Background: Metastasis is one of the main reasons for the high mortality associated with pancreatic ductal adenocarcinoma (PDAC), and autophagy regulates the metastatic migration of tumor cells, their invasion of tissues, and their formation of focal adhesions. Inhibiting autophagy may suppress tumor growth and metastasis, but the abundant extracellular matrix hinders the deep penetration of therapeutic agents. Methods: To enhance the penetration of drugs that can inhibit metastasis of pancreatic cancer, a pH-responsive drug delivery system was formulated. Gemcitabine (GEM), a first-line chemotherapeutic drug against PDAC, was loaded in 6PA-modified DGL (PDGL) nanoparticles to afford PDGL-GEM. Then PDGL-GEM was co-precipitated with the autophagy inhibitor chloroquine phosphate (CQ) and calcium phosphate to formulate PDGL-GEM@CAP/CQ. The size and morphology of the resulting "nanobomb" PDGL-GEM@CAP/CQ were characterized, and their uptake into cells, cytotoxicity and ability to inhibit autophagy were analyzed at pH 6.5 and 7.4. The anti-tumor and anti-metastasis effects of the nanobomb were explored on mice carrying Pan 02 pancreatic tumor xenografts or orthotopic tumors. Results: The pH-induced dissolution of calcium phosphate facilitated the release of CQ from the nanobomb and deep penetration of PDGL-GEM. The internalization of PDGL-GEM and subsequent intracellular release of GEM inhibited tumor growth, while CQ downregulated autophagy in tumor cells and fibroblasts. In fact, inhibition of xenograft and orthotopic tumor growth was greater with the complete PDGL-GEM@CAP/CQ than with subassemblies lacking GEM or CQ. More importantly, mechanistic studies in vitro and in vivo suggested that the nanobomb inhibits metastasis by downregulating MMP-2 and paxillin, as well as reducing fibrosis. Conclusion: The pH-sensitive PDGL-GEM@CAP/CQ shows potential for inhibiting proliferation and metastasis of pancreatic cancer through an autophagy-dependent pathway.

中文翻译：

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使用可激活 pH 值的核壳纳米弹共同递送自噬抑制剂和吉西他滨可抑制胰腺癌的进展和转移。

背景：转移是胰腺导管腺癌（PDAC）相关高死亡率的主要原因之一，自噬调节肿瘤细胞的转移迁移、其对组织的侵袭以及它们的粘着斑形成。抑制自噬可以抑制肿瘤的生长和转移，但丰富的细胞外基质阻碍了治疗药物的深度渗透。方法：为提高抑制胰腺癌转移的药物的渗透性，研制了一种pH响应性给药系统。吉西他滨 (GEM) 是一种针对 PDAC 的一线化疗药物，它被加载到 6PA 修饰的 DGL (PDGL) 纳米颗粒中以提供 PDGL-GEM。然后将PDGL-GEM与自噬抑制剂磷酸氯喹（CQ）和磷酸钙共沉淀，形成PDGL-GEM@CAP/CQ。对所得“纳米炸弹”PDGL-GEM@CAP/CQ 的大小和形态进行了表征，并在 pH 6.5 和 7.4 下分析了它们对细胞的吸收、细胞毒性和抑制自噬的能力。在携带 Pan 02 胰腺肿瘤异种移植物或原位肿瘤的小鼠身上探索了纳米炸弹的抗肿瘤和抗转移作用。结果：pH诱导的磷酸钙溶解促进了CQ从纳米弹中的释放和PDGL-GEM的深度渗透。PDGL-GEM 的内化和随后 GEM 的细胞内释放抑制了肿瘤生长，而 CQ 下调了肿瘤细胞和成纤维细胞中的自噬。事实上，与缺乏 GEM 或 CQ 的组件相比，完整的 PDGL-GEM@CAP/CQ 对异种移植物和原位肿瘤生长的抑制作用更大。更重要的是，体外和体内的机理研究表明，纳米炸弹通过下调 MMP-2 和桩蛋白以及减少纤维化来抑制转移。结论：pH敏感性PDGL-GEM@CAP/CQ具有通过自噬依赖性途径抑制胰腺癌增殖和转移的潜力。