Exploring in vivo combinatorial chemo-immunotherapy: Addressing p97 suppression and immune reinvigoration in pancreatic cancer with tumor microenvironment-responsive nanoformulation

• Published in: Biomedicine & pharmacotherapy 2024-06, Vol.175, p.116660, Article 116660
• Main Authors: Lo, Yu-Li, Li, Ching-Yao, Chou, Tsui-Fen, Yang, Ching-Ping, Wu, Li-Ling, Chen, Chun-Jung, Chang, Yih-Hsin
• Format: Article
• Language: English
• Subjects: Animals; B7-H1 Antigen - antagonists & inhibitors; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Endoplasmic reticulum stress; Female; Humans; Immune Checkpoint Inhibitors - pharmacology; Immunotherapy - methods; Liposomes; Mice; MicroRNA; Nanoparticle Drug Delivery System - chemistry; Nanoparticles; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Polyethylene Glycols - chemistry; Polyglutamic acid (PGA)-polyethylene glycol (PEG); Tumor microenvironment (TME); Tumor Microenvironment - drug effects; VCP/p97 inhibitor
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.116660

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. [Display omitted] •Novel preclinical chemo-immunotherapy for PDAC.•Encapsulated VCP inhibitor, PD-L1 inhibitor, and immunoadjuvant.•Tailored peptide delivery targets critical pathways.•Nanoformulation enhances antitumor immune responses.•Enhanced safety profile and affirmed clinical potential.