Leveraging Novel Unimolecular Renal-Clearable Fluorophores for Developing Activatable Probes for Imaging Rhabdomyolysis-Induced Acute Kidney Injury

Effective monitoring of the physiological progression of rhabdomyolysis-induced acute kidney injury (RAKI) is crucial for early therapeutic interventions. Especially, the near-infrared activatable fluorescent probe can potentially provide high-resolution imaging through sensitive analyte detection. However, the complex synthesis process of the reported kidney-imaging fluorophores restricts their practical application in the development of an activatable probe for RAKI imaging. Herein, a novel renal-clearable hemicyanine fluorophore (HA) featuring a positive charge and a facile synthesis route was first developed by replacing methine with quaternary ammonium cations. A structure-property study revealed that the renal clearance of HA was strongly associated with good blood circulation enabled by positive charge-regulated amphiphilicity and positive charge-mediated electrostatic interactions. Leveraging the tunable optical properties of fluorophore HA, an activatable probe (HA-G) with a prominent glutathione response (GSH) was constructed for evaluating RAKI. Notably, the probe HA-G exhibited high selectivity and sensitivity toward GSH detection in vitro and in living cells. More importantly, probe HA-G can be further used to assess RAKI and drug-induced kidney injury through the dynamic fluorescence signal response that correlates with changes in GSH levels. This study not only presents a novel kidney-clearable imaging platform HA, but also highlights an activatable probe capable of elucidating the pathological progression of different kidney diseases.