对于中晚期不可切除胆管癌，光动力治疗(PDT)是一种局部、微创、有效的治疗方法，但仍面临光敏剂特异性差、治疗抵抗和复发等难题。前期我们利用聚集诱导发光(AIE)特性的荧光分子作为光敏剂，成功制备了胆管癌靶向的诊疗一体化纳米探针，在改善肿瘤靶向性的同时，还克服了传统光敏剂聚集诱导淬灭效应。但治疗抵抗和肿瘤复发依然是阻碍PDT疗效进一步提高的瓶颈。预实验发现，抑制P21活化激酶1 (PAK1)的活性能有效增强胆管癌细胞对PDT的敏感性，并抑制PDT后细胞血管生成因子的表达，提示PAK1可作为一个有效增强PDT疗效的靶点。本项目作为前期研究的延续和拓展拟制备AIE光敏剂和PAK1抑制剂共载的靶向纳米系统，通过体内体外实验检测该纳米系统对胆管癌的协同治疗效果，并进一步探究PAK1影响 PDT敏感性及治疗后血管生成的分子机制。本研究的完成对改善胆管癌效果将提供新策略，具有较高的转化应用价值。

Photodynamic therapy (PDT) is a local, minimally invasive and effective therapeutic technique for unresectable cholangiocarcinoma (CC). However, it still faces some problems such as poor selective of photosensitizer (PS), therapy resistance and tumor recurrence. In our previous study, We fully took advantage of a red emissive aggregation- induced emission (AIE) PS to fabricate CC targeted organic theranostic AIE nanodots for image- guided PDT. The obtained AIE nanodots exhibit high specificity to cholangiocarcinoma as well as excellent antitumor effect. Furthermore, different from conventional PSs, the AIE nanodots do not suffer from aggregation- caused fluorescence quenching and reduction in reactive oxygen species production when the AIE PS molecules are in an aggregated state. However, how to reduce resistance and recurrence after treatment remain challenges to improve therapeutic effect. We recently found that PDT could induce PAK1 overexpression and phosphorylation at Thr423. Inhibition of the activity of PAK1 can effectively enhance the sensitivity of CC cells to PDT and repress angiogenesis after treatment. These results suggest PAK1 may be an ideal target for enhanced PDT. As a continuation and expansion of our previous studies, this project is intended to fabricate a targeted nano- system for the co- loading of AIE PS (TTD) and PAK1 inhibitor (IPA-3). The synergistic effect of this nano- system on enhanced PDT will investigate both in vivo and in vitro. Molecular mechanism of PAK1 sensitizing PDT and inhibiting angiogenesis after treatment will be explored. This project will provide new strategy for improving the therapeutic effect of PDT and have high value for future translational research.