Distribution of thiolated mucoadhesive nanoparticles on intestinal mucosa.

It was the aim of the present study to evaluate and compare the distribution of thiolated mucoadhesive anionic poly(acrylic acid) (PAA) and cationic chitosan (CS) nanoparticles on intestinal mucosa. Modifications of these polymers were achieved by conjugation with cysteine (PAA-Cys) and 2-iminothiolane (CS-TBA). Nanoparticles (NP) were prepared by ionic gelation and labelled with the strong hydrophilic fluorescent dye Alexa Fluor 488 (AF 488) and hydrophobic fluorescein diacetate (FDA). Unmodified and modified CS and PAA NP were examined in vitro in terms of their mucoadhesive and mucus penetrating properties on the mucosa of rat small intestine. To investigate the transport of NP across the mucus layer, their diffusion behaviour through natural porcine intestinal mucus was studied through a new diffusion method developed by our group. Lyophilised particles displayed 526 μmol/g (CS) and 513 μmol/g (PAA) of free thiol groups and a zeta potential of 20 mV (CS) and -14 mV for PAA NP. Nanoparticle distribution on rat intestine suggested that mucoadhesion of thiolated NP is higher than the diffusion into the intestinal mucosa. Modified particles displayed more than a 6-fold increase in mucoadhesion compared to unmodified ones. The rank order with regard to mucoadhesion of all particles was: CS-TBA>PAA-Cys>CS>PAA, whereas CS-TBA showed 2-fold higher mucoadhesive properties compared to PAA-Cys NP. Diffusion through intestinal mucus was much higher for unmodified than for thiolated as well as for anionic compared to cationic particles. Overall, it was shown that thiolated particles of both anionic and cationic polymers have improved mucoadhesive properties and could be promising carriers for mucosal drug delivery.

Dünnhaupt S ，Barthelmes J ，Hombach J ，Sakloetsakun D ，Arkhipova V ，Bernkop-Schnürch A ... -  《-》

Mucus permeating thiomer nanoparticles.

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.

Köllner S ，Dünnhaupt S ，Waldner C ，Hauptstein S ，Pereira de Sousa I ，Bernkop-Schnürch A ... -  《-》

Thiolated nanocarriers for oral delivery of hydrophilic macromolecular drugs.

It was the aim of this study to investigate the effect of unmodified as well as thiolated anionic poly(acrylic acid) (PAA) and cationic chitosan (CS) utilized in free-soluble form and as nanoparticulate system on the absorption of the hydrophilic compound FD4 across intestinal epithelial cell layer with and without a mucus layer. Modifications of these polymers were achieved by conjugation with cysteine to PAA (PAA-Cys) and thioglycolic acid to CS (CS-TGA). Particles were prepared via ionic gelation and characterized based on their amount of thiol groups, particle size and zeta potential. Effects on the cell layer concerning absorption enhancement, transepithelial electrical resistance (TEER) and cytotoxicity were investigated. Permeation enhancement was evaluated with respect to in vitro transport of FD4 across Caco-2 cells, while mucoadhesion was indirectly examined in terms of adsorption behaviour when cells were covered with a mucus layer. Lyophilized particles displayed around 1000 μmol/g of free thiol groups, particle sizes of less than 300 nm and a zeta potential of 18 mV (CS-TGA) and -14 mV (PAA-Cys). Cytotoxicity studies confirmed that all polymer samples were used at nontoxic concentrations (0.5% m/v). Permeation studies revealed that all thiolated formulations had pronounced effects on the paracellular permeability of mucus-free Caco-2 layers and enhanced the permeation of FD4 3.0- to 5.3-fold. Moreover, polymers administered as particles showed a higher permeation enhancement than their corresponding solutions. However, the absorption-enhancing effect of each thiolated formulation was significantly (p<0.05) reduced when cells were covered with mucus layer. In addition, all formulations were able to decrease the TEER of the cell layer significantly (p<0.05). Therefore, both thiolated polymers as nanoparticulate delivery systems represent a promising tool for the oral administration of hydrophilic macromolecules.

Dünnhaupt S ，Barthelmes J ，Köllner S ，Sakloetsakun D ，Shahnaz G ，Düregger A ，Bernkop-Schnürch A ... -  《-》

Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery.

Yin L ，Ding J ，He C ，Cui L ，Tang C ，Yin C ... -  《-》

A comprehensive in vitro and in vivo evaluation of thiolated matrix tablets as a gastroretentive delivery system.

Senyigit ZA ，Vetter A ，Guneri T ，Bernkop-Schnürch A ... -  《-》