Advanced Theranostics in a Pancreatic Cancer Model Integrating Dual Optoacoustic‐Photodynamic Performance of Asymmetric Zinc Phthalocyanines

ABSTRACT Ensuring the effective delivery and activity of photosensitizers as a diagnostic, therapeutic, or both, within deep‐seated hypoxic and treatment‐resistant tumors remains a significant challenge. The primary limitations of current small‐molecule photosensitizers are their short circulating half‐lives and activation in the visible light spectrum, thereby restricting tissue penetration. Herein, we report the rational design of asymmetric zinc phthalocyanine scaffolds that address the limitations of current photosensitizers and demonstrate enhanced optoacoustic behavior enabling deep‐tissue diagnostic imaging. Our asymmetric design incorporates glycerol functionalities that enhance solubility, photostability, and cellular internalization, along with a heavy‐atom (‐iodo) moiety that dramatically enhances singlet oxygen generation, resulting in a more potent photodynamic therapy. Another striking feature of these developed scaffolds is their long circulation lifetimes, resulting in enriched accumulation at the tumor site, and minimal adverse effects at off‐target organs without the need for additional encapsulation. Notably, these near‐infrared (NIR‐activated photosensitizers can effectively penetrate tumor tissues with low oxygen levels, as studied within a hypoxic, preclinical, gemcitabine‐resistant pancreatic tumor mouse model. The integrated diagnostic and therapeutic capabilities hold strong promise for real‐time assessment of treatment response in next‐generation phototheranostics, especially in locally advanced pancreatic cancer, which remains refractory to conventional treatment strategies.