Synthesis and Photodynamic Activities of Pyridine- or Pyridinium-Substituted Aza-BODIPY Photosensitizers

In this work, various novel pyridinyl- and pyridinium-modified Aza-BODIPY PSs were designed and constructed based on monoiodo Aza-BODIPY PSs (<b>BDP-4</b> and <b>BDP-15</b>) in an attempt to construct "structure-inherent organelles-targeted" PSs to endow potential organelle-targeting ability. Pyridinyl PSs displayed potent photodynamic efficacy, and monorigidified PSs were very effective. The monorigidified PS <b>20</b> with <i>meta</i>-pyridinyl moiety displayed the most potent photoactivity and negligible dark toxicity with a favorable dark/phototoxicity ratio (>4800). To our surprise, monorigidified PS with <i>meta</i>-pyridinyl moiety (e.g., <b>20</b>) was lipid droplet-targeted. <b>20</b> showed good cellular uptake and intracellular ROS generation compared with <b>BDP-15</b>. The preliminary cell death process exploration indicated that <b>20</b> resulted in lipid peroxidation and induced cell death through an iron-independent ferroptosis-like cell death pathway. In vivo antitumor efficacy experiments manifested that <b>20</b> significantly inhibited tumor growth and outperformed <b>BDP-15</b> and <b>Ce6</b> even under a single low-dose light irradiation (30 J/cm²).