Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 36, Pages 8954-8959Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1805337115
Keywords
activity-based nanosensors; proteolytic enzymes; prostate cancer; diagnostic biomarkers; prognostic biomarkers
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Funding
- Janssen Research Development
- Koch Institute Support Grant from the National Cancer Institute (Swanson Biotechnology Center) [P30-CA14051]
- National Institute of Environmental Health Sciences [P30-ES002109]
- Ludwig Fund for Cancer Research
- Koch Institute Marble Center for Cancer Nanomedicine
- Ludwig Center fellowship
- National Science Foundation Graduate Research Fellowships Program
- NATIONAL CANCER INSTITUTE [P30CA014051] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [P30ES002109] Funding Source: NIH RePORTER
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Improved biomarkers are needed for prostate cancer, as the current gold standards have poor predictive value. Tests for circulating prostate-specific antigen (PSA) levels are susceptible to various noncancer comorbidities in the prostate and do not provide prognostic information, whereas physical biopsies are invasive, must be performed repeatedly, and only sample a fraction of the prostate. Injectable biosensors may provide a new paradigm for prostate cancer biomarkers by querying the status of the prostate via a noninvasive readout. Proteases are an important class of enzymes that play a role in every hallmark of cancer; their activities could be leveraged as biomarkers. We identified a panel of prostate cancer proteases through transcriptomic and proteomic analysis. Using this panel, we developed a nanosensor library that measures protease activity in vitro using fluorescence and in vivo using urinary readouts. In xenograft mouse models, we applied this nanosensor library to classify aggressive prostate cancer and to select predictive substrates. Last, we coformulated a subset of nanosensors with integrin-targeting ligands to increase sensitivity. These targeted nanosensors robustly classified prostate cancer aggressiveness and outperformed PSA. This activity-based nanosensor library could be useful throughout clinical management of prostate cancer, with both diagnostic and prognostic utility.
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