{"title":"开发颗粒酶 B 靶向智能正电子发射断层扫描探针,用于监测肿瘤对免疫疗法的早期反应","authors":"Jiayu Fu, Hongjie Xi, Shuyue Cai, Ying Peng, Qingzhu Liu, Ling Qiu, Jianguo Lin","doi":"10.1021/acsnano.4c01157","DOIUrl":null,"url":null,"abstract":"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 [<sup>18</sup>F]SF-M-14 and [<sup>18</sup>F]SF-H-14 targeting granzyme B are designed based on the intramolecular cyclization scaffold SF. [<sup>18</sup>F]SF-M-14 and [<sup>18</sup>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, [<sup>18</sup>F]SF-M-14 and [<sup>18</sup>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. <i>In vivo</i> 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 [<sup>18</sup>F]SF-M-14 and [<sup>18</sup>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.","PeriodicalId":21,"journal":{"name":"ACS Nano","volume":null,"pages":null},"PeriodicalIF":15.8000,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Development of Granzyme B-targeted Smart Positron Emission Tomography Probes for Monitoring Tumor Early Response to Immunotherapy\",\"authors\":\"Jiayu Fu, Hongjie Xi, Shuyue Cai, Ying Peng, Qingzhu Liu, Ling Qiu, Jianguo Lin\",\"doi\":\"10.1021/acsnano.4c01157\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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 [<sup>18</sup>F]SF-M-14 and [<sup>18</sup>F]SF-H-14 targeting granzyme B are designed based on the intramolecular cyclization scaffold SF. [<sup>18</sup>F]SF-M-14 and [<sup>18</sup>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, [<sup>18</sup>F]SF-M-14 and [<sup>18</sup>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. <i>In vivo</i> 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 [<sup>18</sup>F]SF-M-14 and [<sup>18</sup>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.\",\"PeriodicalId\":21,\"journal\":{\"name\":\"ACS Nano\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":15.8000,\"publicationDate\":\"2024-07-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Nano\",\"FirstCategoryId\":\"88\",\"ListUrlMain\":\"https://doi.org/10.1021/acsnano.4c01157\",\"RegionNum\":1,\"RegionCategory\":\"材料科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Nano","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1021/acsnano.4c01157","RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
摘要
颗粒酶 B 是一种与细胞毒性 T 淋巴细胞(CTL)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。本研究以分子内环化支架 SF 为基础,设计了两种靶向颗粒酶 B 的正电子发射断层扫描(PET)探针[18F]SF-M-14 和[18F]SF-H-14。[18F]SF-M-14和[18F]SF-H-14能与颗粒酶B和谷胱甘肽(GSH)发生分子内环化反应,并自组装成纳米聚集体,从而提高探针在靶点的保留率。这两种探针的放射化学纯度都很高(98%),在 PBS 和小鼠血清中的稳定性也很高。在与T淋巴细胞共培养的4T1细胞中,[18F]SF-M-14和[18F]SF-H-14在0.5小时时的最大摄取量分别为6.71±0.29% ID/mg和3.47±0.09% ID/mg,但在未与T淋巴细胞共培养的4T1细胞中,它们的摄取量仍低于1.95±0.22% ID/mg和1.47±0.21% ID/mg。体内 PET 成像显示,免疫治疗后 4T1 肿瘤小鼠的肿瘤摄取量明显高于未治疗组(3.5 倍)。在接受 BEC 治疗的小鼠体内,[18F]SF-M-14 和[18F]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,而在未接受治疗的小鼠体内,[18F]SF-M-14 和[18F]SF-H-14 的最大肿瘤摄取量分别为 1.04 ± 0.79 和 1.41 ± 0.11% ID/g。这些结果表明,这两种探针在早期评估临床免疫疗法疗效方面具有巨大潜力。
Development of Granzyme B-targeted Smart Positron Emission Tomography Probes for Monitoring Tumor Early Response to Immunotherapy
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 [18F]SF-M-14 and [18F]SF-H-14 targeting granzyme B are designed based on the intramolecular cyclization scaffold SF. [18F]SF-M-14 and [18F]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, [18F]SF-M-14 and [18F]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. In vivo 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 [18F]SF-M-14 and [18F]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.
期刊介绍:
ACS Nano, published monthly, serves as an international forum for comprehensive articles on nanoscience and nanotechnology research at the intersections of chemistry, biology, materials science, physics, and engineering. The journal fosters communication among scientists in these communities, facilitating collaboration, new research opportunities, and advancements through discoveries. ACS Nano covers synthesis, assembly, characterization, theory, and simulation of nanostructures, nanobiotechnology, nanofabrication, methods and tools for nanoscience and nanotechnology, and self- and directed-assembly. Alongside original research articles, it offers thorough reviews, perspectives on cutting-edge research, and discussions envisioning the future of nanoscience and nanotechnology.