,  Roger Stupp 1 2 7 9,  Sunitha Nagrath 10 11 12,  Adam M Sonabend 13 14
Affiliations

Affiliations

  • 1 Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 2 Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 3 Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 4 Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
  • 5 Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 6 Division of Biostatistics, Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
  • 7 Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 8 Carthera, Lyon, France.
  • 9 Department of Medicine, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 10 Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 11 Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 12 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 13 Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [email protected].
  • 14 Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [email protected].
  • # Contributed equally.
PMID: 41402297 DOI: 10.1038/s41467-025-65681-4
Abstract

Liquid biopsies hold promise to improve the diagnosis, assessment of response to therapy, and ultimately guide the management of Cancer patients. However, implementation of this approach in brain tumors has proven challenging due to the limited passage of molecules across the blood-brain barrier (BBB). We recently reported results from a phase I clinical trial in which the BBB was transiently opened in glioblastoma (GBM) patients using skull-implantable low-intensity pulsed ultrasound combined with microbubbles (LIPU/MB). In this study, treatment and BBB opening was performed every 3 weeks with paclitaxel administration until disease progression or up to 6 cycles (NCT04528680). As an exploratory objective of this trial, here we investigate extracellular vesicles and particles (EVPs/EPs) released into circulation in the context of tumor cell death as a potential biomarker for response to treatment. We develop and validate a microfluidic device designed to capture tumor-derived EVPs in glioblastoma patients (GlioExoChip). This approach leverages GBM-based expression of phosphatidylserine and Annexin-V chemistry that is traditionally used to measure Apoptosis. EVPs are characterized using nanoparticle tracking analysis, proteomics, western blot, and scanning electron microscopy. Proteomic analysis of circulating EVPs isolated from GBM patients reveals distinct expression patterns to that of healthy individuals, and scRNA-seq analysis of these genes supported their tumoral origin within the GBM microenvironment. In vitro, paclitaxel-susceptible glioma cells treated with this drug exhibit Apoptosis and dose-dependent EVP release. In concordance, we find changes in EVP release following the initiation of paclitaxel with LIPU/MB correlated with overall survival in GBM patients. Thus, our study introduces an efficient microfluidic platform for the capture of circulating GBM EVPs and demonstrates that release upon BBB opening is predictive of outcomes following paclitaxel treatment. This approach represents a real-time surrogate biomarker for treatment response for a disease where imaging-based assessment of response has not been shown to be reliable. Future prospective validation is warranted.

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