Molecular optical imaging probes for early diagnosis of drug-induced acute kidney injury

Abstract

Drug-induced acute kidney injury (AKI) with a high morbidity and mortality is poorly diagnosed in hospitals and deficiently evaluated in drug discovery. Here, we report the development of molecular renal probes (MRPs) with high renal clearance efficiency for in vivo optical imaging of drug-induced AKI. MRPs specifically activate their near-infrared fluorescence or chemiluminescence signals towards the prodromal biomarkers of AKI including the superoxide anion, N-acetyl-β-d-glucosaminidase and caspase-3, enabling an example of longitudinal imaging of multiple molecular events in the kidneys of living mice. Importantly, they in situ report the sequential occurrence of oxidative stress, lysosomal damage and cellular apoptosis, which precedes clinical manifestation of AKI (decreased glomerular filtration). Such an active imaging mechanism allows MRPs to non-invasively detect the onset of cisplatin-induced AKI at least 36 h earlier than the existing imaging methods. MRPs can also act as exogenous tracers for optical urinalysis that outperforms typical clinical/preclinical assays, demonstrating their clinical promise for early diagnosis of AKI.

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Fig. 1: Design and mechanisms of MRPs for molecular imaging and early detection of drug-induced AKI
Fig. 2: In vitro evaluation of the sensing capabilities of the MRPs.
Fig. 3: Renal clearance and in vivo stability studies of MRPs and the uncaged fluorophores.
Fig. 4: Real-time in vivo NIRF imaging of cisplatin-induced AKI.
Fig. 5: Real-time in vivo dual-channel imaging of cisplatin-induced AKI.
Fig. 6: In vitro diagnosis of drug-induced AKI in living mice.

Data availability

The authors declare that all relevant data supporting the findings of this study are available within the article and in the Supplementary Information, or from the corresponding author on reasonable request.

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Acknowledgements

K.P. thanks Nanyang Technological University (startup grant: M4081627) and Singapore Ministry of Education, Academic Research Fund Tier 1 (2017–T1–002–134–RG147/17) and Academic Research Fund Tier 2 (MOE2016–T2–1–098) for the financial support.

Author information

K.P. and J.H. conceived and designed the study. J.H. and Q.M. performed the probe synthesis experiments. J.H. performed the in vivo experiments. J.H, J.L. and Y.L. performed the histology experiments. K.P. and J.H. contributed to the analysis and interpretation of the results and the writing of the manuscript.

Correspondence to Kanyi Pu.

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Supplementary Figs. 1–38, Supplementary Tables 1–7 and Supplementary refs. 1–11.

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