| Autor: |
Gutmann M; Institute of Pharmacy and Food Chemistry, University of Würzburg, DE-97074 Würzburg, Germany., Reinhardt D; Institute of Pharmacy and Food Chemistry, University of Würzburg, DE-97074 Würzburg, Germany., Seidensticker C; Medizinische Klinik und Poliklinik Für Innere Medizin II, Klinikum Rechts der Isar der TU München, Ismaninger Str. 22, 81675 Munich, Germany., Raschig M; Institute of Pharmacy and Food Chemistry, University of Würzburg, DE-97074 Würzburg, Germany., Hahn L; Institute of Pharmacy and Food Chemistry, University of Würzburg, DE-97074 Würzburg, Germany., Moscaroli A; Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland., Behe M; Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland., Meinel L; 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., Lühmann T; Institute of Pharmacy and Food Chemistry, University of Würzburg, DE-97074 Würzburg, Germany. |
| Abstrakt: |
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. |
