Robust oil-core nanocapsules with hyaluronate-based shells as promising nanovehicles for lipophilic compounds

Abstract

The design of nanodelivery systems has been recently considered as a solution to the major challenge in pharmaceutical research - poor bioavailability of lipophilic drugs. Nanocapsules with liquid oil cores and shells based on amphiphilic polysaccharides were developed here as robust carriers of hydrophobic active compounds. A series of modified charged hyaluronates were synthesized and used as stabilizing shells ensuring also the biocompatibility of the nanocapsules that is crucial for applications related to the delivery of lipophilic drugs in vivo. Importantly, the oil nanodroplets were found to be stably suspended in water for at least 15 months without addition of low molar mass surfactants. Moreover, their size and stability may be tuned by varying the relative content of hydrophobic and hydrophilic groups in the hyaluronate derivatives as was confirmed by dynamic light scattering and nanoparticle tracking analysis as well as electron microscopy. In vivo studies demonstrated that hyaluronate-based nanocapsules accumulated preferentially in the liver as well as in the lungs. Moreover, their accumulation was dramatically potentiated in endotoxemic mice. In vitro studies showed that the nanocapsules were taken up by liver sinusoidal endothelial cells and by mouse lung vascular endothelial cells. Importantly, the capsules were found to be nontoxic in an acute oral toxicity experiment even at a dose of 2000 mg per kg b.w. Biocompatible hyaluronate-based nanocapsules with liquid cores described herein represent a promising and tunable nanodelivery system for lipophilic active compounds via both oral and intravenous administration.

The Endothelium as a Driver of Liver Fibrosis and Regeneration

“…KC are also able to uptake HA but in a much lower proportion [259]. As a result, this ligand has been explored to increase LSEC delivery by decorating cationic liposomes [259], DNA nanoassociates [260], nanocapsules [261,262] and nanogels [263]. Chondroitin sulphate is also a ligand of the scavenger receptor stabilin-2.…”

Engineering, on‐demand manufacturing, and scaling‐up of polymeric nanocapsules

“…On the other hand, a combination of the solvent‐displacement technique with the layer‐by‐layer approach offers interesting possibilities to modify the NCs surface properties and, hence, to influence the stability of the NCs and their interaction with the biological systems. Moreover, the nature of the multiple shell polymers may facilitate the loading of different drugs, and their controlled release …”

“…Moreover, the nature of the multiple shell polymers may facilitate the loading of different drugs, and their controlled release. 24,45,46 Taking all this into consideration, our goal in this study was to design formulation and technological approaches to produce tailormade polymeric NCs, and to do so according to different scale-down (microliters) and scale-up (liter) techniques. The knowledge generated during these studies will hopefully contribute to a more straightforward translation of polymeric NCs from bench to clinic.…”

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

“…Electrostatic interactions between the positively and negatively charged polymers are becoming an interesting alternative in obtaining nanogel systems [7,27]. Recently, nanocarriers and nanogels prepared by ionic crosslinking of polyelectrolytes [27,28] have been studied in a wide range of biomedical applications, including drug delivery systems [29][30][31][32][33], as well as systems for medical imaging [34,35] and theranostics.Here we propose a simple drug delivery system based on two polyions derived from naturally occurring, highly biocompatible polysaccharides, pullulan and dextran, which instantly and spontaneously self-assembly to form nanohydrogel particles of adjustable size and surface charge. Due to the electrostatic interactions between two strong polyions, the obtained system should possess high colloidal stability while its size and charge can be optimized to facilitate cell penetration and effective delivery.For this purpose pullulan (PUL) was first cationically modified by grafting with N-acrylamidopropyl-N,N,N-trimethylammonium chloride (APTMAC).…”

“…Electrostatic interactions between the positively and negatively charged polymers are becoming an interesting alternative in obtaining nanogel systems [7,27]. Recently, nanocarriers and nanogels prepared by ionic crosslinking of polyelectrolytes [27,28] have been studied in a wide range of biomedical applications, including drug delivery systems [29][30][31][32][33], as well as systems for medical imaging [34,35] and theranostics.…”