Ultrasensitive tumour-penetrating nanosensors of protease activity
Name
nihms856834.pdf
Description
Accepted version
Size
2.65 MB
Format
Adobe PDF
Checksum (MD5)
f2c2d289919a065cf5ac055d864d7ba6
Author(s)
Kwon, Ester J
Dudani, Jaideep S
Bhatia, Sangeeta N
Date Issued
2017
Journal
Nature Biomedical Engineering
Publisher
Springer Science and Business Media LLC
Version
Author's final manuscript
Abstract
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Howard Hughes Medical Institute
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
10.1038/S41551-017-0054
https://doi.org/10.1038/S41551-017-0054
