肿瘤特异性酶响应的诊疗一体化大分子前药的制备

Three important processes are involved in anticancer chemotherapy, i.e. cell endocytosis, drug release, and cell apoptosis. Thus, in real-time and in-situ visualization of all these three processes is very important to optimize clinical results and explore personalized medicine. Here, in this proposal, a personalized tumor-specific enzyme-responsive theranostic prodrug will be synthesized via the combination of self-immolative chemistry and combinational chemistry. The prodrug contains a therapy function moiety and an imaging function moiety, i.e. cathepsin B-activable drug release moiety and an imaging moiety. The former one is a caged camptothecin (CPT) prodrug that can be released as a cytotoxic active anti-tumor drug in the presence of cathepsin B (an overexpressed enzyme in the lysosome of tumor cell). While the latter one is a rationally designed fluorescent probe which comprises a permanent green emission BODIPY fluorophore and a cathepsin B-activable DCM fluorophore. These two fluorophores are built as FRET sensor by linking them with caspase-3-responsive DEVD peptide. Thus, the imaging moiety is capable of sequential imaging of its binding process with tumor cell, then monitoring the activation of prodrug, and finally early evaluating the therapy efficacy in real time and in situ.

大分子化疗药物或纳米药物载体从静脉注射到最终杀死肿瘤细胞通常会经历三个重要的过程，即通过细胞内吞被投递到肿瘤细胞、在胞内实现原药释放、产生细胞毒性诱导细胞凋亡，实时监控并准确评估这三个过程的任何一个过程对于优化诊疗效果和开发个性化药物都非常重要。到目前为止，尚未有能够实时原位全程可视化的诊疗一体化药物的报道。本项目拟基于Self-Immolative化学和连接化学，将几种用于生物成像和治疗的功能模块巧妙的装配起来，设计并制备集药物追踪、药物控释与疗效评估一体化的靶向个性化药物。该前药分子预计不仅可以实现肿瘤特异性酶触发的原药释放，并能基于内建的肿瘤标志物荧光探针和细胞凋亡FRET探针之间的巧妙协作，在细胞水平上实现顺序监控及定量评估 “药物投递-原药释放-细胞凋亡” 三个重要过程的目标，为新一代抗肿瘤诊疗一体化药物的设计提供新的指导。

在细胞水平上实现顺序监控及定量评估大分子/纳米药物经历的“药物投递-原药释放-细胞凋亡”三个重要过程意义重大，因为对每个过程的(半)定量评估都有助于不断优化纳米药物载体的设计，并提供相对精准的个体化治疗方案。在生命体系复杂环境中实现可视化的关键依赖于荧光探针工具的开发，本项目设计并开发了多种全新的通用制备策略，用于构筑有机高分子/超分子荧光探针及诊疗试剂，为细胞内复杂生化过程的探测以及生物活性分子的动态测量提供了强有力的工具，并有望提升疾病诊断与治疗的精准性。另外，在解决一些未能预期的科学问题和挑战时，我们受到启发并成功开发了一类全新的激活型光敏剂的制备方案，实现了光敏性能从彻底抑制到应激开启的剧烈转变,这项研究成果为按需定制激活型光敏剂提供了一个通用平台，以更好地服务于肿瘤的特异性光动力治疗。