Pharmaceutical Research

, Volume 34, Issue 1, pp 58–72 | Cite as

Matrix Metalloproteinase Responsive Delivery of Myostatin Inhibitors

  • Alexandra C. Braun
  • Marcus Gutmann
  • Regina Ebert
  • Franz Jakob
  • Henning Gieseler
  • Tessa Lühmann
  • Lorenz Meinel
Research Paper



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.

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.


bioorthogonal chemistry bioresponsive drug delivery controlled release myostatin protease cleavable linker 



Activin receptor IIB


Arbitrary units


Bicinchoninic acid


Bovine serum albumin


Copper(I)-catalyzed azide-alkyne cycloaddition




Drug delivery system


Differentiation medium


Duchenne muscular dystrophy


Extracellular matrix






Growth differentiation factor 8


High-performance liquid chromatography


Insulin-like growth factor I


Interleukin 1β


Matrix-assisted laser desorption ionization mass spectrometry


Myostatin inhibitor


Matrix metalloproteinase




Myosin heavy chain


Nuclear factor-kappa B




Protease cleavable linker


Polyethylene glycol


Poly(methyl methacrylate)


Relative light unit


Real time polymerase chain reaction


SMAD binding element


Satellite cell


Strain-promoted azide-alkyne cycloaddition


Solid phase peptide synthesis


Transglutaminase (human, fXIIIa)


Transforming growth factor beta




Tumor necrosis factor α



We thank Petra Knaus (Freie Universität Berlin, Germany) for providing us with the pGl3ti-SBE constructs and Melanie Krug for excellent technical assistance. We thank Dr. Joachim Nickel for providing C2C12 myoblast cells. The financial support of the Bavarian research foundation (grant # AZ-1044-12 ‘FORMOsA’) and the Deutsche Forschungsgemeinschaft (DFG; ME 3820/3-1) are gratefully acknowledged. H.G. is full time associate of Gilyos GmbH.

Supplementary material

11095_2016_2038_MOESM1_ESM.pdf (779 kb)
ESM 1 (PDF 779 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Institute for Pharmacy and Food ChemistryUniversity of WürzburgWürzburgGermany
  2. 2.Orthopedic Center for Musculoskeletal ResearchUniversity of WürzburgWürzburgGermany
  3. 3.GILYOS GmbHWürzburgGermany

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