School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, U.K.
North of England Bone and Soft Tissue Tumour Service, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Road, Newcastle Upon Tyne NE7 7DN, U.K.
Bioconjug Chem. 2022 Aug 17;33(8):1564-1573. doi: 10.1021/acs.bioconjchem.2c00306. Epub 2022 Jul 22.
Bone sarcomas are devastating primary bone cancers that mostly affect children, young adults, and the elderly. These aggressive tumors are associated with poor survival, and surgery remains the mainstay of treatment. Surgical planning is increasingly informed by positron emission tomography (PET), and tumor margin identification during surgery is aided by near-infrared fluorescence (NIRF) imaging, yet these investigations are confounded by probes that lack specificity for sarcoma biomarkers. We report the development of a dual-modal (PET/NIRF) immunoconjugate ([Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW) that targets MT1-MMP, a matrix metalloproteinase overexpressed in high-grade sarcomas. [Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW was synthesized site-specific chemoenzymatic glycan modification, characterized, and isolated in high specific activity and radiochemical purity. Saturation binding and immunoreactivity assays indicated only minor perturbation of binding properties. A novel mouse model of dedifferentiated chondrosarcoma based on intrafemoral inoculation of HT1080 WT or KO cells (high and low MT1-MMP expression, respectively) was used to evaluate target binding and biodistribution. Fluorescence and Cerenkov luminescence images of [Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW showed preferential uptake in HT1080 WT tumors. gamma counting revealed that uptake in MT1-MMP-positive tumors was significantly higher than that in control groups. Taken together, [Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW is a promising dual-modal sarcoma imaging agent for pre-operative surgical planning and intraoperative surgical guidance.
骨肉瘤是一种破坏性的原发性骨癌，主要影响儿童、青少年和老年人。这些侵袭性肿瘤的存活率较低，手术仍然是主要的治疗方法。正电子发射断层扫描（PET）越来越多地用于手术规划，近红外荧光（NIRF）成像有助于术中识别肿瘤边界，但这些研究受到缺乏肉瘤生物标志物特异性的探针的干扰。我们报告了一种双模式（PET/NIRF）免疫偶联物（[Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW）的开发，该偶联物针对 MT1-MMP，这是一种在高级别肉瘤中过度表达的基质金属蛋白酶。[Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW 通过定点化学酶糖基化修饰合成，经过特征分析和高比活度和放射化学纯度的分离。饱和结合和免疫反应性测定表明结合特性只有轻微改变。基于 HT1080 WT 或 KO 细胞（高和低 MT1-MMP 表达）股骨内接种的去分化软骨肉瘤的新型小鼠模型用于评估靶结合和生物分布。[Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW 的荧光和契伦科夫发光图像显示在 HT1080 WT 肿瘤中有优先摄取。γ计数显示，在 MT1-MMP 阳性肿瘤中的摄取明显高于对照组。总之，[Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW 是一种有前途的双模式肉瘤成像剂，可用于术前手术规划和术中手术指导。
