NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China.
Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
ACS Nano. 2024 Jul 23;18(29):18910-18921. doi: 10.1021/acsnano.4c01157. Epub 2024 Jul 13.
Granzyme B is an immune-related biomarker that closely correlates with cytotoxic T lymphocytes (CTLs), and hence detecting the expression level of granzyme B can provide a dependable scheme for clinical immune response assessment. In this study, two positron emission tomography (PET) probes [F]SF-M-14 and [F]SF-H-14 targeting granzyme B are designed based on the intramolecular cyclization scaffold SF. [F]SF-M-14 and [F]SF-H-14 can respond to granzyme B and glutathione (GSH) to conduct intramolecular cyclization and self-assemble into nanoaggregates to enhance the retention of probe at the target site. Both probes are prepared with high radiochemical purity (>98%) and high stability in PBS and mouse serum. In 4T1 cells cocultured with T lymphocytes, [F]SF-M-14 and [F]SF-H-14 reach the maximum uptake of 6.71 ± 0.29 and 3.47 ± 0.09% ID/mg at 0.5 h, respectively, but they remain below 1.95 ± 0.22 and 1.47 ± 0.21% ID/mg in 4T1 cells without coculture of T lymphocytes. PET imaging shows that the tumor uptake in 4T1-tumor-bearing mice after immunotherapy is significantly higher (3.5 times) than that in the untreated group. The maximum tumor uptake of [F]SF-M-14 and [F]SF-H-14 in the mice treated with BEC was 4.08 ± 0.16 and 3.43 ± 0.12% ID/g, respectively, while that in the untreated mice was 1.04 ± 0.79 and 1.41 ± 0.11% ID/g, respectively. These results indicate that both probes have great potential in the early evaluation of clinical immunotherapy efficacy.
颗粒酶 B 是一种与细胞毒性 T 淋巴细胞（CTLs）密切相关的免疫相关生物标志物，因此检测颗粒酶 B 的表达水平可为临床免疫反应评估提供可靠的方案。在本研究中，基于分子内环化支架 SF，设计了两种针对颗粒酶 B 的正电子发射断层扫描（PET）探针 [F]SF-M-14 和 [F]SF-H-14。[F]SF-M-14 和 [F]SF-H-14 可以响应颗粒酶 B 和谷胱甘肽（GSH）进行分子内环化，并自组装成纳米聚集体，以增强探针在靶部位的保留。两种探针均以高放射化学纯度（>98%）和在 PBS 和小鼠血清中的高稳定性制备。在与 T 淋巴细胞共培养的 4T1 细胞中，[F]SF-M-14 和 [F]SF-H-14 在 0.5 h 时的最大摄取量分别为 6.71±0.29%和 3.47±0.09% ID/mg，但在没有 T 淋巴细胞共培养的 4T1 细胞中，摄取量仍低于 1.95±0.22%和 1.47±0.21% ID/mg。PET 成像显示，免疫治疗后荷 4T1 肿瘤小鼠的肿瘤摄取量明显高于（3.5 倍）未治疗组。BEC 治疗组小鼠中 [F]SF-M-14 和 [F]SF-H-14 的最大肿瘤摄取量分别为 4.08±0.16%和 3.43±0.12% ID/g，而未治疗组小鼠的摄取量分别为 1.04±0.79%和 1.41±0.11% ID/g。这些结果表明，这两种探针在临床免疫治疗效果的早期评估中具有很大的潜力。
