Abstract：
The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase linked to the proliferation, survival, invasion, and metastasis of several types of cancers, including colorectal cancer (CRC), particularly when aberrantly activated. Our study strategically designs peptides derived from interactions between c-Met and the antibody Onartuzumab. By utilizing a cyclic strategy, we achieved significantly enhanced peptide stability and affinity. Our in vitro assessments confirmed that the cyclic peptide HYNIC-cycOn exhibited a higher affinity (KD = 83.5 nM) and greater specificity compared with its linear counterpart. Through in vivo experiments, [99mTc]Tc-HYNIC-cycOn displayed exceptional tumor-targeting capabilities and minimal absorption in nontumor cells, as confirmed by single-photon emission computed tomography. Notably, the ratios of tumor to muscle and tumor to intestine, 1 h postinjection, were 4.78 ± 0.86 and 3.24 ± 0.47, respectively. Comparable ratios were observed in orthotopic CRC models, recording 4.94 ± 0.32 and 3.88 ± 0.41, respectively. In summary, [99mTc]Tc-HYNIC-cycOn shows substantial promise as a candidate for clinical applications. We show that [99mTc]Tc-HYNIC-cycOn can effectively target and visualize c-Met-expressing tumors in vivo, providing a promising approach for enhancing diagnostic accuracy when detecting c-Met in CRC.
摘要：
间充质上皮转化因子(c-Met)是一种与细胞增殖相关的受体酪氨酸激酶,生存,入侵,以及几种癌症的转移，包括结直肠癌（CRC），特别是在异常激活时。我们的研究策略性地设计了源自c-Met和抗体Onartuzumab之间相互作用的肽。通过利用循环策略，我们实现了显著增强的肽稳定性和亲和力。我们的体外评估证实,与线性对应物相比,环状肽HYNIC-cycOn表现出更高的亲和力(KD=83.5nM)和更高的特异性。通过体内实验,[99mTc]Tc-HYNIC-cycOn在非肿瘤细胞中显示出优异的肿瘤靶向能力和最小的吸收，如单光子发射计算机断层扫描所证实。值得注意的是,肿瘤与肌肉和肿瘤与肠道的比例，注射后1小时，分别为4.78±0.86和3.24±0.47。在原位CRC模型中观察到相当的比率，记录分别为4.94±0.32和3.88±0.41。总之,[99mTc]Tc-HYNIC-cycOn显示出作为临床应用的候选物的实质性希望。我们表明[99mTc]Tc-HYNIC-cycOn可以有效地靶向和观察体内表达c-Met的肿瘤，为在CRC中检测c-Met时提高诊断准确性提供了一种有前途的方法。
