Abstract
Glioblastoma (GBM) is one of the most aggressive tumors and its 5-year survival is approximately 5%. Fluorescence-guided surgery (FGS) improves the extent of resection and leads to better prognosis. Molecular near-infrared (NIR) imaging appears to outperform conventional FGS, however, novel molecular targets need to be identified in GBM. Proteoglycan glypican-1 (GPC-1) is believed to be such a target as it is highly expressed in GBM and is associated with poor prognosis. We hypothesize that an anti-GPC-1 antibody, Miltuximab®, conjugated with the NIR dye, IRDye800CW (IR800), can specifically accumulate in a GBM xenograft and provide high-contrast in vivo fluorescent imaging in rodents following systemic administration. Miltuximab® was conjugated with IR800 and intravenously administered to BALB/c nude mice bearing a subcutaneous U-87 GBM hind leg xenograft. Specific accumulation of Miltuximab®-IR800 in subcutaneous xenograft tumor was detected 24 h later using an in vivo fluorescence imager. The conjugate did not cause any adverse events in mice and caused strong fluorescence of the tumor with tumor-to-background ratio (TBR) reaching 10.1 ± 2.8. The average TBR over the 10-day period was 5.8 ± 0.6 in mice injected with Miltuximab®-IR800 versus 2.4 ± 0.1 for the control group injected with IgG-IR800 (p = 0.001). Ex vivo assessment of Miltuximab®-IR800 biodistribution confirmed its highly specific accumulation in the tumor. The results of this study confirm that Miltuximab®-IR800 holds promise for intraoperative fluorescence molecular imaging of GBM and warrants further studies.
Highlights
Glioblastoma is a malignant astrocytoma and the most common primary tumor of the brain [1].Despite surgery and adjuvant therapy, GBM has one of the worst prognoses of all cancers with the median survival of only 12–15 months after diagnosis and a 5-year survival of approximately 5% [2,3,4].While most of the radiologically defined tumor can often be surgically resected, the infiltrative nature of Cancers 2020, 12, 984; doi:10.3390/cancers12040984 www.mdpi.com/journal/cancersCancers 2020, 12, 984 this disease does not allow good visualization and complete removal of the margins between invasive tumor and radiologically normal brain [5]
Several studies have demonstrated that the extent of the initial resection correlates with better patient outcomes [3,5,6,7,8], which means that better intraoperative visualization has the potential to benefit GBM patients by improving the extent of resection [9,10,11]
The presence of GPC-1 on GBM cells U-251 and U-87 was confirmed by flow cytometry
Summary
Glioblastoma is a malignant astrocytoma and the most common primary tumor of the brain [1]. Monoclonal antibodies, peptides, and other targeting ligands can recognize such molecules and deliver fluorescent dyes to cancer cells and not the normal tissue [19,23] This concept was initially approached by conjugating conventional passive dyes, such as fluorescein [24] and ICG [25], to targeting molecules but the interest shifted towards more suitable fluorescent dyes which need be well tolerated, able to produce high-contrast image, and suitable for bioconjugation [22,26,27]. The conjugate of IR800 with anti-EGFR antibody cetuximab has been shown to access contrast-enhancing brain tumors and bind to glioma cells expressing target antigen without accumulation in the normal brain tissue in mice [30] and patients [28]. We synthesized and characterized the conjugate Miltuximab®-IR800 and investigated its application for fluorescence imaging of GBM in vitro and in vivo
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