Chen Liping, Fu Haitian, Li Wenjin, Shen Qiaolin, Luo Yihui, Fu Junjie, Shao Chong, He Huihui, Lou Kequan, Wang Jialiang, Feng Guokai, Yu Chunjing
Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi 214062, PR China.
Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, PR China.
Bioorg Chem. 2024 Dec;153:107892. doi: 10.1016/j.bioorg.2024.107892. Epub 2024 Oct 17.
Integrin-α6 is an attractive diagnostic and therapeutic biomarker in cancer, because it is highly expressed in several types of malignancies. Based on our previous findings, we designed a cyclic peptide, NOTA-A6P, to enhancing affinity, tumor uptake and serum stability, and then developed a cyclic radiotracer, [F]AlF-NOTA-A6P, for the specific detection of early colorectal cancer by PET/CT imaging. [F] AlF-NOTA-A6P was automatically labeled for colorectal cancer imaging in a novel synthesis module. The affinity, stability, radiochemical yield (RCY), radiochemical purity (RCP), molar activity (Am), and octanol-water partition coefficient of [F]AlF-NOTA-A6P were investigated. Results demonstrated that the tracer exhibited high serum stability, high RCY (58.1 ± 4.1 %) (undecay-corrected, n = 5) and hydrophilicity. In vivo microPET/CT imaging of LS174T and HT29 xenograft tumor models with high integrin-α6 expression indicated that [F]AlF-NOTA-A6P exhibited higher tumor uptake and tumor-to-muscle ratio than SW620, which has low integrin-α6 expression. Moreover, the specificity of [F]AlF-NOTA-A6P for integrin-α6 was confirmed by additional methods, including autoradiography, hematoxylin and eosin staining, and immunohistochemical staining. In conclusion, a cyclic peptide NOTA-A6P targeting integrin-α6 was designed and a promising PET tracer [F]AlF-NOTA-A6P was synthesized in a novel cassette-type synthesis module. The tracer demonstrated a favorable binding affinity with integrin-α6, stability in human serum and specificity for colorectal cancer xenograft mice. These properties render it a promising non-invasive PET radiotracer for the detection of integrin-α6-overexpressing cancers, including colorectal cancer.
整合素α6是一种极具吸引力的癌症诊断和治疗生物标志物，因为它在多种恶性肿瘤中高表达。基于我们之前的研究结果，我们设计了一种环肽NOTA-A6P，以增强亲和力、肿瘤摄取和血清稳定性，然后开发了一种环放射性示踪剂[F]AlF-NOTA-A6P，用于通过PET/CT成像特异性检测早期结直肠癌。[F]AlF-NOTA-A6P在一个新型合成模块中自动标记用于结直肠癌成像。研究了[F]AlF-NOTA-A6P的亲和力、稳定性、放射化学产率（RCY）、放射化学纯度（RCP）、摩尔活性（Am）和正辛醇-水分配系数。结果表明，该示踪剂具有高血清稳定性、高RCY（58.1±4.1%）（未校正衰变，n=5）和亲水性。对整合素α6高表达的LS174T和HT29异种移植肿瘤模型进行体内微型PET/CT成像表明，[F]AlF-NOTA-A6P比整合素α6低表达的SW620表现出更高的肿瘤摄取和肿瘤与肌肉比值。此外，通过放射自显影、苏木精和伊红染色以及免疫组织化学染色等其他方法证实了[F]AlF-NOTA-A6P对整合素α6的特异性。总之，设计了一种靶向整合素α6的环肽NOTA-A6P，并在一个新型盒式合成模块中合成了一种有前景的PET示踪剂[F]AlF-NOTA-A6P。该示踪剂显示出与整合素α6良好的结合亲和力、在人血清中的稳定性以及对结直肠癌异种移植小鼠的特异性。这些特性使其成为一种有前景的用于检测整合素α6过表达癌症（包括结直肠癌）的非侵入性PET放射性示踪剂。
