A Reductively Activatable Phototheranostic Agent Based on a Water‐Soluble Nickel Naphthalocyanine Precursor

Metal naphthalocyanine (MNc) is one of the most promising near-infrared (NIR) dyes as a photosensitizer for phototheranostics, combining photoacoustic imaging (PAI) and photothermal therapy (PTT). However, the extremely low solubility of MNc has limited its practical application as a theranostic agent. In this research, we synthesized NiNc precursors (ox-NiNc) having two alkoxy groups on the α-carbons of the diagonal pyrroles with significantly improved solubility. We also prepared an amphiphilic derivative, ox-NiNc-PEG, and investigated its conversion to NiNc through reductive aromatization. We demonstrated that ox-NiNc-PEG was efficiently converted to NiNc in cancer cells with elevated glutathione levels, resulting in enhanced photoacoustic signals and increased phototoxicity based on photothermal conversion under NIR light irradiation. The target-oriented reductive aromatization in response to the reducing environment in cancer cells offers a critical strategy for developing PAI/PTT theranostic agents.