Unlocking the in vivo therapeutic potential of radiation-activated photodynamic therapy for locally advanced rectal cancer with lymph node involvement

Rui Sang; Sheri Nixdorf; Tzongtyng Hung; Carl Power; Fei Deng; Thuy Anh Bui; Alexander Engel; Ewa M Goldys; Wei Deng

doi:10.1016/j.ebiom.2025.105724

Unlocking the in vivo therapeutic potential of radiation-activated photodynamic therapy for locally advanced rectal cancer with lymph node involvement

EBioMedicine. 2025 Jun:116:105724. doi: 10.1016/j.ebiom.2025.105724. Epub 2025 May 12.

Authors

Rui Sang¹, Sheri Nixdorf², Tzongtyng Hung³, Carl Power³, Fei Deng⁴, Thuy Anh Bui², Alexander Engel⁵, Ewa M Goldys⁶, Wei Deng⁷

Affiliations

¹ Graduate School of Biomedical Engineering, ARC Centre of Excellence in Nanoscale Biophotonics, Faculty of Engineering, University of New South Wales, Sydney, NSW, 2052, Australia; School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, 2007, Australia.
² School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, 2007, Australia.
³ Biological Resources Imaging Laboratory, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, NSW, 2052, Australia.
⁴ Graduate School of Biomedical Engineering, ARC Centre of Excellence in Nanoscale Biophotonics, Faculty of Engineering, University of New South Wales, Sydney, NSW, 2052, Australia.
⁵ Sydney Medical School, University of Sydney, Sydney, NSW, 2050, Australia; Department of Colorectal Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW, 2065, Australia.
⁶ Graduate School of Biomedical Engineering, ARC Centre of Excellence in Nanoscale Biophotonics, Faculty of Engineering, University of New South Wales, Sydney, NSW, 2052, Australia. Electronic address: e.goldys@unsw.edu.au.
⁷ School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, 2007, Australia. Electronic address: Wei.Deng@uts.edu.au.

Abstract

Background: Rectal cancer is a leading cause of cancer-related mortality worldwide. The recurrence of locally advanced rectal cancer (LARC), particularly in cases involving lymph node-positive tumours, remains a critical challenge in rectal cancer management. In this study, a therapeutic strategy, radiation-activated photodynamic therapy (RA-PDT), for the treatment of LARC with lymph node-positive tumours was developed and evaluated.

Methods: RA-PDT was achieved by using a lipid-polymer hybrid nanoplatform loaded with verteporfin (VP) and functionalised with folic acid (FA) as a targeting molecule. Upon receiving a single 4 Gy fraction of radiation, VP was effectively activated, generating sufficient reactive oxygen species (ROS) to induce cancer cell death-however surrounding tissue was less affected and was spared. The efficacy of this strategy was assessed through in vitro cytotoxicity studies in HCT116 cells, as well as in orthotopic and subcutaneous mouse models. In vivo lymph node tumour progression was also evaluated.

Findings: RA-PDT effectively generated ROS following 4 Gy irradiation and exhibited significant cytotoxicity in HCT116 cells. In vivo, this strategy largely inhibited primary tumour growth in both orthotopic and subcutaneous mouse models while also suppressing lymph node tumour progression. Surrounding tissues were minimally affected, highlighting the precision and safety of this approach.

Interpretation: RA-PDT demonstrates potential as a safe therapeutic strategy for LARC, paving the way for its clinical translation.

Funding: This study was supported by the Australian National Health and Medical Research Council (GNT1181889), fellowship award (2019/CDF1013) from Cancer Institute NSW, Australia, the Australian Research Council Centre of Excellence for Nanoscale Biophotonics (CE140100003), UNSW SHARP funding, project grant from National Foundation for Medical Research and Innovation, Australia, International Research Training Program Scholarship (IRTP) from Australian Government, PhD Research Scholar Award from Sydney Vital Translational Cancer Research, and Translational Cancer Research Network PhD Scholarship Top-up award.

Keywords: Locally advanced rectal cancer; Low dose radiation; Lymph node involvement; Photodynamic therapy; Reactive oxygen species.

MeSH terms

Animals
Cell Line, Tumor
Disease Models, Animal
HCT116 Cells
Humans
Lymph Nodes / pathology
Lymphatic Metastasis
Mice
Photochemotherapy* / methods
Photosensitizing Agents / chemistry
Photosensitizing Agents / pharmacology
Reactive Oxygen Species / metabolism
Rectal Neoplasms* / drug therapy
Rectal Neoplasms* / metabolism
Rectal Neoplasms* / pathology
Rectal Neoplasms* / therapy
Verteporfin / chemistry
Verteporfin / pharmacology
Xenograft Model Antitumor Assays

Substances

Reactive Oxygen Species
Photosensitizing Agents
Verteporfin