化疗是直接影响胰腺癌患者远期生存的重要治疗手段，而肿瘤深层递药则是推动胰腺癌有效治疗的关键。基于此，肿瘤血管修复（即促肿瘤血管正常化）是改善抗癌药物瘤内递送的重要策略。本项目以肿瘤血管为治疗靶点，基于低分子量肝素（LMWH）和藤黄酸（GA）的多元化抗肿瘤作用（即抗肿瘤血管生成、促肿瘤血管正常化以及细胞毒性），结合F3肽的肿瘤血管定位导向作用，构建一种C23介导的“定位减压修复瘤内血管”多元联动纳米药物，用于胰腺癌的治疗。该纳米药物能够通过促肿瘤血管正常化（即肿瘤血管的“定位”与“修复”策略），结合外层肿瘤细胞杀灭的“减压”机制，推动药物向肿瘤内部的渗透与转运，实现从外至内、不同层面的多元联动抗肿瘤治疗；同时，基于纳米体系的同步输送，实现肿瘤血管修复与化疗 “最佳时机”的协同治疗，最大程度发挥化疗的治疗效果，为瘤内药物的高效递送和胰腺癌的有效治疗提供了新的研究思路与策略，具有重大研究意义。

Chemotherapy is an essential treatment tool that directly affects the long-term survival of the majority of pancreatic cancer patients. Additionally, the delivery of drugs to the interior of the tumor plays a key role in promoting the effective treatment of pancreatic cancer. Nowadays, tumor vascular normalization becomes an important strategy to improve the intratumoral drug delivery. Based on the multiple antitumor activities of low molecular weight heparin (LMWH) and gambogic acid (GA) involving anti-angiogenic activity, tumor vascular normalization and cytotoxicity in combination with F3 peptide-mediated tumor vascular targeting delivery, a novel amphiphilic F3-LMWH-GA conjugate with self-assembly property is the first to be synthesized in this project. Furthermore, we developed a C23-mediated multivariate linkage nanodrug for improving intratumoral drug delivery and cancer therapy by tumor vascular normalization. Based on the double strategies of tumor vascular normalization in combination with stress-alleviation by killing the tumor cells in the exterior of the solid tumor, the nanodrugs will facilitate and promote the permeation and transport of the drug to the deeper parts of the tumor, thereby thoroughly eliminating the tumor. More importantly, we combine the LMWH as an anti-angiogenic agent and GA as a cytotoxic drug within a single nanosystem to achieve concurrent co-delivery of the two drugs and timely delivery of chemotherapeutic drug in the window of vascular normalization, i.e. the most accurate timing for combination of anti-angiogenesis and chemotherapy, which will contribute to the maximize therapeutic effect of chemotherapy. This novel nanosystem, as a safe, stable and injectable formulation, provides a novel mode for high-efficient intratumoral drug delivery and effective therapy of pancreatic cancer. We believe that this study will shed light on a new concept in developing multifunctional nanodrugs for targeted and combinatorial cancer therapy.