title: Matrix Metalloproteinase Responsive Delivery of Myostatin Inhibitors.
abstract: The inhibition of myostatin - a member of the transforming growth factor (TGF-β) family - drives regeneration of functional skeletal muscle tissue. We developed a bioresponsive drug delivery system (DDS) linking release of a myostatin inhibitor (MI) to inflammatory flares of myositis to provide self-regulated MI concentration gradients within tissues of need.
  
  
  
  A protease cleavable linker (PCL) - responding to MMP upregulation - is attached to the MI and site-specifically immobilized on microparticle surfaces.
  
  
  
  The PCL disintegrated in a matrix metalloproteinase (MMP) 1, 8, and particularly MMP-9 concentration dependent manner, with MMP-9 being an effective surrogate biomarker correlating with the activity of myositis. The bioactivity of particle-surface bound as well as released MI was confirmed by luciferase suppression in stably transfected HEK293 cells responding to myostatin induced SMAD phosphorylation.
  
  
  
  We developed a MMP-responsive DDS for MI delivery responding to inflammatory flare of a diseased muscle matching the kinetics of MMP-9 upregulation, with MMP-9 kinetics matching (patho-) physiological myostatin levels. ᅟ: Graphical Abstract Schematic illustration of the matrix metalloproteinase responsive delivery system responding to inflammatory flares of muscle disease. The protease cleavable linker readily disintegrates upon entry into the diseased tissue, therby releasing the mystatin inhibitor.
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, DE-97074, Würzburg, Germany.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Braun
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, DE-97074, Würzburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Gutmann
authors.affiliation: Orthopedic Center for Musculoskeletal Research, University of Würzburg, Friedrich-Bergius-Ring 15, 97076, Würzburg, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Ebert
authors.affiliation: Orthopedic Center for Musculoskeletal Research, University of Würzburg, Friedrich-Bergius-Ring 15, 97076, Würzburg, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Jakob
authors.affiliation: GILYOS GmbH, Friedrich-Bergius-Ring 15, 97076, Würzburg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Gieseler
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, DE-97074, Würzburg, Germany.
authors.forename: Tessa
authors.initials: T
authors.lastname: Lühmann
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, DE-97074, Würzburg, Germany. lorenz.meinel@uni-wuerzburg.de.
authors.forename: Lorenz
authors.identifier: 0000-0002-7549-7627
authors.initials: L
authors.lastname: Meinel
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009220:Myositis / Q000188:drug therapy / Q000378:metabolism; D055435:Myostatin / Q000037:antagonists & inhibitors*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D011480:Protease Inhibitors / Q000008:administration & dosage*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D055435:Myostatin; D004364:Pharmaceutical Preparations; D011480:Protease Inhibitors; D016212:Transforming Growth Factor beta; D020782:Matrix Metalloproteinases
keywords: bioorthogonal chemistry; bioresponsive drug delivery; controlled release; myostatin; protease cleavable linker