基于“内含肽介导的多肽定点修饰”技术构建的分支型PET/CT-拉曼多模态成像系统用于精准术前诊断及术中切除肿瘤

Surgical resection is currently the most effective way for prostate cancer treatment. However, limited specificity of preoperative diagnosis and lack of intraoperative imaging method, which would cause microtumor remnant, are the key to prostate cancer surgical treatment. In this proposal, we aim to develop a prostate cancer-targeted PET/CT-Raman multi-modal imaging system, which integrates: (1) Bombesin for prostate cancer cell-overexpressing GRP receptor targeting; (2) PET-CT contrast agent 18F-FDG chelated with peptide carrier for preoperative PET-CT diagnosis; (3) Gap-enhanced Raman tag for intraoperative Raman imaging. “Intein-mediated site-specific peptide modification” is used to develope covalent conjugate of PET/CT contrast agent and Raman probe, which facilities the fine quantitative control of its components and allows for a scale-up process of future clinical translation. We propose to investigate its targeting mechanism, preoperative diagnosis, intraoperative imaging and therapeutic efficacy, and systematic toxicity using orthotopic prostate cancer mice model. If successful, this multi-modal imaging system would substantially achieve synchronized intraoperative imaging of the preoperative diagnostic information, thereby facilitating complete eradication of tumor. This project would lay the groundwork for wider applications in pre- and intra-operative imaging of other types of cancer.

手术切除肿瘤是目前治疗前列腺癌最有效的方法。但是，术前诊断手段的特异性不足，以及缺乏术中成像手段，易导致微小肿瘤残余，是影响前列腺癌手术治疗效果的制约因素。本项目中，我们致力于构建一个肿瘤靶向的分支型PET/CT-拉曼多模态成像系统，其整合了（1）铃蟾肽，用于靶向前列腺癌细胞高表达的GRP受体；（2）多肽载体螯合的PET/CT造影剂18F-FDG，用于术前诊断；（3）缝隙增强拉曼探针，用于术中拉曼成像。运用“内含肽介导的多肽定点修饰”技术以化学偶联的方式连接PET/CT造影剂与拉曼探针，能精确控制各组分的比例，利于重复性高地大批量合成。我们将通过小鼠前列腺原位瘤模型，对该系统的作用机制、术前诊断、术中成像与治疗效果，及体内毒性进行探究。如果成功，该系统有望将术前影像学诊断信息在术中同步成像，帮助彻底切除肿瘤，也将为其他癌症术前与术中的一体化影像学检测提供新的思路与方法。

手术切除肿瘤是目前治疗前列腺癌最有效的方法。但是，术前诊断手段的特异性不足，以及缺乏术中成像手段，易导致微小肿瘤残余，是影响前列腺癌手术治疗效果的制约因素。本项目中，我们构建了一个肿瘤靶向的分支型PET/CT-拉曼多模态成像系统，其整合了（1）分支型肿瘤靶向多肽，用于靶向前列腺癌细胞；（2）连接于分支型靶向多肽的螯合剂DOTA并螯合PET/CT造影剂68Ga，用于术前诊断；（3）缝隙增强拉曼探针，用于术中拉曼成像。我们运用“内含肽介导的多肽定点修饰”技术以化学偶联的方式连接肿瘤靶向分子、PET/CT造影剂与拉曼探针，能精确控制各组分的比例，利于重复性高地大批量合成。我们通过小鼠前列腺原位瘤模型，对分支型肿瘤靶向肽和分支型多模态成像系统的肿瘤靶向性进行了验证。更进一步，运用多模态成像系统，我们进行了体外、体内的肿瘤PET/CT和拉曼成像，并对成像机制进行了研究。该系统有望将术前影像学诊断信息在术中同步成像，帮助彻底切除肿瘤，也将为其他癌症术前与术中的一体化影像学检测提供新的思路与方法。