Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Faculty of Pharmacy, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
Biomed Pharmacother. 2024 Jun;175:116660. doi: 10.1016/j.biopha.2024.116660. Epub 2024 May 2.
Pancreatic ductal adenocarcinoma (PDAC) has an extremely devastating nature with poor prognosis and increasing incidence, making it a formidable challenge in the global fight against cancer-related mortality. In this innovative preclinical investigation, the VCP/p97 inhibitor CB-5083 (CB), miR-142, a PD-L1 inhibitor, and immunoadjuvant resiquimod (R848; R) were synergistically encapsulated in solid lipid nanoparticles (SLNs). These SLNs demonstrated features of peptides targeting PD-L1, EGFR, and the endoplasmic reticulum, enclosed in a pH-responsive polyglutamic (PGA)-polyethylene glycol (PEG) shell. The homogeneous size and zeta potential of the nanoparticles were stable for 28 days at 4°C. The study substantiated the concurrent modulation of key pathways by the CB, miR, and R-loaded nanoformulation, prominently affecting VCP/Bip/ATF6, PD-L1/TGF-β/IL-4, -8, -10, and TNF-α/IFN-γ/IL-1, -12/GM-CSF/CCL4 pathways. This adaptable nanoformulation induced durable antitumor immune responses and inhibited Panc-02 tumor growth by enhancing T cell infiltration, dendritic cell maturation, and suppressing Tregs and TAMs in mice bearing Panc-02 tumors. Furthermore, tissue distribution studies, biochemical assays, and histological examinations highlighted enhanced safety with PGA and peptide-modified nanoformulations for CB, miR, and/or R in Panc-02-bearing mice. This versatile nanoformulation allows tailored adjustment of the tumor microenvironment, thereby optimizing the localized delivery of combined therapy. These compelling findings advocate the potential development of a pH-sensitive, three-in-one PGA-PEG nanoformulation that combines a VCP inhibitor, a PD-L1 inhibitor, and an immunoadjuvant for cancer treatment via combinatorial chemo-immunotherapy.
胰腺导管腺癌（PDAC）具有极其恶劣的性质，预后不良且发病率不断上升，这使其成为全球对抗癌症相关死亡率的一个巨大挑战。在这项创新的临床前研究中，VCP/p97 抑制剂 CB-5083（CB）、miR-142、PD-L1 抑制剂和免疫佐剂瑞喹莫德（R848；R）被协同包封在固体脂质纳米粒（SLN）中。这些 SLN 表现出靶向 PD-L1、EGFR 和内质网的肽的特征，被 pH 响应性聚谷氨酸（PGA）-聚乙二醇（PEG）壳包裹。纳米粒的均匀大小和zeta 电位在 4°C 下稳定 28 天。该研究证实，CB、miR 和负载纳米制剂的同时调节关键途径，显著影响 VCP/Bip/ATF6、PD-L1/TGF-β/IL-4、-8、-10 和 TNF-α/IFN-γ/IL-1、-12/GM-CSF/CCL4 途径。这种适应性强的纳米制剂通过增强 T 细胞浸润、树突状细胞成熟以及抑制 Panc-02 荷瘤小鼠中的 Tregs 和 TAMs，诱导持久的抗肿瘤免疫反应并抑制 Panc-02 肿瘤生长。此外，组织分布研究、生化测定和组织学检查突出了 PGA 和肽修饰纳米制剂在增强 CB、miR 和/或 R 在 Panc-02 荷瘤小鼠中的安全性。这种多功能纳米制剂允许对肿瘤微环境进行定制调整，从而优化联合治疗的局部递送。这些引人注目的发现支持开发一种 pH 敏感的三功能 PGA-PEG 纳米制剂的潜力，该制剂将 VCP 抑制剂、PD-L1 抑制剂和免疫佐剂结合在一起，通过联合化疗免疫疗法治疗癌症。
