Self-assembled gellan-based nanohydrogels as a tool for prednisolone delivery

In recent years, significant efforts have been devoted to the development of amphiphilic polymers consisting of hydrophilic polysaccharides and hydrophobic moieties because of their ability to form nanoparticle self-assemblies in aqueous media. The intermolecular interactions between the hydrophilic and hydrophobic segments allow the creation of a hydrophilic shell that faces towards the solvent and an inner hydrophobic core with minimal interactions with the aqueous medium. In recent years, a variety of self-assembled nanoparticles have been developed for their potential application as drugs and their ability to increase the therapeutic efficacy of the drugs and to reduce drug side effects. Numerous examples of nanoparticles (NPs) are currently used in clinical practice (Doxil and Daunoxome) and others are in clinical development (Cyclosert). Moreover, self-assembled nanoparticles have been proposed as anticancer drug carriers because they exhibit prolonged systemic circulation time and can accumulate in the tumor masses (EPR, Enhanced Permeability and Retention effect). The nanoparticle surface can then be functionalized to improve targeting to the site of action of the drug, thereby reducing non-specific distribution. In particular, surface functionalization can address the drug release, avoid NP aggregation, and reduce the rapid clearance of the drug.

As applied to drug delivery systems, natural polysaccharides have the advantages of their abundance in nature, low cost, safety, general biocompatibility, biodegradability, and high stability. Among all natural polysaccharides, gellan is a promising candidate for biomedical applications because of its peculiar physico-chemical properties and its biocompatibility. Gellan gum is an anionic polysaccharide produced by Sphingomonas elodea with a complex tetrasaccharide repeating unit of β-D-glucose, b-D-glucuronic acid, β-D-glucose, and a-L-rhamnose, with a free carboxyl group. Gellan is largely used in the food industry and biotechnology because it forms transparent hydrogels that are more resistant to heat and acidic medium as compared to other polysaccharide hydrogels. Recently, gellan gum hydrogels showed potential usefulness in the engineering of cartilaginous tissues due to their viscoelastic properties and lack of cytotoxicity. The polymer solution gelation is due to the thermally reversible ordered helix-coil transition of the polymer chains and the formation of junction zones by the stacking of the macromolecules in the double helix form. The helix aggregation and gel formation are enhanced by cations, with divalent cations being a stronger promoter of the gelation of gellan gum than monovalent cations. The ability of gellan gum to form strong hydrogels in the presence of ions and then to be transformed into a nanohydrogel offers a promising strategy that combines the properties of hydrogels with the advantages of nanotechnology.

Herein, we prepared gellan nanohydrogels (NHs) by self-assembly of the polymer chains, after an appropriate hydrophobic chemical derivatization with cholesterol and prednisolone moieties. Gellan was ultrasonicated to reduce the molecular weight, thus obtaining a more reliable and suitable polymer system for NH formation. Prednisolone was chosen as the hydrophobic moiety for its wide spectrum of activities in cell trafficking, cell–cell interactions, and cell communication and for its pronounced anti-inflammatory and immunosuppressive effects. Prednisolone is a prodrug that is enzymatically activated to prednisone in the liver. Prednisone then acts as a classical steroid hormone and diffuses through the cell membrane, interacting with a cytosolic receptor that forms a complex that then translocates to the nucleus where it directly modulates DNA transcription of a variety of genes. Moreover, over the last two decades, glucocorticoids have been shown to inhibit solid tumor growth in experimental animal models.

In the present investigation, the prednisolone moiety, linked to the polymer chains by means of a short hydrocarbon chain, simultaneously acts as a pharmacological agent and a promoter of NH formation whereas cholesterol was chosen as a moiety able to promote the formation of reference NHs with no pharmacological activity. This approach allows us to combine the advantages of nanotechnology, such as high stability, high carrier capacity, and feasibility of different routes of administration with an immobilized form of prednisolone that displays improved bioavailability, thus increasing its therapeutic effects and reducing its dosing frequency.

In this work, the chemical derivatization of gellan with prednisolone and cholesterol is described; the obtained self-assembled NHs were characterized and the cytotoxicity of the NHs was tested using theMTS assay.



Giorgia D’Arrigo, Chiara Di Meo, Elisa Gaucci, Silvia Chichiarelli, Tommasina Coviello, Donatella Capitani, Franco Alhaique and Pietro Matricardi*.Soft Matter, 2012, 8, 11557–11564


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