基于铁代谢调控的多层杂化纳米载体联合药物输运体系治疗胰腺癌的疗效研究

Pancreatic cancer is a malignant tumor with poor prognosis, and pancreatic cancer patients exhibit poor response to the current clinical first-line chemotherapy regimen, with urgent need to the new therapeutic methods. Compared to normal cells, tumor cells need more iron for their rapid proliferation, and using iron chelators to regulate iron metabolism is a potential treatment method for cancer. However, there are some problems for iron chelators as antitumor drugs, such as the extremely short half-life and low accumulation in the tumor tissue, the autophagy-mediated rapid supplement way after iron chelation and the iron chelation-induced HIF1 overexpression. In our previous work, we found that liposome-based drug delivery system can increase the half-life and accumulation of iron chelator into the tumor tissue, and combination with the HIF1 inhibitor or autophagy inhibitor can enhance the antitumor efficiency of iron chelators. In this project, we plan to use liposome, polymer and polypeptides as basic composition elements to design and build multilayer hybrid nanocarriers with long circulation time and active targeting effect to pancreatic cancer. Then, we will encapsulate the iron chelator, HIF1 inhibitor and autophagy inhibitor to the different layer in the multilayer hybrid nanocarriers. The combined drug delivery system will improve the metabolism of iron chelator and realize efficient enrichment of three drugs into pancreatic cancer tissue, which ultimately effectly inhibit pancreatic cancer through iron metabolism regulation-based mechanism.

胰腺癌患者的预后极差，临床一线化疗方案反应率低，亟待发现新的治疗靶点和药物。肿瘤细胞的旺盛代谢和增殖使其对铁代谢的依赖性明显高于正常细胞，通过铁螯合剂对肿瘤细胞的铁代谢进行调控是一种潜在的肿瘤治疗手段。然而铁螯合剂作为肿瘤治疗手段仍存在许多问题，比如极短的体内半衰期和极低的肿瘤组织富集量，细胞内自噬介导的快速铁补充代偿途径和铁螯合导致的癌基因HIF1过度表达。前期工作发现，通过脂质体输运可以增加铁螯合剂的体内半衰期和在胰腺癌组织中的富集量，而联合应用HIF1抑制剂或自噬抑制剂都可以增强铁螯合剂的抗胰腺癌效应。在本项目中，我们拟以脂质体、多聚物和多肽为基本构成元件，设计构建具有长循环性和胰腺癌主动靶向性的多层杂化纳米载体，同时将铁螯合剂、HIF1抑制剂和自噬抑制剂分层包载在纳米载体中，从而改善铁螯合剂的代谢缺点，实现高效的三种药物在胰腺癌组织的富集，最终达到基于铁代谢调控的联合抗胰腺癌效应。

胰腺导管腺癌被称为“癌中之王”，患者预后极差总体5年生存率小于5%，已经成为人类健康的巨大威胁，需要开发出新的治疗靶点和策略。相比于正常细胞，肿瘤细胞对缺铁环境更加敏感，下调肿瘤细胞内铁水平可破坏其能量代谢平衡，抑制肿瘤细胞的侵袭和增殖。铁螯合剂对肿瘤细胞的铁代谢进行调控是一种潜在的肿瘤治疗手段，然而铁螯合剂作为肿瘤治疗手段仍存在许多问题，比如极短的体内半衰期、极低的肿瘤组织富集量以及铁螯合剂导致的癌基因缺氧诱导因子（Hypoxia induction factor 1, HIF1）过度表达。因此本项目设计构建了一种具有长循环性和胰腺癌主动靶向性（在载体表面修饰转铁蛋白）的多层杂化纳米载体，同时将铁螯合剂去铁胺（Deferoxamine, DFO）、HIF1抑制剂lificiguat（也称YC1）和自噬抑制剂分层包载在纳米载体中，从而改善铁螯合剂的代谢缺点，实现药物在胰腺癌组织高效的富集，最终达到基于铁代谢调控的联合抗胰腺癌效应。.一、我们首先通过大批量临床组织芯片中铁代谢相关蛋白的表达分析，证实了胰腺癌细胞中存在明显增高的铁代谢水平，提示了铁螯合剂治疗胰腺癌的可能性。然后检测YC1与DFO联用对不同胰腺癌细胞系增殖的影响，试验结果显示DFO与YC1在胰腺癌细胞中发挥联合抗肿瘤作用。.二、成功构建出了一种简单的、能够载带DFO和YC1并具有靶向性的多层杂化纳米载体载药体系（命名为TNP-DFO-YC1），并对其进行了表征。然后我们还发现，在体外实验中，该体系能够靶向结合胰腺癌细胞以及增强DFO的抗肿瘤效果。在后续体内实验中极大的延长了DFO的半衰期，并表现出精准的正反馈式的胰腺癌靶向性。.三、在活体治疗中，无论是原位肿瘤模型还是皮下瘤模型，TNP-DFO-YC1组都表现出更强的抗癌效果和低水平的HIF1α表达量。最后我们还阐明了该体系发挥高效治疗作用的具体机制。