Asymmetric Heptamethine Cyanine: A Phototheranostic Agent for Primary Liver Cancer Treatments

Abnormal pH and viscosity are defining features of the tumor microenvironment, offering valuable targets for cancer diagnostics and therapy. Here, we introduce Cy7-TCF-Mpip, a triple-functional near-infrared (NIR) probe that integrates pH responsiveness, viscosity sensitivity, and photodynamic activity within a single heptamethine cyanine scaffold. Cy7-TCF-Mpip exhibits substantial fluorescence enhancement under acidic and high-viscosity conditions, as well as NIR absorption/emission (724-870 nm), and efficient singlet oxygen generation (ΦΔ up to 0.065) upon 660 nm irradiation. The probe selectively accumulates in hepatocellular carcinoma and cholangiocarcinoma (CCA) cells, responding dynamically to changes in hypoxia-induced acidity and cellular viscosity. Upon light activation, Cy7-TCF-Mpip induces potent, ROS-mediated photodynamic cytotoxicity with minimal dark toxicity and preferential phototoxicity toward CCA cells compared with nonmalignant cholangiocytes under the tested conditions. In vivo, the probe significantly suppresses tumor growth in a CCA xenograft model after local 660 nm light irradiation, with no observable body-weight loss or obvious behavioral abnormalities under the tested conditions. Overall, Cy7-TCF-Mpip represents a compact and versatile NIR theranostic platform for image-guided photodynamic therapy of primary liver cancers.