Endoscopically guided interventional photodynamic therapy for orthotopic pancreatic ductal adenocarcinoma based on NIR-II fluorescent nanoparticles

Rationale: Pancreatic cancer, comprising mostly pancreatic ductal adenocarcinoma (PDAC), is a highly malignant disease, typically known as a hypoxic tumor microenvironment. The application of PDT in pancreatic cancer in clinic is still hampered by several shortcomings, including the (i) deep location of pancreatic cancer, (ii) tissue damage induced by optical fibers, (iii) hypoxic microenvironment, (iv) short excitation wavelengths of traditional photosensitizers, and (v) poor delivery efficiency of photosensitizers. Methods: We designed an organic nanoparticle as photosensitizer for near-infrared II (NIR-II) fluorescent (FL) imaging that exerts a type I PDT effect on deep orthotopic pancreatic tumors under excitation by a NIR (808 nm) laser. Results: This novel photosensitizer exhibits enhanced accumulation in orthotopic pancreatic cancer in mice and could be used to effectively detect pancreatic cancer and guide subsequent laser irradiation for accurate PDT of deep pancreatic cancer. In addition, we built an endoscopic platform monitored by NIR-II FL imaging to achieve minimally invasive endoscopically guided interventional photodynamic therapy (EG-iPDT) with efficient inhibition of orthotopic pancreatic cancer, which prolonged overall survival up to 78 days compared to PBS + EG-iPDT group (*p < 0.05) in a mouse model. Conclusions: Minimally invasive EG-iPDT has promise as an intraoperative treatment for early-stage or unresectable or metastatic pancreatic cancer.