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Renal clearable polyfluorophore nanosensors for early diagnosis of cancer and allograft rejection

Nature Materials volume 21, pages 598–607 (2022)Cite this article

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Abstract

Optical nanoparticles are promising diagnostic tools; however, their shallow optical imaging depth and slow clearance from the body have impeded their use for in vivo disease detection. To address these limitations, we develop activatable polyfluorophore nanosensors with biomarker-triggered nanoparticle-to-molecule pharmacokinetic conversion and near-infrared fluorogenic turn-on response. Activatable polyfluorophore nanosensors can accumulate at the disease site and react with disease-associated proteases to undergo in situ enzyme-catalysed depolymerization. This disease-specific interaction liberates renal-clearable fluorogenic fragments from activatable polyfluorophore nanosensors for non-invasive longitudinal urinalysis and outperforms the gold standard blood and urine assays, providing a level of sensitivity and specificity comparable to those of invasive biopsy and flow cytometry analysis. In rodent models, activatable polyfluorophore nanosensors enable ultrasensitive detection of tumours (1.6 mm diameter) and early diagnosis of acute liver allograft rejection. We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test.

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Fig. 1: Design and mechanisms of renal-clearable polyfluorophore nanosensors for early diagnosis of cancer and acute liver allograft rejection.
Fig. 2: In vitro sensing evaluation of APNs.
Fig. 3: Biodistribution and clearance pathway of APNs and their activated fragments.
Fig. 4: Real-time imaging and urinalysis of orthotopic liver cancer.
Fig. 5: Real-time imaging and longitudinal urinalysis of acute immune-mediated hepatitis.
Fig. 6: Longitudinal optical urinalysis of acute liver allograft rejection in living rats.

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Data availability

Source data are provided with this paper. The authors declare that data generated or analysed during this study are provided as source data or included in the Supplementary Information. Further data are available from the corresponding authors upon request.

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Acknowledgements

K.P. thanks the Ministry of Education Singapore, Academic Research Fund Tier 1 (2019-T1-002-045 RG125/19 and RT05/20) and Academic Research Fund Tier 2 (MOE2018-T2-2-042 and MOE-T2EP30220-0010) for financial support. H.W. thanks the Zhejiang Provincial Natural Science Foundation of China (LR19H160002) and the National Natural Science Foundation of China (82073296 and 81773193) for financial support.

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Authors and Affiliations

  1. School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, Singapore

    Jiaguo Huang, Yuyan Jiang, Chi Zhang, Shasha He & Kanyi Pu

  2. The First Affiliated Hospital, Zhejiang University School of Medicine; NHC Key Laboratory of Combined Multi-Organ Transplantation; Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou, P. R. China

    Xiaona Chen & Hangxiang Wang

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Contributions

J.H. and K.P. conceived and designed the study. J.H. performed the probe synthesis and in vivo experiments. X.C., Y.J. and J.H. performed the flow cytometry and histology experiments. Y.J., C.Z. and S.H. performed cell imaging experiments. J.H., H.W. and K.P. analysed the data. J.H. and K. P. drafted the manuscript. All authors contributed to the writing of this article.

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Correspondence to Kanyi Pu.

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Nature Materials thanks Hak Soo Choi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–38 and Tables 1–3.

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Source data

Source Data Fig. 2

Data for spectrum, selectivity studies, HPLC spectrum and so on.

Source Data Fig. 3

Data for NIRF intensity in liver and kidney, residual probes in livers and blood, clearance efficiencies and so on.

Source Data Fig. 4

Data for NIRF intensity in urine, liver and kidneys, data for liver and kidney function tests and so on.

Source Data Fig. 5

Data for NIRF intensity of liver and kidneys, signal enhancement in urine, flow cytometry and cytokines and so on.

Source Data Fig. 6

Data for NIRF intensity in urine, liver and kidneys, data for ROC curves and so on.

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Huang, J., Chen, X., Jiang, Y. et al. Renal clearable polyfluorophore nanosensors for early diagnosis of cancer and allograft rejection. Nat. Mater. 21, 598–607 (2022). https://doi.org/10.1038/s41563-022-01224-2

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