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Published June 2024 | Published
Journal Article Open

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

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.

Copyright and License

© 2024 The Authors. Published by Elsevier Masson SAS Under a Creative Commons license.

Acknowledgement

This project received financial support through grants from the National Science and Technology Council (NSTC) of Taiwan (MOST 110–2320-B-A49A-510-MY3 and MOST 107–2320-B-010–015-MY3), the National Yang Ming Chiao Tung University and Cheng Hsin General Hospital (CY113–15 and CY112–14), and the Veterans General Hospitals and University System of Taiwan (VGHUST113-G2–2–3 and VGHUST112-G2–2–3). We extend our appreciation to the Small Animal Imaging Core Facility of the Brain Research Center at National Yang Ming Chiao Tung University and Taiwan Animal Consortium for the technical support in Bruker 7 T PET/MR. In addition, we acknowledge the National Laboratory Animal Center, National Applied Research Laboratories in Taipei, Taiwan, for providing the experimental animals.

Contributions

Yu-Li Lo: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization. Ching-Yao Li: Methodology, Investigation. Li-Ling Wu: Data curation. Chun-Jung Chen: Conceptualization. Tsui-Fen Chou: Conceptualization. Ching-Ping Yang: Writing – review & editing. Yih-Hsin Chang: Conceptualization.

Data Availability

Appendix A. Supplementary material

Ethics

All animal protocols received approval from the Institutional Animal Care and Use Committee (IACUC) of National Yang Ming Chiao Tung University (approval number 1100411r). All in vivo investigations adhered to the criteria authorized by the IACUC.

Conflict of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Additional details

Created:
May 30, 2024
Modified:
June 4, 2024