Inhibiting COX-2/PGE2 pathway with biodegradable NIR-Ⅱ fluorescent polymeric nanoparticles for enhanced photodynamic immunotherapy

Abstract

Photodynamic therapy (PDT) capable of eliciting antitumor immune responses by inducing immunogenic cell death (ICD) holds promise for tumor suppression. However, most photosensitizers suffer from limited degradation, insufficient biocompatibility, and inabilities to generate long-wavelength fluorescence for in vivo tracking. Moreover, PDT has the inherent problem of activating the cyclooxygenase-2/prostaglandin-E2 (COX-2/PGE2) pathway and upregulating programmed cell death ligand 1 (PD-L1) expression, resulting in insufficient efficacy of photodynamic immunotherapy. Herein, we designed and synthesized a dihydroxy-containing BODIPY monomer (MonoBodipy), and then formed the biodegradable polymer (PPDT) by polycondensation reaction, which could generate reactive oxygen species (ROS) for photodynamic immunotherapy and emit near-infrared-Ⅱ (NIR-Ⅱ) fluorescence for bioimaging. Subsequently, we further utilized PPDT to encapsulate the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) to form NPPDT@CXB that could inhibit the COX-2/PGE2 pathway. NPPDT@CXB displayed great anticancer potency on osteosarcoma and ovarian cancer in vitro. Further, NPPDT@CXB could accumulate at tumor site after intravenous administration into tumor-bearing mice, generate ROS, induce ICD cascade, and trigger antitumor immune responses under an 808 nm laser irradiation. The ROS further breaks up thioketal linkages in PPDT, resulting in a rapid CXB release to inhibit the COX-2/PGE2 pathway and then downregulate the PD-L1 expression in tumor cells, which in turn leads to an effective suppression of the primary and distant tumors. This work highlighted a well biocompatible and biodegradable photosensitizer that generates ROS, emits long-wavelength fluorescence, inhibits the COX-2/PGE2 pathway, and downregulates PD-L1 expression simultaneously, exhibiting a robust photodynamic immunotherapy efficacy. This study proposed a new strategy to overcome the inherent problems of photodynamic immunotherapy and pointed out the path of future PDT development.