68Ga标记CD146-ScFv分子探针靶向肺结节及相关微血管显像的研究

Over 80% lung cancer patients are initially diagnosed at their progressive stage, making their 5-year survival rate less than 15.6%. There are barely effective methods for the early differential diagnosis of pulmonary nodules. This project is designed for early identification of malignant pulmonary nodules, chiefly using molecular imaging techniques that focus on pulmonary nodules and related microvessel. We select melanoma cell-adhesion molecules (CD146) as the molecular target which is highly expressed in neovascular endothelial cells and plays an important role in angiogenesis. The CD146 holistic single antibody is generated by cell membrane-based phage surface display techniques, and the CD146-ScFv will then be labelled by radioactive nuclide 68Ga which is easily coupled with antibodies and small molecules. Utilizing its high specificity and tissue tropism , we will use CD146-ScFv to target malignant components of pulmonary nodules and related microvessels, then collect the imaging features of lung nodules dynamically, and use a computer-aided new algorithm to extract image feature, and finally analyze the correlations between molecular imaging features, pathological types and tumoral molecular-biological index. The current project aimed to provide new molecular imaging strategies for early non-invasive diagnosis of malignant lung nodules, as well as elucidating the development of tumor angiogenesis.

超过80%的肺癌患者在诊断时已属晚期，5年生存率不超过15.6%；目前尚缺乏早期鉴别肺结节良恶性的有效方法，本项目针对肺结节的早期定性诊断这一临床难题，围绕肺结节及相关血管组织成分的分子影像显影技术，选择肿瘤及相关新生血管组织中高表达、且在肿瘤血管新生过程中发挥重要作用的黑色素瘤细胞黏附分子(CD146)为靶点，通过基于细胞膜的噬菌体展示技术筛选制备CD146的全人单链抗体（ScFv），采用易与抗体小分子物质偶联的核素68Ga标记，以CD146-ScFv的高特异性和组织亲和性，靶向肺结节恶性成分及相关新生血管组织，在分子水平上示踪肺结节成分细胞及相关微血管的形成和发展，并动态采集肺结节影像，计算机辅助新算法提取影像特征，最终分析归纳影像特征与病理分型及分子生物学指标的相关性，为无创性早期诊断恶性肺结节，探讨肿瘤新生血管的发生、发展提供分子影像新策略。

肺癌是我国发病率和死亡率最高的恶性肿瘤，早期肺癌的筛查仍是亟待解决的问题；低剂量CT的应用使肺结节的检出率增高，但目前尚缺乏早期鉴别肺结节良恶性的有效方法，本项目针对肺结节早期定性诊断的难题，设计实验并完成以下研究内容：（1）基于Mayo模型，建立全新的修正模型和扩展模型，对比分析各种模型的预测效能，择出最优模型实现对高危肺结节的术前风险评估（2）联合液体活检和AI分析数据，基于临床特征、影像学特征，建立并验证早期肺癌的风险预测模型，用于提高肺癌的早期诊断效能（3）选择肿瘤及相关新生血管组织中高表达、且在肿瘤血管新生过程中发挥重要作用的黑色素瘤细胞黏附分子(CD146)为靶点，基于噬菌体展示技术和哺乳动物细胞表面展示技术筛选、表达CD146特异性抗体，为早期恶性肺结节的诊断提供新策略，并为CD146作为肺癌早期治疗的潜在靶点提供研究基础（4）探索sCD146与膜CD146表达的相关性，及其在肺癌细胞系中发挥的生物学功能，为sCD146作为肺癌潜在治疗靶点提供科学依据。