Mucin-mediated nanocarrier disassembly for triggered uptake of oligonucleotides as a delivery strategy for the potential treatment of mucosal tumours

Abstract

This work demonstrates gastric mucin-triggered nanocarrier disassembly for release of antisense oligonucleotides and consequent unassisted cellular entry as a novel oral delivery strategy. A fluorescence activation-based reporter system was used to investigate the interaction and mucin-mediated disassembly of chitosan-based nanocarriers containing a 13-mer DNA oligonucleotide with a flanked locked RNA nucleic acid gapmer design. Gastric mucins were shown to trigger gapmer release from nanocarriers that was dependent on the interaction time, mucin concentration and N : P ratio with a maximal release at N : P 10. In contrast to siRNA, naked gapmers exhibited uptake into mucus producing HT-MTX mono-cultures and HT-MTX co-cultured with the carcinoma epithelial cell line Caco-2. Importantly, in vivo gapmer uptake was observed in epithelial tissue 30 min post-injection in murine intestinal loops. The findings present a mucosal design-based system tailored for local delivery of oligonucleotides that may maximize the effectiveness of gene silencing therapeutics within tumours at mucosal sites.

Intestinal Mucin Induces More Endocytosis but Less Transcytosis of Nanoparticles across Enterocytes by Triggering Nanoclustering and Strengthening the Retrograde Pathway

“…3 Notably, the mucus layer, which covers the intestinal epithelium as the first barrier, creates obstacles for the transportation of nanomedicines into blood circulation through the intestinal mucosa. 4,5 As the key component, proteoglycans in the mucus layer interact with each other to form a reticular structure, thus protecting the gastrointestinal (GI) tract against the access of exogenous substances including many types of nanomedicines. 6−9 Because of the negative effects of the mucus layer on nanomedicine transportation, multiple functional nanomedicines have been fabricated to overcome the obstacles.…”

“…Over the last several decades, the successful introduction of nanotechnology has brought more oral nanomedicines into the market, improving the bioavailability or therapy efficacy of drugs; meanwhile, more oral nanomedicines are still in clinical trials and preclinical studies . Notably, the mucus layer, which covers the intestinal epithelium as the first barrier, creates obstacles for the transportation of nanomedicines into blood circulation through the intestinal mucosa. , As the key component, proteoglycans in the mucus layer interact with each other to form a reticular structure, thus protecting the gastrointestinal (GI) tract against the access of exogenous substances including many types of nanomedicines. − Because of the negative effects of the mucus layer on nanomedicine transportation, multiple functional nanomedicines have been fabricated to overcome the obstacles. Mucoadhesive polymers have been adopted to improve the residence time of nanoparticles in the GI tract .…”

Oral Delivery of Biologics for Precision Medicine

“…Mater. 2020, 32,1901935 Intestine asRNA (Gapmers) CS NP [142] Abbreviations in the table; HA hyaluronic acid; NIPAAm-co-Aam poly(N-isopropylacrylamide-co-acrylamide); P[MAA-co-NVP] poly(methacrylic acid-co-N-vinyl-2-pyrrolidone); CMC-G6P carboxymethyl cellulose-glucosamine 6-phosphate.…”

A Polymer Chemistry Point of View on Mucoadhesion and Mucopenetration

“…The pharmaceutical effect of the model peptide was detected even 120 h after the administration by the chitosan‐liposome formulation . Martirosyan et al reported exciting results on chitosan‐based nanocarriers . Their sub‐200 nm sized chitosan particles dissembled in the presence of porcine gastric mucin and released the transported cargo.…”

“…[49] Martirosyan et al reported exciting results on chitosanbased nanocarriers. [50] Their sub200 nm sized chitosan particles dis sembled in the presence of porcine gastric mucin and released the transported cargo. It was even shown that coating/blending the surface with chitosan was already sufficient to enhance mucoadhesion of a given nano/microparticle.…”