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Mass-Encoded Reporters Reporting Proteolytic Activity from within the Extracellular Matrix

  • Katharina Dodt
    Katharina Dodt
    Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
  • Stephanie Lamer
    Stephanie Lamer
    Rudolf-Virchow-Center for Experimental Biomedicine, University of Wuerzburg, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany
  • Marc Drießen
    Marc Drießen
    Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
  • Sebastian Bölch
    Sebastian Bölch
    Department for Orthopedic Surgery, Koenig-Ludwig-Haus, University of Wuerzburg, Brettreichstrasse 11, 97074 Wuerzburg, Germany
  • Andreas Schlosser
    Andreas Schlosser
    Rudolf-Virchow-Center for Experimental Biomedicine, University of Wuerzburg, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany
  • Tessa Lühmann
    Tessa Lühmann
    Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
  • , and 
  • Lorenz Meinel*
    Lorenz Meinel
    Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
    *Email: [email protected]. Fax: +49 931/31-832650.
Cite this: ACS Biomater. Sci. Eng. 2020, 6, 9, 5240–5253
Publication Date (Web):July 30, 2020
https://doi.org/10.1021/acsbiomaterials.0c00691
Copyright © 2020 American Chemical Society

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    Abstract

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    Reporting matrix metalloproteinase (MMP) activity directly from the extracellular matrix (ECM) may provide critical insights to better characterize 2D and 3D cell culture model systems of inflammatory diseases and potentially leverage in vivo diagnosis. In this proof-of-concept study, we designed MMP-sensors, which were covalently linked onto the ECM by co-administration of the activated transglutaminase factor XIIIa (FXIIIa). Elements of the featured MMP-sensors are the D-domain of insulin-like growth factor I (IGF-I) through which co-administered FXIIIa covalently links the sensor to the ECM followed by an MMP sensitive peptide sequence and locally reporting on MMP activity, an isotopically labeled mass tag encoding for protease activity, and an affinity tag facilitating purification from fluids. All sensors come in identical pairs, other than the MMP sensitive peptide sequence, which is synthesized with l-amino acids or d-amino acids, the latter serving as internal standard. As a proof of concept for multiplexing, we successfully profiled two MMP-sensors with different MMP sensitive peptide sequences reporting MMP activity directly from an engineered 3D ECM. Future use may include covalently ECM bound diagnostic depots reporting MMP activity from inflamed tissues.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsbiomaterials.0c00691.

    • Figure S1: Purity and identification of reporter peptides by RP-HPLC and ESI; Figure S2: RP-HPLC and MALDI of L-MMP substrate sequence 1 in presence of MMPs; Figure S3: RP-HPLC and MALDI of L- and D-MMP substrate sequence 1 in the presence of MMPs; Figure S4: RP-HPLC and MALDI of L MMP substrate sequence 2 in the presence of MMPs; Figure S5: RP-HPLC and MALDI of L- and D-MMP substrate sequence 2 in the presence of MMPs; Figure S6: Confocal images of reporter pair 1 on the ECM; Figure S7: Confocal images of reporter pair 2 on the ECM; Figure S8: Time-dependent cleavage of the photolabile linker; Figure S9: MALDI spectra of the N-terminal part of L-reporter 2 after UV irradiation Figure S10: RP-HPLC and ESI of reporter pair 1 and 2 after incubation with TEV protease; Figure S11: Base peak chromatograms and MS2 spectra of S1–S3; Figure S12: MS2 spectra of reporter pair 1 and 2 (PDF)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 6 publications.

    1. Björn ter Mors, Valerie Spieler, Eduardo Merino Asumendi, Benedikt Gantert, Tessa Lühmann, Lorenz Meinel. Bioresponsive Cytokine Delivery Responding to Matrix Metalloproteinases. ACS Biomaterials Science & Engineering 2024, 10 (1) , 29-37. https://doi.org/10.1021/acsbiomaterials.2c01320
    2. Dorothee Haas, Niklas Hauptstein, Michael Dirauf, Marc D. Driessen, Matthias Ruopp, Ulrich S. Schubert, Tessa Lühmann, Lorenz Meinel. Chemo-Enzymatic PEGylation/POxylation of Murine Interleukin-4. Bioconjugate Chemistry 2022, 33 (1) , 97-104. https://doi.org/10.1021/acs.bioconjchem.1c00495
    3. Katharina Dodt, Marc D. Driessen, Stephanie Lamer, Andreas Schlosser, Tessa Lühmann, Lorenz Meinel. A Complete and Versatile Protocol: Decoration of Cell-Derived Matrices with Mass-Encoded Peptides for Multiplexed Protease Activity Detection. ACS Biomaterials Science & Engineering 2020, 6 (12) , 6598-6617. https://doi.org/10.1021/acsbiomaterials.0c01134
    4. Prisca Hamm, Lorenz Meinel, Denise Beckmann, Rafael Worschech, Alexandra Braun, Marcus Gutmann, Adelheid Korb-Pap, Tessa Lühmann, Thomas Pap. Transglutaminase-Catalyzed Covalent Anti-Myostatin Peptide Depots. 2024https://doi.org/10.2139/ssrn.4801105
    5. Chi Wang, Han-Shi Zeng, Kai-Xuan Liu, Yi-Na Lin, Hao Yang, Xin-Ying Xie, Dai-Xu Wei, Jian-Wen Ye. Biosensor-based therapy powered by synthetic biology. Smart Materials in Medicine 2023, 4 , 212-224. https://doi.org/10.1016/j.smaim.2022.10.003
    6. Lukas Hahn, Matthias Beudert, Marcus Gutmann, Larissa Keßler, Philipp Stahlhut, Lena Fischer, Emine Karakaya, Thomas Lorson, Ingo Thievessen, Rainer Detsch, Tessa Lühmann, Robert Luxenhofer. From Thermogelling Hydrogels toward Functional Bioinks: Controlled Modification and Cytocompatible Crosslinking. Macromolecular Bioscience 2021, 21 (10) https://doi.org/10.1002/mabi.202100122

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