Structural modification of heptamethine indocyanine dyes with improved aqueous solubility and stability for photothermal therapy.

Heptamethine indocyanine dyes (HMICDs) have excellent near-infrared (NIR) properties and are capable of converting light energy into heat energy under NIR laser irradiation, enabling their use in photothermal therapy (PTT) of tumors. However, their photostability is poor, and they are easily inactivated by photobleaching after prolonged and repeated exposure to NIR laser. In addition, unmodified HMICDs have poor water solubility and tend to aggregate, limiting their biological applications. Herein, we designed and synthesized HMICDs with hydrophilic side chains and different substituent groups on polymethine chain, and explored the effects of these modifications on the water solubility, photostability and photothermal properties of the dyes. The introduction of tri-ethylene glycol hydrophilic side chains can improve the water solubility of HMICDs, and enhance the photostability and photothermal properties by increasing the spatial hindrance of the dyes. Furthermore, the incorporation of substituents with strong electron-withdrawing ability into the polymethine chain can improve the photostability and photothermal effect of the dyes. Under laser irradiation, the dyes can inhibit the proliferation of tumor cells by enhancing intracellular reactive oxygen species levels, decreasing mitochondrial membrane potential, and inducing cell apoptosis. In two tumor-bearing mouse models, dye 11 can effectively inhibit tumor growth by exerting photothermal effects with good biosafety. This work can provide a research foundation for the subsequent construction of HMICDs-based photothermal therapeutic agents for clinical applications.