Mulero Francisca, Oteo Marta, Garaulet Guillermo, Magro Natalia, Rebollo Lluvia, Medrano Guillermo, Santiveri Clara, Romero Eduardo, Sellek Ricela E, Margolles Yago, Campos-Olivas Ramón, Arroyo Alicia G, Fernández Luis Angel, Morcillo Miguel Angel, Martínez-Torrecuadrada Jorge L
Molecular Imaging Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Medical Applications of Ionizing Radiations Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.
Front Med (Lausanne). 2022 Nov 24;9:1058455. doi: 10.3389/fmed.2022.1058455. eCollection 2022.
Triple-negative breast cancer (TNBC) is characterized by aggressiveness and high rates of metastasis. The identification of relevant biomarkers is crucial to improve outcomes for TNBC patients. Membrane type 1-matrix metalloproteinase (MT1-MMP) could be a good candidate because its expression has been reported to correlate with tumor malignancy, progression and metastasis. Moreover, single-domain variable regions (VHHs or Nanobodies) derived from camelid heavy-chain-only antibodies have demonstrated improvements in tissue penetration and blood clearance, important characteristics for cancer imaging. Here, we have developed a nanobody-based PET imaging strategy for TNBC detection that targets MT1-MMP. A llama-derived library was screened against the catalytic domain of MT1-MMP and a panel of specific nanobodies were identified. After a deep characterization, two nanobodies were selected to be labeled with gallium-68 (Ga). ImmunoPET imaging with both ([Ga]Ga-NOTA-3TPA14 and [Ga]Ga-NOTA-3CMP75) in a TNBC mouse model showed precise tumor-targeting capacity with high signal-to-background ratios. (Ga)Ga-NOTA-3CMP75 exhibited higher tumor uptake compared to (Ga)Ga-NOTA-3TPA14. Furthermore, imaging data correlated perfectly with the immunohistochemistry staining results. In conclusion, we found a promising candidate for nanobody-based PET imaging to be further investigated as a diagnostic tool in TNBC.
三阴性乳腺癌（TNBC）具有侵袭性和高转移率的特点。识别相关生物标志物对于改善TNBC患者的治疗效果至关重要。膜型1-基质金属蛋白酶（MT1-MMP）可能是一个很好的候选者，因为据报道其表达与肿瘤恶性程度、进展和转移相关。此外，源自骆驼科动物仅重链抗体的单域可变区（VHHs或纳米抗体）在组织穿透和血液清除方面表现出改善，这是癌症成像的重要特征。在此，我们开发了一种基于纳米抗体的PET成像策略用于TNBC检测，该策略靶向MT1-MMP。针对MT1-MMP的催化结构域筛选了一个源自美洲驼的文库，并鉴定出一组特异性纳米抗体。经过深入表征后，选择了两种纳米抗体用镓-68（Ga）进行标记。在TNBC小鼠模型中用两种纳米抗体（[Ga]Ga-NOTA-3TPA14和[Ga]Ga-NOTA-3CMP75）进行免疫PET成像显示出精确的肿瘤靶向能力，具有高信噪比。与[Ga]Ga-NOTA-3TPA14相比，[Ga]Ga-NOTA-3CMP75表现出更高的肿瘤摄取。此外，成像数据与免疫组织化学染色结果完美相关。总之，我们发现了一种基于纳米抗体的PET成像的有前景的候选物，有待进一步研究作为TNBC的诊断工具。
