A Self-Assembling Janus Dendron-Modified Phthalocyanine Enables Deep Tumor-Targeted Therapy for Gastric Cancer Peritoneal Metastases.

Abstract

Peritoneal metastasis is a leading cause of mortality in end-stage gastric cancer and remains poorly responsive to conventional chemotherapy. To address this unmet need, Janus dendron-modified phthalocyanines were developed as tumor-targeted photosensitizers for photodynamic therapy (PDT). A series of Janus dendron-modified phthalocyanines with tailored surface functionalities s synthesized, exhibiting spontaneous self-assembly into nanoparticles with augmented fluorescence, amplified reactive oxygen species (ROS) production, and improved tumor-targeting specificity. Among them, the lead compound TT1-4PYR, bearing pyrrolidone moieties, demonstrated ascites-derived protein corona and macropinocytosis-mediated cellular internalization, enabling deep penetration and selective accumulation in peritoneal metastasis lesions. Comprehensive evaluation in vitro, in vivo, and in human-derived gastric cancer organoid models confirmed its potent and targeted photodynamic cytotoxicity, effectively suppressing tumor progression without inducing systemic toxicity, achieving a favorable biosafety profile. These results highlight TT1-4PYR as a promising and deep-penetrating therapeutic agent for peritoneal metastasis, with potential applicability to other metastatic malignancies.