Nephrotoxicity

Sanz, Ana B.; Sanchez-Niño, María Dolores; Ramos, Adrián M.; Ortíz, Alberto

doi:10.1002/9781119329725.ch10

“…Hence, unimolecular probes with homogeneous yet non‐degradable renal clearance tails offer greater promise for scalable production and clinical translation, whereas their molecular design warrants further study. On another note, existing activatable renal probes primarily target caspase3/7 which act downstream in apoptosis, [30] whereas very few efforts have been devoted to detecting the most upstream protease caspase‐8 (Casp8) in vivo [31] …”

Section: Introductionmentioning

confidence: 99%

“…On another note, existing activatable renal probes primarily target caspase3/7 which act downstream in apoptosis, [30] whereas very few efforts have been devoted to detecting the most upstream protease caspase-8 (Casp8) in vivo. [31] Herein we report a library of highly renal-clearable zwitterionic unimolecular hemicyanines (named ZCs) amenable to constructing activatable NIRF reporters for early diagnosis and prognostic assessment of DIRF (Figure 1). Instead of hydrophilic polymers, zwitterionic tails comprising diverse combinations of alkyl sulfonates/heptanoates and quaternary ammonium cations (quats) are integrated onto hemicyanine scaffolds to balance charge density, increase hydrophilicity and reduce protein adsorption.…”

Section: Introductionmentioning

confidence: 99%

Tailored Zwitterionic Hemicyanine Reporters for Early Diagnosis and Prognostic Assessment of Acute Renal Failure

Zhou,

Zhu,

Liu

et al. 2023

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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 ammo‐nium 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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Tailored Zwitterionic Hemicyanine Reporters for Early Diagnosis and Prognostic Assessment of Acute Renal Failure

Zhou,

Zhu,

Liu

et al. 2023

Angewandte Chemie

0

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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 ammo‐nium 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.

show abstract