Ultrasensitive tumour-penetrating nanosensors of protease activity
Publication Type:
Journal Article
Authors:
Kwon†, Ester J.; Dudani, Jaideep S.†; Bhatia, Sangeeta N.
Source:
Nature Biomedical Engineering, Volume 1, p.0054 (2017)
URL:
http://www.nature.com/articles/s41551-017-0054
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 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.
