Design and Testing of Efficient Mucus-Penetrating Nanogels-Pitfalls of Preclinical Testing and Lessons Learned.

Autor: Charbaji R; Freie Universität Berlin, Institute for Pharmaceutical Sciences, Königin-Luise-Strasse 2-4, 14195, Berlin, Germany., Kar M; Freie Universität Berlin, Institute for Chemistry and Biochemistry, Takustr. 3, 14195, Berlin, Germany., Theune LE; Freie Universität Berlin, Institute for Chemistry and Biochemistry, Takustr. 3, 14195, Berlin, Germany., Bergueiro J; Freie Universität Berlin, Institute for Chemistry and Biochemistry, Takustr. 3, 14195, Berlin, Germany., Eichhorst A; Freie Universität Berlin, Institute for Pharmaceutical Sciences, Königin-Luise-Strasse 2-4, 14195, Berlin, Germany., Navarro L; Freie Universität Berlin, Institute for Pharmaceutical Sciences, Königin-Luise-Strasse 2-4, 14195, Berlin, Germany., Graff P; Freie Universität Berlin, Institute for Pharmaceutical Sciences, Königin-Luise-Strasse 2-4, 14195, Berlin, Germany., Stumpff F; Institute of Veterinary Physiology, Department of Veterinary Medicine, Freie Universität Berlin, Oertzenweg 19b, 14163, Berlin, Germany., Calderón M; Freie Universität Berlin, Institute for Chemistry and Biochemistry, Takustr. 3, 14195, Berlin, Germany.; POLYMAT, Applied Chemistry Department, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel de Lardizabal 3, Donostia-San Sebastián, 20018, Spain.; IKERBASQUE, Basque Foundation for Science, Bilbao, 48009, Spain., Hedtrich S; Freie Universität Berlin, Institute for Pharmaceutical Sciences, Königin-Luise-Strasse 2-4, 14195, Berlin, Germany.; University of British Columbia, Faculty of Pharmaceutical Sciences, 2405 Wesbrook Mall, Vancouver, V6T1Z3, Canada.
Jazyk: angličtina
Zdroj: Small (Weinheim an der Bergstrasse, Germany) [Small] 2021 Jun; Vol. 17 (23), pp. e2007963. Date of Electronic Publication: 2021 Mar 14.
DOI: 10.1002/smll.202007963
Abstrakt: Mucosal surfaces pose a challenging environment for efficient drug delivery. Various delivery strategies such as nanoparticles have been employed so far; yet, still yielding limited success. To address the need of efficient transmucosal drug delivery, this report presents the synthesis of novel disulfide-containing dendritic polyglycerol (dPG)-based nanogels and their preclinical testing. A bifunctional disulfide-containing linker is coupled to dPG to act as a macromolecular crosslinker for poly-N-isopropylacrylamide (PNIPAM) and poly-N-isopropylmethacrylamide (PNIPMAM) in a precipitation polymerization process. A systematic analysis of the polymerization reveals the importance of a careful polymer choice to yield mucus-degradable nanogels with diameters between 100 and 200 nm, low polydispersity, and intact disulfide linkers. Absorption studies in porcine intestinal tissue and human bronchial epithelial models demonstrate that disulfide-containing nanogels are highly efficient in overcoming mucosal barriers. The nanogels efficiently degrade and deliver the anti-inflammatory biomacromolecule etanercept into epithelial tissues yielding local anti-inflammatory effects. Over the course of this work, several problems are encountered due to a limited availability of valid test systems for mucosal drug-delivery systems. Hence, this study also emphasizes how critical a combined and multifaceted approach is for the preclinical testing of mucosal drug-delivery systems, discusses potential pitfalls, and provides suggestions for solutions.
(© 2021 Wiley-VCH GmbH.)
Databáze: MEDLINE
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