Mathematical Framework for Activity-based Cancer Biomarkers

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Sep 30

PMID 26417077

Citations 32

Authors

Gabriel A Kwong

Jaideep S Dudani

Emmanuel Carrodeguas

Eric V Mazumdar

Seyedeh M Zekavat

Sangeeta N Bhatia

Affiliations

Soon will be listed here.

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.

Citing Articles

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An Activity-Based Nanosensor for Minimally-Invasive Measurement of Protease Activity in Traumatic Brain Injury.

Kudryashev J, Madias M, Kandell R, Lin Q, Kwon E Adv Funct Mater. 2023; 33(28).

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References

Gaster R, Hall D, Nielsen C, Osterfeld S, Yu H, Mach K . Matrix-insensitive protein assays push the limits of biosensors in medicine. Nat Med. 2009; 15(11):1327-32. PMC: 4165514. DOI: 10.1038/nm.2032. View

Hilderbrand S, Weissleder R . Near-infrared fluorescence: application to in vivo molecular imaging. Curr Opin Chem Biol. 2009; 14(1):71-9. DOI: 10.1016/j.cbpa.2009.09.029. View

Edgington L, Verdoes M, Bogyo M . Functional imaging of proteases: recent advances in the design and application of substrate-based and activity-based probes. Curr Opin Chem Biol. 2011; 15(6):798-805. PMC: 3237724. DOI: 10.1016/j.cbpa.2011.10.012. View

Hawkins M, Soon-Shiong P, Desai N . Protein nanoparticles as drug carriers in clinical medicine. Adv Drug Deliv Rev. 2008; 60(8):876-85. DOI: 10.1016/j.addr.2007.08.044. View

Wang A, Langer R, Farokhzad O . Nanoparticle delivery of cancer drugs. Annu Rev Med. 2011; 63:185-98. DOI: 10.1146/annurev-med-040210-162544. View

Bunimovich Y, Shin Y, Yeo W, Amori M, Kwong G, Heath J . Quantitative real-time measurements of DNA hybridization with alkylated nonoxidized silicon nanowires in electrolyte solution. J Am Chem Soc. 2006; 128(50):16323-31. PMC: 3695614. DOI: 10.1021/ja065923u. View

Bremer C, Tung C, Weissleder R . In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat Med. 2001; 7(6):743-8. DOI: 10.1038/89126. View

Lin K, Kwong G, Warren A, Wood D, Bhatia S . Nanoparticles that sense thrombin activity as synthetic urinary biomarkers of thrombosis. ACS Nano. 2013; 7(10):9001-9. PMC: 3807694. DOI: 10.1021/nn403550c. View

Hauck T, Giri S, Gao Y, Chan W . Nanotechnology diagnostics for infectious diseases prevalent in developing countries. Adv Drug Deliv Rev. 2009; 62(4-5):438-48. DOI: 10.1016/j.addr.2009.11.015. View

10.

Zuckerman J, Choi C, Han H, Davis M . Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane. Proc Natl Acad Sci U S A. 2012; 109(8):3137-42. PMC: 3286910. DOI: 10.1073/pnas.1200718109. View

11.

Kummar S, Doroshow J, Tomaszewski J, Calvert A, Lobbezoo M, Giaccone G . Phase 0 clinical trials: recommendations from the Task Force on Methodology for the Development of Innovative Cancer Therapies. Eur J Cancer. 2008; 45(5):741-6. PMC: 2902269. DOI: 10.1016/j.ejca.2008.10.024. View

12.

Thurber G, Schmidt M, Wittrup K . Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Adv Drug Deliv Rev. 2008; 60(12):1421-34. PMC: 2820307. DOI: 10.1016/j.addr.2008.04.012. View

13.

Danino T, Prindle A, Kwong G, Skalak M, Li H, Allen K . Programmable probiotics for detection of cancer in urine. Sci Transl Med. 2015; 7(289):289ra84. PMC: 4511399. DOI: 10.1126/scitranslmed.aaa3519. View

14.

La Thangue N, Kerr D . Predictive biomarkers: a paradigm shift towards personalized cancer medicine. Nat Rev Clin Oncol. 2011; 8(10):587-96. DOI: 10.1038/nrclinonc.2011.121. View

15.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

16.

Kessenbrock K, Plaks V, Werb Z . Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010; 141(1):52-67. PMC: 2862057. DOI: 10.1016/j.cell.2010.03.015. View

17.

Warren A, Kwong G, Wood D, Lin K, Bhatia S . Point-of-care diagnostics for noncommunicable diseases using synthetic urinary biomarkers and paper microfluidics. Proc Natl Acad Sci U S A. 2014; 111(10):3671-6. PMC: 3956200. DOI: 10.1073/pnas.1314651111. View

18.

Park J, von Maltzahn G, Zhang L, Derfus A, Simberg D, Harris T . Systematic surface engineering of magnetic nanoworms for in vivo tumor targeting. Small. 2009; 5(6):694-700. PMC: 3058937. DOI: 10.1002/smll.200801789. View

19.

Heesakkers R, Jager G, Hovels A, de Hoop B, van den Bosch H, Raat F . Prostate cancer: detection of lymph node metastases outside the routine surgical area with ferumoxtran-10-enhanced MR imaging. Radiology. 2009; 251(2):408-14. DOI: 10.1148/radiol.2512071018. View

20.

Schima W, Kulinna C, Langenberger H, Ba-Ssalamah A . Liver metastases of colorectal cancer: US, CT or MR?. Cancer Imaging. 2005; 5 Spec No A:S149-56. PMC: 1665297. DOI: 10.1102/1470-7330.2005.0035. View