Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Ave 1277, Wuhan, 430022, Hubei Province, China.
Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
Eur J Nucl Med Mol Imaging. 2023 Dec;51(1):54-67. doi: 10.1007/s00259-023-06412-z. Epub 2023 Aug 29.
PURPOSE: The integrin αβ and aminopeptidase N (APN/CD13) play vital roles in the tumor angiogenesis process. They are highly expressed in a variety of tumor cells and proliferating endothelial cells during angiogenesis, which have been considered as highly promising targets for tumor imaging. Arginine-glycine-aspartic (RGD) and asparagine-glycine-arginine (NGR) are two peptides specifically binding to the integrin αβ and CD13, respectively. In this study, we optimized our previously developed probe and preclinically evaluated the new integrin αβ and CD13 dual-targeted probe, NOTA-RGD-NGR (denoted as HX01) radiolabeled with Ga, in 10 different subcutaneous and orthotopic tumor models. METHODS: The specific activity and radiochemical purity of [Ga]Ga-HX01 were identified. The dual-receptor targeting ability was confirmed by a series of blocking studies and partly muted tracers using BxPC-3 xenograft model. The dynamic imaging study and dose escalation study were explored to determine the optimal imaging time point and dosage in the BxPC-3 xenograft model. Next, we established a variety of subcutaneous and orthotopic tumor models including pancreas (BxPC-3), breast (MCF-7), gallbladder (NOZ), lung (HCC827), ovary (SK-OV-3), colorectal (HCT-8), liver (HuH-7), stomach (NUGC-4), and glioma (U87) cancers. All models underwent [Ga]Ga-HX01 PET/CT imaging about 2 weeks post-inoculation, with a subset of them undergoing [F]FDG PET/CT scan performed concurrently, and their results were compared. In addition, ex vivo biodistribution studies were also performed for verifying the semi-quantitative results of the non-invasive PET images. RESULTS: [Ga]Ga-HX01 significantly outperformed single target probes in the BxPC-3 xenograft model. All blocking and single target groups exhibited significantly descending tumor uptake. The high tumor uptakes were found in BxPC-3, MCF-7, and NOZ subcutaneous tumors (%ID/g > 1.1), while middle uptakes were observed in HCC827, SK-OV-3, HCT-8, and HuH-7 subcutaneous tumor (%ID/g 0.7-1.0). Due to the low background, the tumor-to-muscle and tumor-to-blood ratios of [Ga]Ga-HX01 were higher than that of [F]FDG. CONCLUSIONS: [Ga]Ga-HX01, as a dual target imaging agent, exhibited superior in vivo performance in different subcutaneous and orthotopic mice models of human tumors over [F]FDG and its respectively mono-receptor targeted agents, which warrants the future clinical translation for tumor imaging.
目的：整合素 αβ 和氨肽酶 N（APN/CD13）在肿瘤血管生成过程中发挥重要作用。它们在血管生成过程中在各种肿瘤细胞和增殖的内皮细胞中高度表达，已被认为是肿瘤成像极具前景的靶点。精氨酸-甘氨酸-天冬氨酸（RGD）和天冬酰胺-甘氨酸-精氨酸（NGR）是两种分别特异性结合整合素 αβ 和 CD13 的肽。在这项研究中，我们优化了之前开发的探针，并在 10 种不同的皮下和原位肿瘤模型中，对新型整合素 αβ 和 CD13 双重靶向探针 NOTA-RGD-NGR（表示为 HX01）进行了临床前评估，该探针用 Ga 标记。
方法：确定了 [Ga]Ga-HX01 的比活度和放射化学纯度。通过一系列阻断研究和使用 BxPC-3 异种移植模型的部分沉默示踪剂，证实了双重受体靶向能力。在 BxPC-3 异种移植模型中，进行了动态成像研究和剂量递增研究，以确定最佳成像时间点和剂量。接下来，我们建立了各种皮下和原位肿瘤模型，包括胰腺（BxPC-3）、乳腺（MCF-7）、胆囊（NOZ）、肺（HCC827）、卵巢（SK-OV-3）、结直肠（HCT-8）、肝脏（HuH-7）、胃（NUGC-4）和脑胶质瘤（U87）。所有模型在接种后约 2 周进行 [Ga]Ga-HX01 PET/CT 成像，其中一部分同时进行 [F]FDG PET/CT 扫描，并对其结果进行比较。此外，还进行了离体生物分布研究，以验证非侵入性 PET 图像的半定量结果。
结果：[Ga]Ga-HX01 在 BxPC-3 异种移植模型中的表现明显优于单靶探针。所有阻断和单靶组的肿瘤摄取均显著下降。BxPC-3、MCF-7 和 NOZ 皮下肿瘤的摄取较高（%ID/g>1.1），而 HCC827、SK-OV-3、HCT-8 和 HuH-7 皮下肿瘤的摄取中等（%ID/g 0.7-1.0）。由于背景较低，[Ga]Ga-HX01 的肿瘤与肌肉和肿瘤与血液的比值高于 [F]FDG。
结论：[Ga]Ga-HX01 作为一种双重靶向成像剂，在不同的人肿瘤皮下和原位小鼠模型中的体内性能优于 [F]FDG 及其各自的单受体靶向剂，这为肿瘤成像的未来临床转化提供了依据。
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