Highly Photostable Deep-NIR Chromophore with a Superior Molar Absorptivity for Efficient Photothermal Therapy

Organic chromophores, especially those absorbing/emitting in the deep near-infrared region (deep-NIR, i.e., 800 nm and beyond), have prominent potentials in photothermal cancer therapy due to the deep tissue penetration and good biocompatibility. Although many cyanine/DAD-based photothermal agents have been successfully used in clinical and preclinical trials, they are limited to poor photostability and poor molar absorptivity. There is still an imperative demand for robust deep-NIR photothermal agents exhibiting high photostability and high molar absorptivity. We previously invented a bright push–pull fluorochromic scaffold (EC5) absorbing and emitting in the deep-NIR spectral region. In this work, EC5 was rationally tailored to suppress its fluorescence emission and promote its photothermal conversion efficiency. This led to the design and synthesis of EC5PM and EC5DP by changing two or four of its N-alkyl groups of the push–pull headgroups of EC5 into phenyl groups, respectively. The fluorescence intensities of EC5PM and EC5DP are completely quenched due to the TICT effect associated with the N–Ph bonds. In particular, EC5DP maximally absorbs at a longer wavelength of 879 nm with a superior photostability, a high photothermal conversion efficiency of 54.8%, and a superior molar extinction coefficient of 224,000 M–1 cm–1. Upon encapsulation in DSPE-mPEG2000 micelles, the phototoxicity of EC5DP was showcased in 4T1 cells and a remarkable therapeutic effect of tumors was showcased with a 4T1 tumor-bearing mouse model. This work provides a rational strategy to design ultraphotostable and highly deep-NIR absorbing organic chromophores for photothermal therapy.