Nanohydrogels Based on Self-Assembly of Cationic Pullulan and Anionic Dextran Derivatives for Efficient Delivery of Piroxicam

Abstract

A cationic derivative of pullulan was obtained by grafting reaction and used together with dextran sulfate to form polysaccharide-based nanohydrogel cross-linked via electrostatic interactions between polyions. Due to the polycation-polyanion interactions nanohydrogel particles were formed instantly and spontaneously in water. The nanoparticles were colloidally stable and their size and surface charge could be controlled by the polycation/polyanion ratio. The morphology of the obtained particles was visualized by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and atomic force microscopy (AFM). The resulting structures were spherical, with hydrodynamic diameters in the range of 100-150 nm. The binding constant (K a ) of a model drug, piroxicam, to the cationic pullulan (C-PUL) was determined by spectrophotometric measurements. The value of K a was calculated according to the Benesi-Hildebrand equation to be (3.6 ± 0.2) × 10 3 M −1 . After binding to cationic pullulan, piroxicam was effectively entrapped inside the nanohydrogel particles and released in a controlled way. The obtained system was efficiently taken up by cells and was shown to be biocompatible.Pharmaceutics 2019, 11, 622 2 of 16 bioactive compound (e.g., low molecular weight drugs, proteins, DNA or RNA) and release it in a controlled way [5][6][7][8]. In order to adjust the release profile of a bioactive substance to the needs of the therapy the ability of nanogels to respond to the microenvironmental stimuli such as light, magnetic field, changes in ionic strength, pH, temperature, or redox potential, are often exploited [9][10][11][12][13]. For example, sodium alginate was combined with N-isopropylacrylamide to obtain a dual-responsive system for oxytetracycline delivery, where the drug release could be effectively controlled by both pH and temperature [14]. Chitosan based nanogel which showed pH-dependent drug release which mimicked the skin cancer micro-environment was very recently proposed by Sahu et al. [15].It is, however, worth noticing, that many of the studied nanogel systems are based on the combination of polysaccharide and synthetic polymer, which often makes them less biocompatible. Other large group of nanogels is made by the hydrophobic modifications of polysaccharides. For these polymers the formation of the stable nanogel usually requires additional steps (solvent removal, heating, ionotrpic gelation, cross-linking).Pullulan is a natural polysaccharide produced from starch by the fungus Aureobasidium pullulans. This water-soluble polymer has a linear structure consisting of repeating maltotriose units [16]. Due to its ordered structure pullulan has film-forming ability, considerable mechanical strengths and adhesiveness, thus it is widely used as a component of composite polymer materials, in the construction of electrospun fibres and gels [16][17][18]. The latter are usually obtained by chemical cross-linking [19], a highly universal method which allows to obtain hydrogels and nanohydrogels with high mec...

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