Caspase-3/7激活的光声影像探针进行活体水平早期检测肿瘤凋亡信号的研究

Tumor response to treatment often requires the iatrogenic induction of tumor cell death through apoptosis, noninvasive monitoring of which will provide important information for predicting therapy efficacy and for early screening of anti-cancer drugs in vivo. Capsase-3/7 has been identified as a key mediator of cell apoptosis, and its activation is a common effector to tumor cell death. Therefore, development of caspase-3/7 specific molecular imaging probes can provide an efficient method for early detection of tumor apoptosis. Recently, photoacoustic imaging (PAI) has been emerging as an attractive biomedicine imaging technology, which can break through the imaging depth limit and create multi-scale images with high sensitivity and high resolution. However, due to the lack of design methods, there is still no report on the caspase-3/7 sensitive PAI probes. Herein, by taking the advantages of PAI and caspase-3/7 substrate, we are aiming to apply our developed biocompatible reaction-mediated in situ self-assembly strategy to develop the first caspase-3/7 activatable PAI probes that report on caspase-3/7 activity and thus chemotherapy-induce tumor apoptosis in living mice. These novel PAI probes will allow for the early detection of tumor apoptosis with high sensitivity, and high-resolution tracking of the heterogeneous response to therapy in tumor tissues.

肿瘤在治疗过程中通常会诱导肿瘤细胞凋亡，对其信号检测可以用于活体上早期筛选抗肿瘤药物和预测肿瘤治疗效果。Caspase-3/7作为细胞凋亡通路上的关键效应酶，其活化过程最终执行肿瘤细胞死亡。因此，设计caspase-3/7特异性的分子影像探针可以实现早期检测肿瘤的凋亡信号。光声成像是近年来新兴发展的生物医学成像技术，具有高灵敏度、高分辨率和高组织成像深度的优点，但是，发展caspase-3/7响应的PAI探针用于检测肿瘤的凋亡信号目前还缺少有效的方法。本项目拟就结合PAI成像优点和caspase-3/7作用底物特性，通过采取生物正交反应调控小分子化合物细胞内原位自组装的策略来设计caspase-3/7特异性激活的有机小分子PAI探针，用于小鼠体内高灵敏度的检测肿瘤在药物治疗过程中的凋亡信号，同时进行高分辨率的分析这些凋亡信号在肿瘤组织中分布，从而为肿瘤治疗效果的早期评价建立新方法。

光声成像有效的结合了光学和超声这两种成像技术的优点，可以在活体上实现同时具有高灵敏度、高分辨率、较深成像深度的三维空间成像分析，已广泛应用于活体上生物功能分子的检测。然而，目前尚缺少有效的方法来构建caspase-3响应的光声成像探针用于检测肿瘤的凋亡信号。本研究通过采取生物正交反应调控小分子化合物细胞内原位自组装的策略来构建了第一例肿瘤细胞靶向、caspase-3特异性激活的有机小分子光声成像探针，成功应用于小鼠体内检测皮下移植人脑胶质肿瘤（U87MG）在抗癌药物阿霉素（DOX）治疗后产生的凋亡信号；进一步利用光声成像具有较深组织成像深度和较高分辨率的优点，我们成功分析了肿瘤在化疗过程中产生的局部凋亡信号，并阐明了肿瘤在治疗过程中逐渐增强的凋亡信号以及肿瘤组织在治疗过程中产生的局部凋亡信号。这一研究进一步扩展于发展一系列新型分子影像探针和诊疗探针，从而为活体成像分析研究提供新方法。