深层渗透阻断胰腺导管腺癌内神经支配的纳米载药系统

鉴于胰腺导管腺癌（PDAC）外周的基质、内部低氧环境和由神经细胞供给营养的特性导致PDAC治疗效果差，本项目拟通过将阻断肿瘤神经支配介导的饥饿疗法与化疗结合的策略，构建逐级靶向NRP-1和CAIX促进深层渗透的纳米药物递送系统分别在肿瘤微环境低氧/pH响应释放抑制剂LOXO-101阻断肿瘤神经支配和在癌细胞内ROS响应地释放化疗药物联合抑制癌细胞，实现PDAC的高效治疗。设计合成聚乙二醇-偶氮-聚赖氨酸-聚鸟氨酸，在其端基键合促进穿越基质的NRP-1配体，侧基键合靶向低氧肿瘤的CAIX配体、偶氮连接的LOXO-101、酮缩硫醇连接的喜树碱，构建新型高分子前药。通过揭示逐级靶向NRP-1和CAIX对促进PDAC低氧肿瘤渗透的影响规律，阻断肿瘤神经支配介导的饥饿疗法和化疗的协同相关性，以实现PDAC的高效治疗。本项目的实施促进肿瘤深层渗透的纳米药物递送系统的发展，为PDAC的治疗提供新的思路。

Since the surrounding dense matrix, hypoxic internal microenvironment and supply of nutrients by nerve cells lead to poor treatment effects of PDAC, this project intends to combine blocking tumor innervation mediated starvation therapy and chemotherapy for high-efficiency treatment of PDAC. Construct a nano-drug delivery system with progressively targets NRP-1 and CAIX to promote deep penetration in the tumor microenvironment, hypoxia/pH responsive release inhibitor LOXO-101 to block tumor innervation, and ROS-responsive release chemotherapeutics in cancer cells to kill cancer cells. A new polymer prodrug was constructed by synthesizing polyethylene glycol-azo-polylysine-polyornithine block polymer, and conjugating NRP-1 ligand at its end group to promote across the matrix, and conjugating target hypoxic tumors CAIX ligand, Azo-linked LOXO-101 and thioketal-linked camptothecin to the side group. By revealing the effect of progressive targeting of NRP-1 and CAIX on the promotion of PDAC hypoxic tumor penetration, and the synergistic correlation between blocking tumor innervation-mediated starvation therapy and chemotherapy, to achieve high-efficiency treatment of PDAC. The implementation of this project promotes the development of nano-drug delivery systems for deep tumor penetration, and provides new ideas for the treatment of PDAC.