Ultrasensitive tumour-penetrating nanosensors of protease activity

Ultrasensitive tumour-penetrating nanosensors of protease activity


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ABSTRACT The ability to identify cancer lesions with endogenous biomarkers is currently limited to tumours ~1 cm in diameter. We recently reported an exogenously administered


tumour-penetrating nanosensor that sheds, in response to tumour-specific proteases, peptide fragments that can then be detected in the urine. Here, we report the optimization, informed by a


pharmacokinetic mathematical model, of the surface presentation of the peptide substrates to both enhance on-target protease cleavage and minimize off-target cleavage, and of the


functionalization of the nanosensors with tumour-penetrating ligands that engage active trafficking pathways to increase activation in the tumour microenvironment. The resulting nanosensor


discriminated sub-5 mm lesions in human epithelial tumours and detected nodules with median diameters smaller than 2 mm in an orthotopic model of ovarian cancer. We also demonstrate enhanced


receptor-dependent specificity of signal generation in the urine in an immunocompetent model of colorectal liver metastases, and _in situ_ activation of the nanosensors in human tumour


microarrays when re-engineered as fluorogenic zymography probes. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution


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subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS MICROENVIRONMENT-TRIGGERED MULTIMODAL PRECISION DIAGNOSTICS Article 15 July 2021 RENAL


CLEARABLE POLYFLUOROPHORE NANOSENSORS FOR EARLY DIAGNOSIS OF CANCER AND ALLOGRAFT REJECTION Article 14 April 2022 AND-GATED PROTEASE-ACTIVATED NANOSENSORS FOR PROGRAMMABLE DETECTION OF


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engineering of magnetic nanoworms for _in vivo_ tumor targeting. _Small_ 5, 694–700 (2009). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank H. Fleming (MIT) for


critical editing of the manuscript, and A. Warren (MIT), G. Kwong (Georgia Institute of Technology), J. Voog (MIT, Massachusetts General Hospital), V. Ramanan and C. Buss (MIT) for helpful


discussion. We are grateful to the Koch Institute Swanson Biotechnology Core at MIT, especially S. Malstrom, K. Cormier and veterinary pathologist R. T. Bronson. This study was supported in


part by a Koch Institute Support Grant P30-CA14051 from the National Cancer Institute (Swanson Biotechnology Center), a Core Center Grant P30-ES002109 from the National Institute of


Environmental Health Sciences, the Ludwig Fund for Cancer Research, and the Koch Institute Marble Center for Cancer Nanomedicine. E.J.K. acknowledges support from the Ruth L. Kirschstein


National Research Service Award (1F32CA177094-01). J.S.D. thanks the National Science Foundation Graduate Research Fellowship Program for support. S.N.B. is a Howard Hughes Institute


Investigator. AUTHOR INFORMATION Author notes * Ester J. Kwon and Jaideep S. Dudani: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Koch Institute for Integrative


Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, 02139, Massachusetts, USA. Ester J. Kwon, Jaideep S. Dudani & Sangeeta N. Bhatia * Harvard–MIT Division of


Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA. Ester J. Kwon & Sangeeta N.


Bhatia * Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA. Jaideep S. Dudani * Department of Electrical Engineering and


Computer Science, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA. Sangeeta N. Bhatia * Department of Medicine, Brigham and Women’s Hospital and Harvard Medical


School, Boston, 02115, Massachusetts, USA. Sangeeta N. Bhatia * Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, 02139, Massachusetts, USA. Sangeeta N. Bhatia


* Howard Hughes Medical Institute, Cambridge, 02139, Massachusetts, USA. Sangeeta N. Bhatia Authors * Ester J. Kwon View author publications You can also search for this author inPubMed 


Google Scholar * Jaideep S. Dudani View author publications You can also search for this author inPubMed Google Scholar * Sangeeta N. Bhatia View author publications You can also search for


this author inPubMed Google Scholar CONTRIBUTIONS E.J.K. and J.S.D. performed the experiments and analysed the data. E.J.K., J.S.D. and S.N.B. designed the experiments and wrote the


manuscript. CORRESPONDING AUTHOR Correspondence to Sangeeta N. Bhatia. ETHICS DECLARATIONS COMPETING INTERESTS The authors are listed as inventors on patent applications related to the


content of this work. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION Supplementary text, figures and references. (PDF 12491 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT


THIS ARTICLE CITE THIS ARTICLE Kwon, E., Dudani, J. & Bhatia, S. Ultrasensitive tumour-penetrating nanosensors of protease activity. _Nat Biomed Eng_ 1, 0054 (2017).


https://doi.org/10.1038/s41551-017-0054 Download citation * Received: 14 August 2016 * Accepted: 01 March 2017 * Published: 10 April 2017 * DOI: https://doi.org/10.1038/s41551-017-0054 SHARE


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