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Drug-sensing hydrogels for the inducible release of biopharmaceuticals

Nature Materials volume 7, pages 800–804 (2008)Cite this article

Abstract

Drug-dependent dissociation or association of cellular receptors represents a potent pharmacologic mode of action for regulating cell fate and function1,2. Transferring the knowledge of pharmacologically triggered protein–protein interactions to materials science will enable novel design concepts for stimuli-sensing smart hydrogels. Here, we show the design and validation of an antibiotic-sensing hydrogel for the trigger-inducible release of human vascular endothelial growth factor3. Genetically engineered bacterial gyrase subunit B (GyrB) (ref. 4) coupled to polyacrylamide was dimerized by the addition of the aminocoumarin antibiotic coumermycin, resulting in hydrogel formation. Addition of increasing concentrations of clinically validated novobiocin (Albamycin) dissociated the GyrB subunits, thereby resulting in dissociation of the hydrogel and dose- and time-dependent liberation of the entrapped protein pharmaceutical VEGF121 for triggering proliferation of human umbilical vein endothelial cells. Pharmacologically controlled hydrogels have the potential to fulfil the promises of stimuli-sensing materials5,6,7,8,9 as smart devices for spatiotemporally controlled delivery of drugs within the patient.

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Figure 1: Design of pharmacologically controlled hydrogels.
Figure 2: Synthesis and characterization of pharmacologically controlled hydrogels.
Figure 3: Adjustable pharmacologically triggered disintegration of the hydrogel.
Figure 4: Antibiotic-inducible release of VEGF121.
Figure 5: Biocompatibility of pharmacologically triggered hydrogels and bioavailability of the cargo growth factor.

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Acknowledgements

We are grateful to M. Lütolf for his critical comments on the manuscript as well as his advice on the rheology measurements. We thank B. Keller for cloning plasmid pWW873, R. Wirz for infrared spectra analysis, S. Gobaa for expertise in rheology measurements, M. Rimann for providing HUVECs and J. Loebus for technical assistance. The project has been made possible owing to start-up financing by the GEBERT RÜF STIFTUNG (Grant No. GRS-042/07) to W.W.

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Authors and Affiliations

  1. Department of Cranio-Maxillofacial Surgery, University Hospital Zurich, Frauenklinikstrasse 24, 8091 Zurich, Switzerland

    Martin Ehrbar

  2. Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland

    Ronald Schoenmakers, Erik H. Christen, Martin Fussenegger & Wilfried Weber

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  1. Martin Ehrbar
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  2. Ronald Schoenmakers
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Contributions

The experiments were designed by M.E., R.S. and W.W. and carried out by M.E., R.S., E.H.C. and W.W. The manuscript was written by M.F. and W.W. The principal investigator is W.W.

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Correspondence to Wilfried Weber.

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ETH Zurich has filed an application for a patent on the technology described in this manuscript, of which M.F. And W.W. are inventors.

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Ehrbar, M., Schoenmakers, R., Christen, E. et al. Drug-sensing hydrogels for the inducible release of biopharmaceuticals. Nature Mater 7, 800–804 (2008). https://doi.org/10.1038/nmat2250

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