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Matrix Metalloproteinase-Responsive Delivery of PEGylated Fibroblast Growth Factor 2
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    Matrix Metalloproteinase-Responsive Delivery of PEGylated Fibroblast Growth Factor 2
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    • Marcus Gutmann
      Marcus Gutmann
      Institute of Pharmacy and Food Chemistry, University of Würzburg, DE-97074 Würzburg, Germany
    • Debora Reinhardt
      Debora Reinhardt
      Institute of Pharmacy and Food Chemistry, University of Würzburg, DE-97074 Würzburg, Germany
    • Christian Seidensticker
      Christian Seidensticker
      Medizinische Klinik und Poliklinik Für Innere Medizin II, Klinikum Rechts der Isar der TU München, Ismaninger Str. 22, 81675 Munich, Germany
    • Martina Raschig
      Martina Raschig
      Institute of Pharmacy and Food Chemistry, University of Würzburg, DE-97074 Würzburg, Germany
    • Lukas Hahn
      Lukas Hahn
      Institute of Pharmacy and Food Chemistry, University of Würzburg, DE-97074 Würzburg, Germany
      More by Lukas Hahn
    • Alessandra Moscaroli
      Alessandra Moscaroli
      Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland
    • Martin Behe
      Martin Behe
      Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland
      More by Martin Behe
    • Lorenz Meinel
      Lorenz Meinel
      Institute of Pharmacy and Food Chemistry, University of Würzburg, DE-97074 Würzburg, Germany
      Helmholtz Institute for RNA-Based Infection Research (HIRI), Helmholtz Center for Infection Research (HZI), DE-97080 Würzburg, Germany
    • Tessa Lühmann*
      Tessa Lühmann
      Institute of Pharmacy and Food Chemistry, University of Würzburg, DE-97074 Würzburg, Germany
      *Email: [email protected]. Tel.: +49 931 318 28 07. Fax: +49 931 318 46 08.
    Other Access OptionsSupporting Information (4)

    ACS Biomaterials Science & Engineering

    Cite this: ACS Biomater. Sci. Eng. 2024, 10, 1, 156–165
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    https://doi.org/10.1021/acsbiomaterials.3c01511
    Published November 21, 2023
    Copyright © 2023 American Chemical Society

    Abstract

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    Attachment of polyethylene glycol (PEG) chains is a common, well-studied, and Food and Drug Administration-approved method to address the pharmacokinetic challenges of therapeutic proteins. Occasionally, PEGylation impairs the activity of pharmacodynamics (PD). To overcome this problem, disease-relevant cleavable linkers between the polymer and the therapeutic protein can unleash full PD by de-PEGylating the protein at its target site. In this study, we engineered a matrix metalloproteinase (MMP)-responsive fibroblast growth factor 2 (FGF-2) mutant that was site-specifically extended with a PEG polymer chain. Using bioinspired strategies, the bioconjugate was designed to release the native protein at the desired structure/environment with preservation of the proliferative capacity in vitro on NIH3T3 cells. In vivo, hepatic exposure was diminished but not its renal distribution over time compared to unconjugated FGF-2. By releasing the growth factor from the PEG polymer in response to MMP cleavage, restored FGF-2 may enter hard-to-reach tissues and activate cell surface receptors or nuclear targets.

    Copyright © 2023 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsbiomaterials.3c01511.

    • Synthesis scheme and 1H-NMR spectrum of azido-lysine, RP-HPLC and mass spectrometry of N3–8(TAG)-PSL-FGF-2 and cleaved FGF-2, purification of PEG-PSL-FGF-2 and cleaved-FGF-2, cleavage of PEG-PSL-FGF-2 over time, and ERK/pERK Western blot after treatment with FGF-2 derivates (PDF)

    • Animated SPECT images for PEG-PSL-FGF-2 for 4 h(MP4)

    • Animated SPECT images for PEG-PSL-FGF-2 for 24 h(MP4)

    • Animated SPECT images for PEG-PSL-FGF-2 for 48 h(MP4)

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    ACS Biomaterials Science & Engineering

    Cite this: ACS Biomater. Sci. Eng. 2024, 10, 1, 156–165
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsbiomaterials.3c01511
    Published November 21, 2023
    Copyright © 2023 American Chemical Society

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