Title: Targeting intracranial patient-derived glioblastoma (GBM) with a NIR-I fluorescent immunoconjugate for facilitating its image-guided resection

Abstract

Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor type and is associated with a high mortality rate borne out of such affording a survival rate of only 15 months. GBM aggressiveness is associated with the overexpression of epidermal growth factor receptor (EGFR) and its mutants. Targeting GBM with therapeutics is challenging because the blood-brain barrier (BBB) permits primarily select smallmolecule entities across its semipermeable blockade. However, recent preclinical data suggest that large biomolecules, such as the anti-EGFR antibody therapeutic, cetuximab, could be capable of bypassing the BBB despite the relative enormity of its size. As such, we set forth to establish the feasibility of utilizing an EGFR-targeting near-infrared-I (NIR-I) fluorescent construct in the form of an immunoconjugate (cetuxmimab-IRDye800) to achieve visual differentiation between diseased brain tissue arising from a low-passage patient-derived GBM cell line (GBM39) and healthy brain tissue via utilizing orthotopic intracranial murine GBM39 tumor models for in vivo and ex vivo evaluation such that by doing so would establish proof of concept for ultimately facilitating its in vivo fluorescence-guided resection and ex vivo surgical back-table pathological confirmation in the clinic. As anticipated, we were not capable of distinguishing between malignant tumor tissue and healthymore » tissue in resected intact and slices of whole brain ex vivo under white-light illumination (WLI) due to both the diseased tissue and healthy tissue appearing virtually identical to the unaided eye. However, we readily observed over an average 6-fold enhancement in the fluorescence emission in the resected intact whole brain ex vivo when performing NIR-I fluorescence imaging (FLI) on the cohort of GBM39 tumor models that were administered the immunoconjugate compared to controls. In all, we laid the initial groundwork for establishing that NIR-I fluorescent immunoconjugates (theranostics) such as cetuximab–IRDye800 can bypass the BBB to visually afford GBM39 tumor tissue differentiation for its image-guided surgical removal.« less

Authors:

Hettie, Kenneth S.  ^[1];

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Teraphongphom, Nutte Tarn ^[2]; Ertsey, Robert D. ^[2]; Rosenthal, Eben L. ^[2]; Chin, Frederick T. ^[3]

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+ Show Author Affiliations

1. Department of Radiology, Stanford University School of Medicine, Stanford, USA, Department of Otolaryngology - Head & Neck Surgery
2. Department of Otolaryngology - Head & Neck Surgery, Stanford University, Stanford, USA
3. Department of Radiology, Stanford University School of Medicine, Stanford, USA

Publication Date:

Mon Nov 23 00:00:00 EST 2020

Research Org.:

Stanford Univ., CA (United States)

Sponsoring Org.:

USDOE Office of Science (SC), Basic Energy Sciences (BES)

OSTI Identifier:

1777612

Alternate Identifier(s):

OSTI ID: 1816355

Grant/Contract Number:  

SC0008397

Resource Type:

Published Article

Journal Name:

RSC Advances

Additional Journal Information:

Journal Name: RSC Advances Journal Volume: 10 Journal Issue: 69; Journal ID: ISSN 2046-2069

Publisher:

Royal Society of Chemistry (RSC)

Country of Publication:

United Kingdom

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES