肿瘤微环境响应型DSF/nano-ZnO纳米递送体系的构建及其PCSCs靶向治疗的机制研究

Pancreatic cancer stem cells (PCSCs) are the root cause of treatment resistance, cancer metastasis, and recurrence, and they are resistant to conventional radiotherapy/chemotherapy. Therefore, PCSCs-targeted therapy has clinical significance for pancreatic cancer treatment. Studies have shown that disulfiram (DSF) combined with zinc or copper ions could inhibit lipid metabolism and disturb redox balance, and induce PCSCs apoptosis. However, currently, there is no effective DSF delivery system. Based on our previous research and the microenvironmental pathological characteristics of pancreatic cancer, we construct a tumor microenvironment responsive DSF/nano-ZnO delivery system to maximum DSF delivery efficiency and drug efficacy. In response to matrix metalloproteinases, this DSF nanoformulation will enable the active targeting, and exert deep intratumoral penetration and efficient cell internalization. After that, the lysosomal acidity will promote the inner core nano-ZnO dissolution and zinc ions release, which activate the DSF efficacy of inhibiting PCSCs. In this study, we will investigate the tumor microenvironment response characteristics, targeted delivery efficiency, and drug release patterns of constructed DSF nanoformulation. Also, we will determine their PCSCs inhibition capability, as well as the molecular and cellular mechanisms. This project will create a DSF nanoformulation based PCSCs-targeted therapy strategy, and provide a new idea for the clinical treatment of pancreatic cancer.

胰腺癌干细胞（PCSCs）是胰腺癌耐药、转移和复发的根源，且其对常规放化疗具有高度治疗耐受性，因而PCSCs靶向治疗研究具有重要临床价值。研究表明双硫仑（DSF）与锌、铜等离子协同可抑制脂质代谢并破坏氧化还原平衡诱导PCSCs凋亡，但目前尚无有效的药物递送体系。基于前期研究，拟针对胰腺癌病理特点构建肿瘤微环境响应型DSF/nano-ZnO纳米递送体系：首先，基质金属蛋白酶响应激活主动靶向实现DSF在胰腺癌中的深部递送和高效内化；其次，溶酶体微酸性促进内核纳米氧化锌（nano-ZnO）释放锌离子激活DSF药效，实现PCSCs靶向治疗。将研究该纳米制剂的肿瘤微环境应答特性、靶向递送效率和释药规律；在分子、细胞和动物水平揭示其抑制PCSCs的能力和机制。本项目将创建一种基于DSF/nano-ZnO纳米体系的PCSCs靶向治疗策略，为胰腺癌临床治疗提供新的思路。

肿瘤干细胞是肿瘤耐药、转移和复发的根源，且其对常规放化疗具有高度治疗耐受性，因而肿瘤干细胞靶向治疗研究具有重要临床价值。研究表明，双硫仑（DSF）与锌、铜等金属离子协同可抑制脂质代谢并破坏氧化还原平衡诱导肿瘤干细胞凋亡，但目前尚无有效的药物递送体系。本项目构建了肿瘤微环境响应型SF/DSF@ZnO纳米粒，联合递送DSF和锌离子，协同发挥抗肿瘤作用。纳米粒经长循环及EPR效应有效分布在肿瘤部位。丝素蛋白修饰提高了DSF/ZnO的循环稳定性和生物相容性，并显著改善了药物递送效率和安全性；同时体系内核nano-ZnO经内化后在内含体微酸性环境中溶解释放锌离子，促进ROS的大量产生和累积，协同DSF破坏氧化还原平衡促进肿瘤细胞凋亡及清除，同时有效减少肿瘤干细胞的数量，最大程度地发挥DSF的抗肿瘤作用。本项目的研究为临床应用DSF治疗恶性肿瘤的研究和应用奠定实验基础。