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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. Keywords: activity-based nanosensors; diagnostic biomarkers; prognostic biomarkers; prostate cancer; proteolytic enzymes.
Conflict of interest statement: J. Development of ABN library responsive to selected metalloproteinases and serine proteases. Please enable it to take advantage of the complete set of features!
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Figures Fig. In silico identification of candidate…. In silico identification of candidate proteases for an ABN library. A Project workflow. Protease targets were identified, substrates were deed and tested, and ABNs were generated to evaluate in vivo and for further translational development.
Gleason 6 samples Indolent. Hits from each analysis are shown in red. D and E : log-rank T test. Experimental validation of increased protease…. Experimental validation of increased protease abundance and activity in PCa. E and F TMA staining score of both proteases. Data shown represent combined samples and substrates with paired cleavage data.
Development of ABN library responsive…. A Hierarchical clustering was used to identify similarly cleaved substrates, which were subsequently eliminated for a second screen red x. B Different nanoparticle formulations were injected i. Scale bar: 1 cm. C Selected substrates were coupled to PEG and exposed to recombinant proteases, and cleavage data across the 26 PEG-peptide conjugates were z -scored and clustered, as above.
D Each substrate was ased an MP and SP score based on mean cleavage of each substrate across proteases in the family. Evaluation of prostate plex ABN….
Evaluation of prostate plex ABN library in vitro and in vivo. B Matrigel invasion assay performed with PC3 and 22Rv1 cells. PI, protease Inhibitor mixture. E Ex vivo cleavage al of the T7 reporter by 22Rv1 tumor homogenates. F Aggregate urine al after injection of the full plex library with mass-encoded barcodes in mice bearing PC3-derived xenografts. G Mean normalized reporter al changes from healthy mice were calculated, and the difference between PC3 and 22Rv1 is plotted for each reporter.
Integrin-targeting of a subset of…. Integrin-targeting of a subset of ABN library for increased sensitivity. G Urine al from the mice shown in E and F presented for each of the three-plex substrates. See this image and copyright information in PMC.
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