title: 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.
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark. kenh@inano.au.dk.
authors.forename: A
authors.initials: A
authors.lastname: Martirosyan
authors.forename: M J
authors.initials: MJ
authors.lastname: Olesen
authors.forename: R A
authors.initials: RA
authors.lastname: Fenton
authors.forename: J
authors.initials: J
authors.lastname: Kjems
authors.forename: K A
authors.initials: KA
authors.lastname: Howard
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D048271:Chitosan; D004337:Drug Carriers; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009077:Mucins / Q000737:chemistry*; D053758:Nanoparticles; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D034741:RNA, Small Interfering; D013552:Swine
chemical_list: D004337:Drug Carriers; D009077:Mucins; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D048271:Chitosan