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

Yu-Li Lo; Ching-Yao Li; Tsui-Fen Chou; Ching-Ping Yang; Li-Ling Wu; Chun-Jung Chen; Yih-Hsin Chang

doi:10.1016/j.biopha.2024.116660

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

Biomed Pharmacother. 2024 May 2:175:116660. doi: 10.1016/j.biopha.2024.116660. Online ahead of print.

Authors

Yu-Li Lo¹, Ching-Yao Li², Tsui-Fen Chou³, Ching-Ping Yang², Li-Ling Wu⁴, Chun-Jung Chen⁵, Yih-Hsin Chang⁶

Affiliations

¹ 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. Electronic address: yulilo@nycu.edu.tw.
² Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
³ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, United States; Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, United States.
⁴ Department and Institute of Physiology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
⁵ Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung City, Taiwan.
⁶ Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.

PMID: 38701563
DOI: 10.1016/j.biopha.2024.116660

Abstract

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.

Keywords: Endoplasmic reticulum stress; MicroRNA; Pancreatic cancer; Polyglutamic acid (PGA)-polyethylene glycol (PEG); Tumor microenvironment (TME); VCP/p97 inhibitor.