基于胰腺癌的“定位减压修复瘤内血管”纳米药物研究

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.

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。

胰腺癌异常的肿瘤微环境（TME）严重地阻碍了治疗药物向肿瘤组织内的高效深层递送，而肿瘤血管修复（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F3肽为肿瘤血管内皮细胞（VECs）靶向指针，构建了基于低分子量肝素（LMWH）和藤黄酸（GA）的F3-LMWH-GA（FLG）纳米药物，以修复肿瘤血管并调控TME，用于胰腺癌的治疗。首先应用点击化学反应制备具有pH响应性和甲基苯醌重排效应的FLG偶联物，可在偏酸条件下降解并重排释放出GA原型。其在水性介质中形成FLG纳米药物，平均粒径为160.0 ± 1.9 nm，Zeta电位为-0.53 ± 0.90 mV，在室温和血清环境等条件下呈较好的稳定性，且安全性良好。FLG纳米药物经静脉注射后被递送至肿瘤部位，能够优先接触并被VECs摄取，直接发挥针对VECs的调控作用，修复肿瘤血管；而部分纳米药物跨过血管进入TME，递送至肿瘤细胞，发挥针对肿瘤细胞的直接杀伤作用和间接血管调控作用。研究显示，在Panc-1荷瘤裸鼠模型，FLG纳米药物在治疗的第5~9天成功诱导了肿瘤血管正常化，且在血管正常化时间窗内明显缓解肿瘤缺氧，降低肿瘤血管的通透性，并有效促进了其自身向肿瘤深部的渗透递送。进而，基于FLG纳米药物的肿瘤血管正常化治疗显著提升了化疗药物吉西他滨（Gem）的抗肿瘤治疗效果。在此基础上，FLG纳米药物与CCL5/CCR5通路阻断剂马拉维诺纳米粒（MAR/MPA）联用不仅强化了肿瘤血管正常化效果，显示出明显延长的血管正常化时间窗（第3~11天）和更佳的修复程度，还可全面改善TME和免疫微环境，实现显著增强的抗肿瘤治疗效果。综上所述，本项目以肿瘤血管正常化治疗为基础，成功建立肿瘤血管修复与TME调控之间的正反馈循环，构建针对肿瘤“治疗抵抗”交互网络的多重调控纳米体系，具有重要研究意义和后续发展潜力。