Divergent phototherapeutic effects via meso cyclic amine substitution on a NIR-II heptamethine cyanine scaffold

Photothermal therapy (PTT) and photodynamic therapy (PDT) are two major modalities of light-activated cancer treatment, each with distinct advantages and limitations. However, a concise and position-specific structural handle for modulating reactive oxygen species (ROS)-related and photothermal outputs within a single heptamethine cyanine scaffold remains lacking. Herein, we report two meso-substituted heptamethine cyanine derivatives, 038 and 048, derived from the second near-infrared (NIR-II) meso-chloro precursor 055, featuring 4-piperidineethanol and pyrrolidine substituents, respectively. These structurally similar compounds exhibited divergent phototherapeutic behaviors. Systematic photophysical studies revealed that meso-amine substitution alters absorption profiles, tunes calculated electronic structures, and differentially enhances ROS-related responses while attenuating photothermal heating. Across the series, 055 retains the strongest photothermal performance, whereas 048 exhibits the strongest ROS-related activity. Notably, under their respective in vivo irradiation conditions (808 nm for 038 and 680 nm for 048), 038 afforded better antitumor outcomes than 048, despite the stronger in vitro ROS-related response of 048. This comparison shows that a stronger in vitro ROS-related response alone did not predict a better in vivo therapeutic effect under the tested conditions. This work highlights meso-cyclic amine substitution as a concise structural handle for modulating ROS-related and photothermal outputs within a heptamethine cyanine scaffold.