title: Mathematical framework for activity-based cancer biomarkers.
abstract: Advances in nanomedicine are providing sophisticated functions to precisely control the behavior of nanoscale drugs and diagnostics. Strategies that coopt protease activity as molecular triggers are increasingly important in nanoparticle design, yet the pharmacokinetics of these systems are challenging to understand without a quantitative framework to reveal nonintuitive associations. We describe a multicompartment mathematical model to predict strategies for ultrasensitive detection of cancer using synthetic biomarkers, a class of activity-based probes that amplify cancer-derived signals into urine as a noninvasive diagnostic. Using a model formulation made of a PEG core conjugated with protease-cleavable peptides, we explore a vast design space and identify guidelines for increasing sensitivity that depend on critical parameters such as enzyme kinetics, dosage, and probe stability. According to this model, synthetic biomarkers that circulate in stealth but then activate at sites of disease have the theoretical capacity to discriminate tumors as small as 5 mm in diameter-a threshold sensitivity that is otherwise challenging for medical imaging and blood biomarkers to achieve. This model may be adapted to describe the behavior of additional activity-based approaches to allow cross-platform comparisons, and to predict allometric scaling across species.
authors.affiliation: Institute for Medical Engineering and Science, Harvard-MIT Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Kwong
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Jaideep S
authors.initials: JS
authors.lastname: Dudani
authors.affiliation: Institute for Medical Engineering and Science, Harvard-MIT Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Carrodeguas
authors.affiliation: Institute for Medical Engineering and Science, Harvard-MIT Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Eric V
authors.initials: EV
authors.lastname: Mazumdar
authors.affiliation: Institute for Medical Engineering and Science, Harvard-MIT Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Seyedeh M
authors.initials: SM
authors.lastname: Zekavat
authors.affiliation: Institute for Medical Engineering and Science, Harvard-MIT Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Howard Hughes Medical Institute, Chevy Chase, MD 20815 sbhatia@mit.edu.
authors.forename: Sangeeta N
authors.initials: SN
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D057054:Molecular Imaging / Q000379:methods*; D050997:Nanomedicine / Q000379:methods; D009374:Neoplasms, Experimental / Q000175:diagnosis* / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor
keywords: activity-based probes; cancer diagnostics; compartmental modeling; nanomedicine; urine biomarkers