Sustained gastrointestinal activity of dendronized polymer–enzyme conjugates

  • A Corrigendum to this article was published on 19 February 2016

Abstract

Methods to stabilize and retain enzyme activity in the gastrointestinal tract are investigated rarely because of the difficulty of protecting proteins from an environment that has evolved to promote their digestion. Preventing the degradation of enzymes under these conditions, however, is critical for the development of new protein-based oral therapies. Here we show that covalent conjugation to polymers can stabilize orally administered therapeutic enzymes at different locations in the gastrointestinal tract. Architecturally and functionally diverse polymers are used to protect enzymes sterically from inactivation and to promote interactions with mucin on the stomach wall. Using this approach the in vivo activity of enzymes can be sustained for several hours in the stomach and/or in the small intestine. These findings provide new insight and a firm basis for the development of new therapeutic and imaging strategies based on orally administered proteins using a simple and accessible technology.

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Figure 1: Gastric stabilization and retention of exogenous enzymes by polymer modification.
Figure 2: In vitro and in vivo characterization of mucoadhesion of dendronized polymer (PG1) and PDL.
Figure 3: Stability and activity of a PEP from MX and MX–polymer conjugates in simulated GI tract conditions.
Figure 4: In vivo activity of a PEP from MX and MX–polymer conjugates.
Figure 5: Activity of a PEP from MX conjugated to a dendronized polymer (MX–PG1) in the stomach.

Change history

  • 21 January 2016

    In the version of this Article originally published, the concentration of trypsin and chymotrypsin in the Methods section 'In vivo imaging of enzyme activity' should have read "0.4 mg ml-1 in 50 mM phosphate buffer pH 7". This error does not affect the conclusions and has been corrected in the online versions of the Article.

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Acknowledgements

We thank B. Castagner, K. Fuhrmann, S. T. Proulx and J. Scholl for their technical help. Financial support from the Swiss National Science Foundation (310030_135732) and IG Zöliakie der Deutschen Schweiz is acknowledged.

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G.F., M.A.G. and J-C.L. designed and conceived the study; PW and ADS participated in the design of the dendronized polymers and coupling chemistry; G.F. and A.G. prepared and characterized conjugates in vitro with the help of R.L. and S.M.; G.F. conducted and analysed all in vivo experiments; P.L., B.Z. and H.Y. synthesized and contributed compounds; G.F., M.A.G., A.G., P.W., A.D.S. and J-C.L. co-wrote the paper. All authors discussed the results and implications and commented on the manuscript at all stages.

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Correspondence to Jean-Christophe Leroux.

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Fuhrmann, G., Grotzky, A., Lukić, R. et al. Sustained gastrointestinal activity of dendronized polymer–enzyme conjugates. Nature Chem 5, 582–589 (2013). https://doi.org/10.1038/nchem.1675

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