Synthesis of a hemicyanine-based near-infrared fluorescent probe for the diagnosis of pulmonary fibrosis and acute lung injury.
Pulmonary fibrosis (PF) and acute lung injury (ALI) are severe and often fatal pulmonary conditions with high morbidity and limited treatment options, characterized by progressive interstitial scarring or acute diffuse alveolar damage, respectively. Mitochondrial dysfunction is increasingly implicated in their pathogenesis, and LACTB (Lactamase beta), a mitochondrial serine protease, is a potential regulator of these. However, current diagnostics cannot capture early molecular or organelle-level changes. This gap highlights the need for a noninvasive, mitochondria-targeted imaging approach to monitor disease-related biochemical alterations in vivo.
HD-LACTB is a hemicyanine-based Near-Infrared (NIR) fluorescent probe, whose activation is triggered by enzymatic bond cleavage. LACTB recognizes the peptide sequence within the probe and catalyzes hydrolysis at the cleavage site, releasing a free hemicyanine fluorophore and the corresponding peptide fragment. It features emission in the NIR spectrum (725 nm) for enhanced tissue penetration, along with high selectivity for LACTB and low cytotoxicity, outperforming previous fluorescent probes. The cationic hemicyanine moiety drives selective mitochondrial accumulation, ensuring that the fluorescence signal specifically reports mitochondrial LACTB activity in cells. In murine models of PF and ALI (bleomycin- and LPS-induced, respectively), systemic administration of HD-LACTB enabled noninvasive lung imaging with robust, organ-specific NIR signals. The probe readily distinguished fibrotic or acutely injured lungs from normal controls by visualizing LACTB-mediated metabolic alterations, with fluorescence intensities correlating with disease severity, thereby improving diagnostic precision over prior non-targeted imaging approaches.
The development of HD-LACTB showcases a conceptual advance in probe design: a mitochondria-targeted, enzyme-responsive NIR fluorophore that bridges a critical gap in lung disease imaging. This strategy illustrates how rationally engineered chemical probes can provide unprecedented molecular specificity in vivo, heralding a new class of materials-based diagnostics for respiratory diseases. By enabling precise, noninvasive visualization of pathological processes at the organelle level, HD-LACTB paves the way for innovative diagnostic approaches in pulmonary medicine.
HD-LACTB is a hemicyanine-based Near-Infrared (NIR) fluorescent probe, whose activation is triggered by enzymatic bond cleavage. LACTB recognizes the peptide sequence within the probe and catalyzes hydrolysis at the cleavage site, releasing a free hemicyanine fluorophore and the corresponding peptide fragment. It features emission in the NIR spectrum (725 nm) for enhanced tissue penetration, along with high selectivity for LACTB and low cytotoxicity, outperforming previous fluorescent probes. The cationic hemicyanine moiety drives selective mitochondrial accumulation, ensuring that the fluorescence signal specifically reports mitochondrial LACTB activity in cells. In murine models of PF and ALI (bleomycin- and LPS-induced, respectively), systemic administration of HD-LACTB enabled noninvasive lung imaging with robust, organ-specific NIR signals. The probe readily distinguished fibrotic or acutely injured lungs from normal controls by visualizing LACTB-mediated metabolic alterations, with fluorescence intensities correlating with disease severity, thereby improving diagnostic precision over prior non-targeted imaging approaches.
The development of HD-LACTB showcases a conceptual advance in probe design: a mitochondria-targeted, enzyme-responsive NIR fluorophore that bridges a critical gap in lung disease imaging. This strategy illustrates how rationally engineered chemical probes can provide unprecedented molecular specificity in vivo, heralding a new class of materials-based diagnostics for respiratory diseases. By enabling precise, noninvasive visualization of pathological processes at the organelle level, HD-LACTB paves the way for innovative diagnostic approaches in pulmonary medicine.