Colorectal cancer is a leading cause of cancer-related morbidity and mortality worldwide. Premalignant lesions that are flat and subtle in morphology are often missed in conventional colonoscopies. Patient-derived adenoma colonoids with high and low cMet expression and normal colonoids were implanted orthotopically in the colon of immunocompromised mice to serve as a preclinical model system. A peptide specific for cMet was labeled with IRDye800, a near-infrared (NIR) fluorophore. This peptide was administered intravenously, and in vivo imaging was performed using a small animal fluorescence endoscope. Quantified intensities showed a peak target-to-background ratio at ~1 h after intravenous peptide injection, and the signal cleared by ~24 h. The peptide was stable in serum with a half-life of 3.6 h. Co-staining of adenoma and normal colonoids showed a high correlation between peptide and anti-cMet antibody. A human-specific cytokeratin stain verified the presence of human tissues implanted among surrounding normal mouse colonic mucosa. Peptide biodistribution was consistent with rapid renal clearance. No signs of acute toxicity were found on either animal necropsy or serum hematology and chemistries. Human colonoids provide a clinically relevant preclinical model to evaluate the specific uptake of a NIR peptide to detect premalignant colonic lesions in vivo.
结直肠癌是全球范围内癌症相关发病率和死亡率的主要原因。传统结肠镜检查中常漏诊形态平坦且细微的癌前病变。本研究将高表达与低表达cMet的患者源性腺瘤结肠类器官及正常结肠类器官原位植入免疫缺陷小鼠结肠，构建临床前模型系统。通过近红外荧光染料IRDye800标记cMet特异性多肽，经静脉注射后使用小动物荧光内镜进行活体成像。定量强度显示静脉注射后约1小时靶向背景比达到峰值，信号在约24小时内清除。该多肽在血清中稳定性良好，半衰期为3.6小时。腺瘤与正常结肠类器官的共染色显示多肽与抗cMet抗体具有高度相关性。人特异性细胞角蛋白染色证实植入组织在周围正常小鼠结肠黏膜中的存在。多肽生物分布特征符合肾脏快速清除规律。动物尸检及血清血液学与生化检测均未发现急性毒性迹象。人源结肠类器官为评估近红外多肽特异性摄取以检测活体结肠癌前病变提供了临床相关的临床前模型。
肿瘤(癌症)患者之家