A micellar nanoprobe for fluorescence image-guided delineation of glioblastoma margins

Abstract

Despite remarkable advancements in (neuro)-oncology, glioblastoma (GBM) remains the most aggressive primary brain tumor with a dismal overall survival of 14-17 months. A critical factor contributing to its poor prognosis is the high local recurrence rate, observed in 80-90 % of patients. This is largely due to the tumor's highly infiltrative growth pattern, which renders complete surgical resection impossible. Although surgery remains a cornerstone of initial treatment, current surgical techniques lack the precision to reliably detect and remove infiltrative margins. Recent state-of-the-art trials have proposed more aggressive surgical strategies aiming to reduce residual disease and mitigating local recurrence. However, implementing such extensive resections requires intraoperative imaging tools with enhanced, real-time sensitivity-capabilities that current technologies lack. Here, we report the preclinical validation of a near-infrared (NIR), fatty acid-based probe formulated in micelles (mFA-ICG) for image-guided surgery of GBM. This includes a comprehensive characterization of its pharmacokinetics, biodistribution, and toxicity profile. Notably, the micellar formulation demonstrated high stability, extended half-life, deep tissue penetration, improved targeting, enhanced fluorescence signal (compared to clinical standards), and a favorable safety profile in relevant models. We further validated the efficacy of mFA-ICG in orthotopic patient-derived, transgenic and organotypic patient' tissue slice models of GBM where our data confirm both in- and ex vivo specificity of NIR signal. Collectively, these findings support the safety and translational potential of mFA-ICG and suggest it may significantly improve delineation at the infiltrative edge. These advantages position mFA-ICG as a promising candidate for a trial in GBM patients.

Keywords: 5-Aminolevulinic Acid (PubChem CID: 137); Chemical compounds studied in this article include: ICG (PubChem CID: 5282412); Dextran (PubChem CID: 4125253); FITC (PubChem CID: 18730); Fatty acid; Formulation; Glioblastoma; Micellar; Near-infrared (NIR); Optical; Solutol HS15 (PubChem CID: 124898).