Micro-and nanomaterials for drug delivery in skin diseases
- Autores: David Limón Magaña
- Directores de la Tesis: Lluisa Pérez García (dir. tes.), Ana C. Calpena Campmany (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Rodolfo Lavilla Grifols (presid.), Olga López Serrano (secret.), Gemma Arsequell Ruiz (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Nanostructured supramolecular hydrogels and gold nanoparticles, as two kinds of nanomaterials, were synthsized, characterized and evaluated for their potential as drug delivery systems.
Two bis-imidazolium cationic surfactants (1•2Br and 2•2Br) were used as low molecular weight gelators that can incorporate anionic neutral and cationic drugs which can be used in the treatment of skin diseases such as Rosacea and Psoriasis. With either gelator and drug, optimum conditions for gel formation were found to be 5 mg/mL concentration of gelator, 50:50 ethanol:water proportion, and room temperature. 2•2Br forms a gel in 90 min while 1•2Br does it in 10 min.
1•2Br and 2•2Br gels can be formed in presence of anionic drugs sodium ibuprofen and indomethacin while 1•2Br gels can also be formed with other anionic, neutral, and cationic drugs such as sodium methotrexate, triamcinolone acetonide, betamethasone 17-valerate, tacrolimus brimonidine tartrate, AEBSF•HCl, and gemcitabine hydrochloride. The type and concentration of drug widely influence the gelling times, rheological behavior, and microscopic morphology of the gel. All formed gels are stable at room temperature for at least six months.
Gels from both gelators can incorporate the drug not only at the intersticial space of the gel but also within the fibers. Gels of 1•2Br incorporate not only anionic drugs but also neutral and even cationic drugs, proving that the electrostatic atraction between the cationic gelator and a drug is not the main force driving this fiber-incorporation.
The fiber-incorporation of AEBSF•HCl and further release to the intersticial space results in remarkable fiber twisting and subsequent coiling, being the first time a morphological change in supramolecular structures as a result of the exit of a guest substance (drug) has been reported.
Suitable drug release from the gel matrix is observed from either gel. Gels of 1•2Br permit the release of up to ten-times more drug from the matrix than the commercial products studied.
Application of gels on human skin permit a suitable permeation of drug, except for gels with tacrolimus and gemcitabine hydrochloride due to the drug physicochemical properties. The application of gel with sodium methotrexate does not involve systemic toxicity. The gels promote the retention of either drug beneath the skin, more than the commercial products studied.
Gels of 2•2Br incorporating NSAID effectively inhibited inflammation in mice ears in vivo, with no significant differences as compared to gels of 1•2Br.
A fast and reliable in vivo model of Rosacea was developed in rabbits. Gels of 1•2Br with triamcinolone acetonide and especially with brimonidine tartrate showed effective in vivo vasoconstrictive and anti-erythema activity using this model, being gel with brimonidine tartrate faster than the commercial Mirvaso®.
Gold nanoparticles (GNP) for the treatment of Rosacea were designed and synthesized using thiolated PEG molecules of sufficient length with a mixture of hydroxyl and carboxyl groups on their surface (GNP.OH/COOH). GNP were further functionalized through their carboxylic acid group with the serine protease inhibitor AEBSF•HCl (covalently or ionically), the anti-KLK5 antibody (covalently), or the α-adrenergic agonist brimonidine tartrate (ionically). All synthesized and functionalized GNP were highly soluble in water. GNP are monodisperse in solution, comprised of a gold core of a ca. 1.5 nm diameter, and hydrodynamic diameters of around 10 nm.
GNP.OH/COOH showed a high in vitro Kallikrein-5 (KLK5) inhibition comparable to AEBSF•HCl alone and to other particles. The highest inhibitions were reached by electrostatically AEBSF functionalized nanoparticles (GNP.COOH AEBSF) and by anti-KLK5 antibody-functionalized particles (GNP.antiKLK5).
Fluorophore-labelled GNP.OH/COOH can be internalized in HaCaT human keratinocytes. The majority of GNP present no toxicity in keratinocytes at the concentrations tested (including KLK5-inhibiting concentrations) with viabilities around 75%. The ionic, and especially, the covalent bond of AEBSF importantly increase cell viabilities as compared to the drug alone.
An in vitro model of Rosacea was developed by stimulating TLR-2 ligands in keratinocytes, which increases their intracellular KLK5 activity and increases IL-8 secretion, also confirming the biochemical pathway of Rosacea.
GNP.OH/COOH, and especially GNP.AEBSF and GNP.antiKLK5 significantly reduce intracellular KLK5 in keratinocytes, which is related to their effective decrease in IL-8 secretion, for which they seem to be most promising option for becoming a new therapeutic strategy in the treatment of Rosacea.
