Design and Testing of Efficient Mucus‐Penetrating Nanogels—Pitfalls of Preclinical Testing and Lessons Learned

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.

Rational Design and Development of Polymeric Nanogels as Protein Carriers

“…Common crosslinkers include disulfide, diselenide and maleimide tioether bonds. [78,117,118] For instance, Huang and co-workers incorporated disulfide-based cystamine residues in HA-methacrylate (MA) based NGs to induce cleavage in tumor cells. The NGs were fabricated via microfluidics by crosslinking using a tetrazolealkene click reaction (Figure 13A).…”

“…Stability of ETN loaded in the NGs based on their TNF𝛼 binding capacity.Both NGs containing ETN retained better the activity of the protein with respect to the free protein solution. Adapted with permission [78]. Copyright 2021, Wiley-VCH.…”

Sniping Cancer Stem Cells with Nanomaterials

“…Polymeric nanomaterials represent another promising strategy for drug delivery systems, offering controlled and sustained drug release with precise targeting . Multiple structural designs of polymeric nanomaterials have been explored, encompassing micelles, nanocapsules, nanogels, and more, yielding encouraging outcomes in cancer treatment and the delivery of vaccines and genes, − showed great potential for targeting CSCs.…”

Dual-reactive nanogels for orthogonal functionalization of hydrophilic shell and amphiphilic network

“…45,46 For example, the volume phase transition temperature of thermoresponsive nanogels can be tuned by changing the ratio between N-isopropylacrylamide and N-isopropylmethacrylamide monomers. 47 However, this approach involves the synthesis of a new nanogel batch for each new network composition. This can lead to variations in the nanogel features and limits the incorporation of our hydrophobic cholesterol groups.…”