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

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.