title: 2,2'Dithiodinicotinyl ligands: Key to more reactive thiomers.
abstract: The aim of this study was to establish a novel type of preactivated thiomers exhibiting a comparatively higher reactivity with mucus and consequently improved mucoadhesive properties. In order to achieve this goal, the dimeric form of 2-mercaptonicotinic acid (MNA-MNA) was directly attached to the polymeric backbone of chitosan (CHI) via amide bond formation mediated by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC) used as a coupling reagent. The remaining free amino groups were in the following reacted with succinic anhydride (Succ) in order to obtain a uniformly anionically charged polymer (CHI-Succ-MNA-MNA). Within this study, different coupling rates of up to 170 μmol MNA-MNA per gram polymer were achieved. The attachment of the dimeric ligand resulted in a preactivated thiomer with a comparatively more reactive disulfide substructure due to the additional nitrogen atom in conjugation over the aromatic moieties. Furthermore, the obtained polymer is entirely preactivated and thus prevented against undesired oxidation reactions. Kinetic studies of disulfide exchange reactions showed a 3.8-fold higher reactivity of CHI-Succ-MNA-MNA in comparison to a state-of-the-art preactivated thiomer. Within rheological measurements, CHI-Succ-MNA-MNA with a coupling rate of 170 μmol (CHI-Succ-MNA-MNA 170) led to a 5.7-fold higher mucus viscosity than the non-thiolated control polymer (CHI-Succ) indicating a rheological synergism due to mucoadhesive properties. These results were confirmed by a second mucoadhesion study, which showed a significantly prolonged retention time of CHI-Succ-MNA-MNA on the small intestinal mucosa compared to CHI-Succ (P<0.02). Accordingly, the double preactivation seems to be a promising strategy in order to obtain entirely preactivated polymers with enhanced mucoadhesive properties.
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Menzel
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Silbernagl
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Flavia
authors.initials: F
authors.lastname: Laffleur
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Leichner
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Max
authors.initials: M
authors.lastname: Jelkmann
authors.affiliation: Center for Chemistry and Biomedicine, Institute of Analytical Chemistry and Radiochemistry, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Huck
authors.affiliation: Center for Chemistry and Biomedicine, Institute of Analytical Chemistry and Radiochemistry, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Shah
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: andreas.bernkop@uibk.ac.at.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000268:Adhesiveness; D000818:Animals; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D005022:Ethyldimethylaminopropyl Carbodiimide / Q000737:chemistry*; D006801:Humans; D007413:Intestinal Mucosa / Q000737:chemistry; D008024:Ligands; D009539:Nicotinic Acids / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology; D013387:Succinic Anhydrides / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013552:Swine
chemical_list: D008024:Ligands; D009539:Nicotinic Acids; D011108:Polymers; D013387:Succinic Anhydrides; D013438:Sulfhydryl Compounds; C031801:succinic anhydride; D048271:Chitosan; C083470:2-mercaptonicotinic acid; D005022:Ethyldimethylaminopropyl Carbodiimide
keywords: Disulfide exchange; Mucoadhesion; Preactivated thiomers; Reactivity of thiomers; Thiomers