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Warren, Andrew D.

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Warren

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Andrew D.

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Warren, Andrew D.
Author's Publications: search.filters.isAuthorOfPublication.80c0e50a-f2ad-44e9-b461-511d30d7611c

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    Nanoparticles That Sense Thrombin Activity As Synthetic Urinary Biomarkers of Thrombosis
    (American Chemical Society, 2013) Lin, Kevin Y.; Kwong, Gabriel A.; Warren, Andrew D.; Wood, David K.; Bhatia, Sangeeta
    Thrombin is a serine protease and regulator of hemostasis that plays a critical role in the formation of obstructive blood clots, or thrombosis, that is a life-threatening condition associated with numerous diseases such as atherosclerosis and stroke. To detect thrombi in living animals, we design and conjugate thrombin-sensitive peptide substrates to the surface of nanoparticles. Following intravenous infusion, these “synthetic biomarkers” survey the host vasculature for coagulation and, in response to substrate cleavage by thrombin, release ligand-encoded reporters into the host urine. To detect the urinary reporters, we develop a companion 96-well immunoassay that utilizes antibodies to bind specifically to the ligands, thus capturing the reporters for quantification. Using a thromboplastin-induced mouse model of pulmonary embolism, we show that urinary biomarker levels differentiate between healthy and thrombotic states and correlate closely with the aggregate burden of clots formed in the lungs. Our results demonstrate that synthetic biomarkers can be engineered to sense vascular diseases remotely from the urine and may allow applications in point-of-care diagnostics.
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    Mass-encoded synthetic biomarkers for multiplexed urinary monitoring of disease
    (2012) Kwong, Gabriel A.; von Maltzahn, Geoffrey; Murugappan, Gayathree; Abudayyeh, Omar; Mo, Steven; Papayannopoulos, Ioannis A.; Sverdlov, Deanna Y.; Liu, Susan B.; Warren, Andrew D.; Popov, Yury; Schuppan, Detlef; Bhatia, Sangeeta N.
    Biomarkers are increasingly important in the clinical management of complex diseases, yet our ability to discover new biomarkers remains limited by our dependence on endogenous molecules. Here we describe the development of exogenously administered `synthetic biomarkers' composed of mass-encoded peptides conjugated to nanoparticles that leverage intrinsic features of human disease and physiology for noninvasive urinary monitoring. These protease-sensitive agents perform three functions in vivo: target sites of disease, sample dysregulated protease activities and emit mass-encoded reporters into host urine for multiplexed detection by mass spectrometry. Using mouse models of liver fibrosis and cancer, we show that they can noninvasively monitor liver fibrosis and resolution without the need for invasive core biopsies and can substantially improve early detection of cancer compared with clinically used blood biomarkers. This approach of engineering synthetic biomarkers for multiplexed urinary monitoring should be broadly amenable to additional pathophysiological processes and to point-of-care diagnostics.