Design And Testing Of Efficient Mucus-Penetrating Nanogels ? Pitfalls Of Preclinical Testing And Lessons Learned

RAWAN CHARBAJI; MRITYUNJOY KAR; LORYN E. THEUNE; JULIÁN BERGUEIRO; LUCILA NAVARRO ; MARCELO CALDERÓN; SARAH HEDTRICH

SMALL

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2021

1613-6810

Mucosal surfaces pose a challenging environmentfor efficient drug delivery. Various delivery strategies such as nanoparticleshave been employed so far; yet, still yielding limited success. To address the need of efficient transmucosaldrug delivery, we report on the synthesis of novel disulphide-containingdendritic polyglycerol (dPG)-based nanogels and their preclinical testing. A bifunctional disulphide-containing linker was coupled to dPG to act asa macromolecular cross-linker for poly-N-isopropylacrylamide (PNIPAM) andpoly-N-isopropylmethacrylamide (PNIPMAM), in a precipitation polymerizationprocess. A systematic analysis of the polymerization revealed the importance ofa careful polymer choice to yield mucus-degradable nanogels with diameters between100-200 nm, low polydispersity and intact disulphide-linkers.Absorption studies in porcine intestinaltissue and human bronchial epithelial models demonstrated thatdisulphide-containing nanogels are highly efficient in overcoming mucosalbarriers. The nanogels efficiently degraded and delivered the anti-inflammatorybiomacromolecule etanercept into epithelial tissues yielding localanti-inflammatory effects. Over the course of this work, several problems were encountered due to a limitedavailability of valid test systems for mucosal drug-delivery systems. Hence,this study also emphasizes how critical a combined and multifaceted approach isfor the preclinical testing of mucosal drug-delivery systems, discussespotential pitfalls and provides suggestions for solutions.