title: Mucus permeating thiomer nanoparticles.
abstract: The aim of this study was to develop and evaluate a novel mucoadhesive drug delivery system based on thiolated poly(acrylic acid) nanoparticles exhibiting mucolytic properties to enhance particle diffusion into deeper mucus regions before adhesion. Mediated by a carbodiimide, cysteine and the mucolytic enzyme papain were covalently attached to poly(acrylic acid) via amide bond formation. The conjugates were co-precipitated with calcium chloride in order to obtain papain modified (PAA-pap) and thiolated nanoparticles (PAA-cys) as well as particles containing both conjugates (PAA-cys-pap). The nanoparticulate systems were characterized regarding particle size distribution and zeta potential. Particle transport was investigated by diffusion studies across intestinal mucus using two different techniques. Furthermore, mucoadhesive properties of all particles were evaluated via rheological measurements. Results demonstrated that all nanoparticles were in a size range of 158-214 nm and showed negative zeta potentials. Due to the presence of papain, the PAA-cys-pap particles were capable of cleaving mucoglycoprotein substructures and consequently exhibited a 2.0-fold higher penetration into the mucus layer in comparison with PAA-cys particles. Within the rheological studies, an 1.9-fold increase in mucoadhesion could be achieved for the nanoparticulate system based on thiolated PAA compared to papain modified particles (PAA-pap). Therefore, the newly developed particulate system (PAA-cys-pap) is characterized by mucoadhesive as well as mucolytic properties. The combination of both effects - mucus-permeating and mucoadhesive properties - might be a promising strategy for the development of oral drug delivery systems to overcome the mucus barrier and providing a prolonged residence time close to the absorption membrane.
authors.affiliation: ThioMatrix GmbH, Research Center Innsbruck, Innsbruck, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Köllner
authors.affiliation: ThioMatrix GmbH, Research Center Innsbruck, Innsbruck, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Dünnhaupt
authors.affiliation: ThioMatrix GmbH, Research Center Innsbruck, Innsbruck, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Waldner
authors.affiliation: University of Innsbruck, Institute of Pharmacy/Pharmaceutical Technology, CCB - Centrum of Chemistry and Biomedicine, Innsbruck, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Hauptstein
authors.affiliation: University of Innsbruck, Institute of Pharmacy/Pharmaceutical Technology, CCB - Centrum of Chemistry and Biomedicine, Innsbruck, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Pereira de Sousa
authors.affiliation: University of Innsbruck, Institute of Pharmacy/Pharmaceutical Technology, CCB - Centrum of Chemistry and Biomedicine, Innsbruck, Austria. Electronic address: Andreas.Bernkop@uibk.ac.at.
authors.forename: A
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry*; D000268:Adhesiveness; D000818:Animals; D002122:Calcium Chloride / Q000737:chemistry; D004058:Diffusion; D016503:Drug Delivery Systems; D007413:Intestinal Mucosa / Q000378:metabolism; D009093:Mucus / Q000378:metabolism*; D053758:Nanoparticles; D010206:Papain / Q000737:chemistry; D010316:Particle Size; D012212:Rheology; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013552:Swine
chemical_list: D000180:Acrylic Resins; D013438:Sulfhydryl Compounds; C006903:carbopol 940; D010206:Papain; D002122:Calcium Chloride
keywords: Drug delivery system; Mucoadhesion; Mucus; Mucus permeation; Nanoparticles; Papain