Abstract
Due to their very poor prognosis and a fatal outcome, secondary brain tumors are one of the biggest challenges in oncology today. From the point of view of the early diagnosis of these brain micro- and macro-tumors, the sensitivity and specificity of the diagnostic tools constitute an obstacle. Molecular imaging, such as Positron Emission Tomography (PET), is a promising technique but remains limited in the search for cerebral localizations, given the commercially available radiotracers. Indeed, the [18F]FDG PET remains constrained by the physiological fixation of the cerebral cortex, which hinders the visualization of cerebral metastases. Tumor angiogenesis is recognized as a crucial phenomenon in the progression of malignant tumors and is correlated with overexpression of the neuropilin-1 (NRP-1) receptor. Here, we describe the synthesis and the photophysical properties of the new gallium-68 radiolabeled peptide to target NRP-1. The KDKPPR peptide was coupled with gallium-68 anchored into a bifunctional NODAGA chelating agent, as well as Cy5 for fluorescence detection. The Cy5 absorbance spectra did not change, whereas the molar extinction coefficient (ε) decreased drastically. An enhancement of the fluorescence quantum yield (φF) could be observed due to the better water solubility of Cy5. [68Ga]Ga-NODAGA-K(Cy5)DKPPR was radiosynthesized efficiently, presented hydrophilic properties (log D = −1.86), and had high in vitro stability (>120 min). The molecular affinity and the cytotoxicity of this new chelated radiotracer were evaluated in vitro on endothelial cells (HUVEC) and MDA-MB-231 cancer cells (hormone-independent and triple-negative line) and in vivo on a brain model of metastasis in a nude rat using the MDA-MB-231 cell line. No in vitro toxicity has been observed. The in vivo preliminary experiments showed promising results, with a high contrast between the healthy brain and metastatic foci for [68Ga]Ga-NODAGA-K(Cy5)DKPPR.
Highlights
From the perspective of the early diagnosis of tumors, the sensitivity and specificity of the diagnostic tools remain important challenges
The relevance of a peptide targeting NRP-1 overexpressed by angiogenic endothelial cells to detect the peripheral infiltrative part of the high-grade brain tumor has been clearly demonstrated; over the past ten years, we have demonstrated the interest of vascular targeting via ATWLPPR, a ligand peptide of NRP-1, and its instability in vivo [17,18,19,20]
The conjugation of the KDKPPR peptide moiety to a fluorescent probe, Cy5, is followed by the grafting of this new fluorescent probe–peptide conjugate to the bifunctional chelator, 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), which is known to form a stable complex with Ga3+ [25] to produce nonradioactive gallium-69 (natGa)-NODAGA-K(Cy5)DKPPR
Summary
From the perspective of the early diagnosis of tumors, the sensitivity and specificity of the diagnostic tools remain important challenges. PET is a technique that is beginning to be widely used in several pathologies, such as neurology, cardiology, and inflammation It remains the most prescribed exam in nuclear oncology, with [18F]FDG as the gold standard. It has been established that [18F]FDG PET has a lower sensitivity [2] in determining the presence, location, and number of metastases than MRI, especially for the detection of small lesions [3]. This suggests that PET imaging can provide valuable complementary information in the evaluation of brain tumors (aggressiveness, differentiation, etc.). New radiotracers based on amino acids ([18F]F-DOPA, [18F]FET, and [11C]-methionine) have shown better results compared to [18F]FDG, but they are not very specific [4]
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