RESUMEN
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.
Asunto(s)
Neoplasias Colorrectales , Péptidos Cíclicos , Proteínas Proto-Oncogénicas c-met , Neoplasias Colorrectales/diagnóstico por imagen , Proteínas Proto-Oncogénicas c-met/metabolismo , Péptidos Cíclicos/química , Humanos , Animales , Ratones , Línea Celular Tumoral , Ratones Desnudos , Tomografía Computarizada de Emisión de Fotón Único/métodos , Ratones Endogámicos BALB C , Femenino , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Colorectal cancer (CRC) is the third most prevalent malignancy and the second leading cause of cancer-related mortality worldwide. Currently, CRC staging heavily relies on invasive surgical procedures for in vitro pathological analysis, which entails long detection cycles and increases the risk of metastasis. There is an urgent need for specific biomarkers to classify adenomas and cancers, while early in vivo staging detection could potentially reduce mortality and morbidity rates. This study focused on Type IV histamine receptor (H4R), which is highly expressed only in the inflammatory stage, and Dopamine receptor D4 (DRD4), which is highly expressed in colorectal adenoma and carcinoma stages. Fluorescent targeted molecular probes H4R-Cy5 and DRD4-M were constructed respectively. The in vitro cell level proves that H4R-Cy5 only has high specificity for RAW264.7 cells, and DRD4-M only has good affinity for HT29 cells. In inflammation-HT29 subcutaneous tumors, H4R-Cy5 and DRD4-M can target inflammation and tumor lesions respectively. In addition, this study is the first to combine the two probes to explore the feasibility of in vivo non-invasive staging on CRC mouse models. The results show that H4R-Cy5 can distinguish and identify the stages of inflammation in vivo, and the DRD4-M probe can accurately identify the stages of colorectal adenoma and carcinoma in vivo. The combination of these two probes can achieve precise non-invasive staging of colitis, adenoma and carcinoma, which is a major advance in the development of accurate diagnostic methods for colorectal precancerous lesions and has important implications for the selection of treatment strategies.