Multi-targeting liposomal codelivery of cisplatin and rapamycin inhibits pancreatic cancer growth and metastasis through stromal modulation.
Multi-targeting liposomal codelivery of cisplatin and rapamycin inhibits pancreatic cancer growth and metastasis through stromal modulation.
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DOI：
10.1016/j.ijpharm.2023.123316
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发表时间：
2023-08
影响因子：
5.8
通讯作者：
Wenting Zhu;Han Yu;Menglei Jia;Caiyan Lin;Zhongwen Yuan;Xiaoxiao Tan;Pengke Yan
中科院分区：
文献类型：
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作者：
Wenting Zhu;Han Yu;Menglei Jia;Caiyan Lin;Zhongwen Yuan;Xiaoxiao Tan;Pengke Yan
胰腺癌的治疗因耐药和肝转移而面临挑战。作为一种治疗胰腺癌的新策略，联合治疗已成为可能，但肿瘤组织中致密的间充质屏障阻碍了药物的传递，影响了其治疗效果。为了解决这个问题，我们制备了一种ATF多肽修饰的脂质体，与顺铂和雷帕霉素共负载(ATF@PT/Rapa LPs)，它针对肿瘤细胞和表达uPAR受体的肿瘤相关成纤维细胞。在肿瘤球体穿透实验中，ATF多肽修饰脂质体显著增强了肿瘤的深度穿透能力。更重要的是，ɑ-SMA、I型胶原和纤维连接蛋白在体外的表达下调表明，ATF@Pt/Rapa LPs破坏了间质。通过这种方式，可以实现对肿瘤细胞的高效药物输送。不出所料，ATF@Pt/Rapa Lpsin体外对细胞增殖和迁移的抑制作用强于游离的Pt/Rapa和Pt/Rapa LPs。此外，ATF@Pt/Rapa Lps对PANC02移植瘤小鼠和肝转移模型小鼠均有较好的治疗作用。最终，与RAPA和顺铂共负载的多靶向纳米药物可能为治疗转移性胰腺癌提供一种新的方法。
Pancreatic cancer treatment faces challenges due to drug resistance as well as liver metastasis. As a new strategy for treating pancreatic cancer, combination therapy is now available, but the dense mesenchymal barrier in the tumor tissue blocks drug delivery and impairs its therapeutic efficacy. To address this issue, we prepared an ATF peptide-decorated liposomal co-loaded with cisplatin and rapamycin (ATF@Pt/Rapa Lps), which targets both tumor cells and cancer-associated fibroblasts that express uPAR receptors. In tumor sphere penetration experiments, ATF peptide modified liposomes significantly enhanced deep penetration. More importantly, the ATF@Pt/Rapa Lps disrupted the stroma, as demonstrated by the downregulation of ɑ-SMA, I collagen, and fibronectin proteinin vivoandin vitro. In this way, highly effective drug delivery to tumor cells can be achieved. As expected, there was a stronger inhibition of cell proliferation and migration by ATF@Pt/Rapa Lpsin vitrocompared to free Pt/Rapa and Pt/Rapa Lps. Furthermore, ATF@Pt/Rapa Lps showed greater therapeutic effects in PANC02 transplanted tumor mice and liver metastasis mice models. Ultimately, multi-targeting nanomedicines co-loaded with Rapa and cisplatin may provide a new approach to treating metastatic pancreatic cancer.