Yao Zhipeng, Qi Chenxue, Zhang Fan, Yao Hong, Wang Cheng, Cao Xiaoxiang, Zhao Chenhui, Wang Zhichun, Qi Min, Yao Chengyun, Wang Xiaoming, Xia Hongping
School of Chemistry and Chemical Engineering & Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing 210009, China; The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China.
Department of Gynecologic Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515041, China.
Acta Biomater. 2024 Jan 1;173:365-377. doi: 10.1016/j.actbio.2023.10.024. Epub 2023 Oct 26.
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease that responds poorly to single-drug immunotherapy with PD-L1 (CD274) inhibitors. Here, we prepared mesoporous nanomaterials CuMoS (CMS)/PEG loaded with PD-L1 inhibitor BMS-1 and CXCR4 inhibitor Plerixafor to form the nanodrug CMS/PEG-B-P. In vitro experiments, CMS/PEG-B-P have a more substantial inhibitory effect on the expression of PD-L1 and CXCR4 as well as to promote the apoptosis of pancreatic cancer cells KPC and suppressed KPC cell proliferation were detected by flow cytometry, qPCR and Western blotting (WB). Promotes the release of the cytotoxic substance reactive oxygen species (ROS) and the production of the immunogenic cell death (ICD) marker calreticulin (CRT) in KPC cells. CMS/PEG-B-P was also detected to have a certain activating effect on mouse immune cells, dendritic cells (mDC) and macrophage RAW264.7. Subcutaneous tumorigenicity experiments in C57BL/6 mice verified that CMS/PEG-B-P had an inhibitory effect on the growth of tumors and remodeling of the tumor immune microenvironment, including infiltration of CD4 and CD8 T cells and polarization of macrophages, as well as reduction of immunosuppressive cells. Meanwhile, CMS/PEG-B-P was found to have different effects on the release of cytokines in the tumor immune microenvironment, including The levels of immunostimulatory cytokines INF-γ and IL-12 are increased and the levels of immunosuppressive cytokines IL-6, IL-10 and IFN-α are decreased. In conclusion, nanomaterial-loaded immune checkpoint inhibitor therapies can enhance the immune response and reduce side effects, a combination that shows great potential as a new immunotherapeutic approach. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease that has a low response to single-drug immunotherapy with PD-L1 (CD274) inhibitors. We preared PEG-modified mesoporous nanomaterials Cu2MoS4 (CMS) loaded with PD-L1 inhibitor BMS-1 and CXCR4 inhibitor Plerixafor to form the nanodrug CMS/PEG-B-P. Our study demonstrated that Nanomaterial-loaded immune checkpoint inhibitor therapies can enhance the immune response and reduce side effects, a combination that shows great potential as a new immunotherapeutic approach.
胰腺导管腺癌（PDAC）是一种致命疾病，对使用PD-L1（CD274）抑制剂的单药免疫疗法反应不佳。在此，我们制备了负载PD-L1抑制剂BMS-1和CXCR4抑制剂普乐沙福的介孔纳米材料CuMoS（CMS）/PEG，以形成纳米药物CMS/PEG-B-P。体外实验中，通过流式细胞术、qPCR和蛋白质免疫印迹法（WB）检测发现，CMS/PEG-B-P对PD-L1和CXCR4的表达具有更显著的抑制作用，同时可促进胰腺癌细胞KPC的凋亡并抑制KPC细胞增殖。它还能促进细胞毒性物质活性氧（ROS）的释放以及免疫原性细胞死亡（ICD）标志物钙网蛋白（CRT）在KPC细胞中的产生。此外，检测发现CMS/PEG-B-P对小鼠免疫细胞、树突状细胞（mDC）和巨噬细胞RAW264.7具有一定的激活作用。在C57BL/6小鼠中进行的皮下致瘤实验证实，CMS/PEG-B-P对肿瘤生长以及肿瘤免疫微环境的重塑具有抑制作用，包括CD4和CD8 T细胞的浸润、巨噬细胞的极化以及免疫抑制细胞的减少。同时，发现CMS/PEG-B-P对肿瘤免疫微环境中细胞因子的释放有不同影响，包括免疫刺激细胞因子INF-γ和IL-12的水平升高，以及免疫抑制细胞因子IL-6、IL-10和IFN-α的水平降低。总之，负载纳米材料的免疫检查点抑制剂疗法可增强免疫反应并减少副作用，这种联合疗法作为一种新的免疫治疗方法显示出巨大潜力。重要性声明：胰腺导管腺癌（PDAC）是一种致命疾病，对使用PD-L1（CD274）抑制剂的单药免疫疗法反应较低。我们制备了负载PD-L1抑制剂BMS-1和CXCR4抑制剂普乐沙福的聚乙二醇修饰的介孔纳米材料Cu2MoS4（CMS），以形成纳米药物CMS/PEG-B-P。我们的研究表明，负载纳米材料的免疫检查点抑制剂疗法可增强免疫反应并减少副作用，这种联合疗法作为一种新的免疫治疗方法显示出巨大潜力。
