Design and testing of efficient mucus-penetrating nanogels-pitfalls of preclinical testing and lessons learned

Item Type:	Article
Title:	Design and testing of efficient mucus-penetrating nanogels-pitfalls of preclinical testing and lessons learned
Creators Name:	Charbaji, R. and Kar, M. and Theune, L.E. and Bergueiro, J. and Eichhorst, A. and Navarro, L. and Graff, P. and Stumpff, F. and Calderón, M. and Hedtrich, S.
Abstract:	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.
Keywords:	Inflammation, Local Drug Delivery, Mucopenetrating, Mucosal Drug Delivery, Polyglycerol-Based Nanogels, Animals, Swine
Source:	Small
ISSN:	1613-6810
Publisher:	Wiley
Volume:	17
Number:	23
Page Range:	e2007963
Date:	10 June 2021
Official Publication:	https://doi.org/10.1002/smll.202007963
PubMed:	View item in PubMed

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