Fluorine-Functionalized Isophorone Near-Infrared Cu2+ Fluorescent Probe for Lung-Targeted Imaging of Diabetic Lung Injury and Lung Cancer

Abstract Traditional small-molecule fluorescent probes suffer from nonspecific accumulation in metabolic organs, limiting their application in lung disease monitoring. Herein, we developed a fluorine-substituted dicyanoisophorone-based probe (PFCu) with picolinate as the Cu2+-recognition moiety. PFCu preferentially illuminated A549 cancer cells and exhibited remarkable lung-targeting accumulation, enabling specific Cu2+ recognition in the lung. The probe allows real-time monitoring of Cu2+ level in living cells and possesses ER-targeting ability, facilitating analysis of Cu2+ fluctuations in high glucose-induced diabetic models and revealing the relationship among hyperglycemia, ER stress, and copper homeostasis. Notably, PFCu effectively distinguished lung tumor-bearing mice from healthy controls and showed significantly higher fluorescence in tumor tissues than in adjacent normal tissues from clinical samples. This study provides a novel molecular tool for lung disease research, supports Cu2+ as a potential biomarker for early diagnosis of lung cancer, and offers new strategies for diagnosing Cu2+-related diseases.