ImmunoPET imaging of Trop2 expression in solid tumors with nanobody tracers
ImmunoPET imaging of Trop2 expression in solid tumors with nanobody tracers
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DOI：
10.1007/s00259-023-06454-3
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发表时间：
2023-10-04
影响因子：
9.1
通讯作者：
Liu，Jianjun
中科院分区：
文献类型：
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作者：
Huang，Wei;Liang，Chenyi;Liu，Jianjun
目的跨膜糖蛋白滋养细胞表面抗原2(Trop2)的高表达与胰腺癌、胃癌等实体瘤的发生发展密切相关。本研究旨在构建Trop2特异性免疫正电子发射断层扫描探针，并评价其在临床前胰腺癌和胃癌模型中的诊断能力。方法采用单细胞测序和组织芯片免疫组织化学方法检测Trop2在胰腺癌中的表达。用流式细胞仪检测胰腺癌细胞株中Trop2的表达。制备了两个针对Trop2的纳米体(RTD98和RTD01)，并用镓-68(68Ga，t1/2= 1.1h)标记，构建了免疫正电子发射计算机断层显像探针。结果单细胞测序结果显示，Trop2在胰腺导管细胞和腺泡细胞中高表达，免疫组织化学染色显示胰腺癌组织中Trop2的表达明显高于癌旁组织。使用[68Ga]Ga-NOTA-RTD98的免疫PET可以清楚地显示皮下肿瘤，无论是细胞来源的胰腺癌模型还是患者来源的胃癌模型，优于使用[18F]-FDG或非特异性探针[68Ga]Ga-NOTA-RTD161的成像。进一步制备了另一种靶向Trop2的探针[68Ga]Ga-NOTA-RTD01，并在临床前胰腺癌模型中显示了良好的诊断能力。结论在本工作中，我们报道了两种靶向人Trop2的纳米体示踪剂，通过非侵入性地显示靶点的表达动态，可能有助于更好地使用Trop2靶向治疗。
PurposeThe high expression of the transmembrane glycoprotein trophoblast cell-surface antigen 2 (Trop2) was strongly associated with the progression of solid tumors, including pancreatic and gastric cancers. Our study aimed to construct Trop2-specific immuno-positron emission tomography (immunoPET) probes and assess the diagnostic abilities in preclinical pancreatic and gastric cancer models.MethodsThe expression of Trop2 in pancreatic cancer was determined by single-cell sequencing and immunohistochemistry on tissue microarray (TMA). Flow cytometry was used to screen the expression of Trop2 in pancreatic cancer cell lines. Two nanobodies (i.e., RTD98 and RTD01) targeting Trop2 were developed and labeled with gallium-68 (68Ga, T1/2= 1.1 h) to construct immunoPET imaging probes. The agents were researched in cell-derived pancreatic and patient-derived gastric cancer models expressing varying Trop2.ResultsSingle-cell sequencing results showed high expression of Trop2 in pancreatic ductal cells as well as acinar cells and immunohistochemical staining of TMA from pancreatic cancers showed significantly higher expression of Trop2 in cancerous than in paracancerous tissues. ImmunoPET utilizing [68Ga]Ga-NOTA-RTD98 could clearly delineate subcutaneous tumors, both in cell-derived pancreatic cancer models and patient-derived gastric cancer models, superior to imaging using [18F]-FDG or a non-specific probe [68Ga]Ga-NOTA-RTD161. Another probe with improved pharmacokinetics targeting Trop2, [68Ga]Ga-NOTA-RTD01, was further prepared and showed advantageous diagnostic capabilities in preclinical pancreatic cancer models.ConclusionIn the work, we reported two nanobody tracers targeting human Trop2 which may facilitate better use of Trop2-targeted therapeutics by noninvasively displaying expression dynamics of the target.