Preparation and characterization of mucus-penetrating papain/poly(acrylic acid) nanoparticles for oral drug delivery applications

  • Christiane Müller
  • Katharina Leithner
  • Sabine Hauptstein
  • Fabian Hintzen
  • Willi Salvenmoser
  • Andreas Bernkop-Schnürch
Research Paper


Particle diffusion through the intestinal mucosal barrier is restricted by the viscoelastic and adhesive properties of the mucus gel layer, preventing their penetration to the underlying absorptive endothelial cells. To overcome this natural barrier, we developed nanoparticles which have a remarkable ability to cleave mucoglycoprotein substructures responsible for the structural and rheological properties of mucus. After rheological screening of various mucolytic proteases, nanoparticles composed of poly(acrylic acid) and papain were prepared and characterized regarding particle size and zeta potential. Analysis of nanoparticles showed mean diameters sub-200 nm (162.8–198.5 nm) and negative zeta potentials advancing the mobility in mucus gel. Using diffusion chamber studies and the rotating diffusion tubes method, we compared the transport rates of papain modified (PAPC) and unaltered poly(acrylic acid) (PAA) particles through freshly excised intestinal porcine mucus. Results of the diffusion assays demonstrated strongly enhanced permeation behavior of PAPC particles owing to local mucus disruption by papain. Improved transport rates, reduction in mucus viscosity and the retarded release of hydrophilic macromolecular compounds make proteolytic enzyme functionalized nanoparticles of substantial interest for improved targeted drug delivery at mucosal surfaces. Although cytotoxicity tests of the nanoparticles could not be performed, safety of papain and PAA was already verified making PAPC particles a promising candidate in the pharmaceutical field of research. The focus of the present study was the development of particles which penetrate the mucus barrier to approach the underlying epithelium. Improvements of particles that penetrate the mucus followed by cell uptake in this direction are ongoing.


Oral drug delivery Mucus barrier Mucus-penetrating particles Poly(acrylic acid) Papain 



This study was supported by the European Commission (EC). ALEXANDER (Mucus Permeating Nanoparticulate Drug Delivery Systems) is an Integrated Project founded within the Seventh Framework Programme of the EC (Grant Agreement Number 280761).


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Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Christiane Müller
    • 1
  • Katharina Leithner
    • 1
  • Sabine Hauptstein
    • 1
  • Fabian Hintzen
    • 1
  • Willi Salvenmoser
    • 2
  • Andreas Bernkop-Schnürch
    • 1
  1. 1.Department of Pharmaceutical Technology, Institute of PharmacyCenter for Molecular Biosciences Innsbruck, University of Innsbruck, CCB—Centrum for Chemistry und BiomedicineInnsbruckAustria
  2. 2.Department for Evolutionary Developmental Biology, Institute of Zoology and Center for Molecular BiosciencesUniversity of InnsbruckInnsbruckAustria

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