AI Article Synopsis

  • Drug-induced renal failure (DIRF) is a serious condition with high mortality that is difficult to diagnose early because current methods rely on detecting late-stage biomarkers.
  • A new library of zwitterionic hemicyanines is introduced for creating activatable reporters that can detect DIRF from its initial stage by targeting the process of apoptosis.
  • An activatable reporter called ZCRR shows promise in live mice for early detection of DIRF by indicating increased caspase-8 activity, allowing for earlier diagnosis and better evaluation of treatment effectiveness.

Article Abstract

Drug-induced renal failure (DIRF) poses a serious medical complication with high mortality risk. However, early diagnosis or prognosis of DIRF remain challenging, as current methods rely on detecting late-stage biomarkers. Herein we present a library of zwitterionic unimolecular hemicyanines (ZCs) available for constructing activatable reporters to detect DIRF since its initial stage. Zwitterionic properties of these probes are achieved through interspersedly integrating alkyl sulfonates and quaternary ammonium cations onto hemicyanine skeleton, which result in record low plasma protein binding (<5 %) and remarkable renal clearance efficiencies (≈96 %). An activatable reporter ZCRR is further developed by masking the optimal candidate ZC6 with a tetrapeptide specifically cleavable by caspase-8, an initiating indicator of apoptosis. In living mice with cisplatin-induced DIRF, systematically administered ZCRR efficiently accumulates in kidneys and responds to elevated caspase-8 for near-infrared fluorescence signals 'turn-on', enabling sensitive detection of intrarenal apoptosis 60 h earlier than clinical methods, and precise evaluation of apoptosis remediation effects by different medications on DIRF mice. As it's urinary excretable, ZCRR also allows for remote detection of DIRF and predicting renoprotective efficacy through in vitro optical urinalysis. This study thus presents unimolecular renal clearable scaffolds that are applicable to developing versatile activatable reporters for renal diseases management.

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http://dx.doi.org/10.1002/anie.202315457DOI Listing

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