Octreotide modified self-assembly Chlorin e6 nanoparticles with redox responsivity and active targeting for highly selective pancreatic neuroendocrine neoplasms photodynamic therapy

• A novel delivery tool was developed and employed to deliver clinical photosensitizer Chlorin e6 (Ce6) to enable highly selective PDT. • GSH/ROS dual stimuli-responsive Ce6-loaded nanoparticles can be obtained by the self-assembly strategy. • The nanoparticles could specifically accumulate in tumor tissues for tumor-selective PDT with high biosafety. • This is first research disclosing the great potential of PDT for pNENs. • The self-assembly nanoparticles based on PDT are expected to provide a new candidate for clinical medical treatment of pNENs. Pancreatic neuroendocrine neoplasms (pNENs) are characterized by high rarity and heterogeneity, simultaneously suffering from a lack of the satisfactory treatment options with high pNENs-selectivity and safety. Therefore, it is urgent for us to develop a novel drug delivery system and/or explore new treatment strategies. Photodynamic therapy (PDT) is a clinically used tumor treatment modality, which yet has not been reported in pNENs. Herein, we designed a redox tumor microenvironment-activatable self-assembly Chlorin e6 (Ce6) nanoparticles (OCNPs) containing the somatostatin receptor (SSTR)-targeted octreotide (OCT), and conducted in vivo and in vitro evaluations on its role in PDT for pNENs. OCNPs exhibited and excellent stability and sensitivity to GSH/ROS to release Ce6 which produced a large amount of 1 O 2 under laser irradiation. In addition, OCNPs could specifically recognize the SSTR on the surface of pNENs cells through OCT and enter the cells by receptor-mediated endocytosis, highlighting a good active targeting ability. The mechanism research elucidated that OCNPs had a significant phototoxic effect (IC 50 = 1.174 μM) on pNENs cells mainly by blocking cells in G0/G1 phase, and increasing cell apoptosis and necrosis. Importantly, the in vivo experiment proved that OCNPs enable selective and prolonged tumor accumulation, thus leading to a better therapeutic efficacy compared with Ce6, with no obvious toxic and side effects on major organs. Our research is the first case that employed PDT for pNENs, and these positive results demonstrated the pNENs-targeted Ce6 delivery system is promising to advance the treatment of pNENs.