Sensitive Brain Tumor Detection Using GNS Nanoprobe

Abstract

Malignant brain tumors are one of the most lethal, heterogeneous, and difficult cancer forms to treat (Tagami et al in Nanomaterials in Pharmacology. Humana Press Inc., New York City, 2016 [1]; Han L et al in ACS Nano 10:4209–4218, 2016 [2]; Rutka et al in ACS Nano 8:9716–9722, 2014 [3]; Kircher et al in Nat Med 18:829–834, 2012 [4]; Kohler et al in J Nat Cancer Inst 103:714–736, 2011 [5]). For the most common malignant glioblastoma (GBM), an advanced grade IV astrocytoma, the median overall survival (OS) is only 15 months with current standard therapies (Krex et al in Brain 130:2596–2606, 2007 [6]). Tumor size has been found to be an independent prognostic factor and patients having small tumors when diagnosed have been reported to show longer OS and better prognosis (Mohammadi et al in J Neurosurg 126(3):1–9 (2016) [7]; Dempsey et al in AJNR Am J Neuroradiol 26:770–776, 2005 [8]). Therefore, novel methods for sensitive brain tumor detection offer an important prospect for significant improvement of patients’ outcomes. The current routine brain tumor diagnosis method is magnetic resonance imaging (MRI) with and without contrast agent enhancement (Schellinger et al in J Neurol Oncololgy 44:275–281,1999 [9]; Sze et al in Am J Neuroradiol 11:785–791, 1990 [10]). The size limit for brain tumor detection with MRI scan has been found to be 3–5 mm and it is highly challenging for MRI to detect a brain tumor less than 1 mm (Erdi in Radionuclide Ther 21:23–28, 2012 [11]; Yuh et al in Am J Neuroradiol 16:373–380, 1995 [12]). Positron emission tomography (PET) provides a sensitive 3D imaging modality (several orders of magnitude more sensitive than MRI for contrast agent detection), and has been applied in clinics for cancer detection using fluorodeoxyglucose ([¹⁸F]FDG) radiotracer due to higher glucose uptake in tumors than in normal tissues (Fletcher in J Nucl Med 49:480–508, 2008 [13]; Rohren et al in Radiology 231:305–332, 2004 [14]; Phelps in J Nucl Med 41:661–681, 2000 [15]; Bradley et al in Int J Radiat Oncol Biol Phys 59:78–86, 2004 [16]; Boellaard et al in Eur J Nucl Med Mol Imaging 37:181–200, 2010 [17]; Antoch et al in Radiology 229:526–533, 2003 [18]; MacManus et al in Radiother Oncol 91:85–94, 1999 [19]). However, PET imaging using [¹⁸F]FDG is not ideal for brain tumor detection due to the high glucose uptake in normal brain tissue, resulting in low tumor-to-normal (T/N) ratio and high false positive rates (Shreve et al in Radiographics 19:61–77, 1999 [20]). To date, no study has demonstrated the feasibility of submillimeter brain tumor detection using noninvasive diagnostic modalities. Sensitive submillimeter brain tumor detection is still an unmet clinical need of critical importance. Our GNS-based nanoprobe for PET imaging has potential to provide a novel method for early brain tumor detection.