Nanotecnología farmacéutica de los siARN / siRNA pharmaceutical nanotechnology

El silenciamiento de genes por medio de siARN constituyeactualmente una estrategia terapéutica que está siendo evaluada endiversos ensayos clínicos. La presente revisión se centra particularmenteen las estrategias no víricas de liberación in vivo de los siARN ya que elloconstituye uno de los más importantes problemas a resolver. Por otraparte es necesario comprender la genocompatibilidad/toxicogenética delos sistemas de liberación para poderlos seleccionar adecuadamentedeacuerdo con la aplicación terapéutica deseada(AU)

Gene silencing using small interfering RNA (siRNA) is atechnology that is now being evaluated in clinical trials as a potentiallynovel therapeutic strategy. This article provides an overview of the majorpharmaceutical challenges facing siRNA therapeutics, focusing on thenon-viral delivery strategies in vivo for synthetic siRNA, as this remainsone of the most important issues to be resolved. It is also important tounderstand the genocompatibility/toxicogenomics of siRNA deliveryreagents in terms of their impact on gene-silencing activity and selectivitybecause this information is essential for the selection of optimally actingsiRNA delivery systems for the many proposed applications of RNAinterference(AU)

Nuevos aspectos biofarmacéuticos en nanotecnología farmacéutica / New biopharmaceutical aspects in pharmaceutical nanotechnology

Para hacer frente al reto de la Nanomedicina, la Tecnología Farmacéutica hadesarrollado sistemas nanométricos que contienen el principio activo incluido enun vehículo que lo transporta. Como sistemas nanométricos permiten que el fármacoque llevan pueda atravesar las diferentes barreras biológicas del organismolo cual no se podía realizar con los sistemas de liberación convencionales ya queen éstos son fundamentalmente las propiedades fisicoquímicas del principio activolas que condicionan su absorción y biodistribución.La Nanotecnología Farmacéutica, término que paulatinamente se va introduciendoen prestigiosas publicaciones como el Journal of Pharmaceutical Sciences,como ciencia y tecnología de los sistemas farmacéuticos nanoparticulares presentaademás de una fuerte base fisicoquímica, un mayor componente biológico ya queen ella intervienen nuevos aspectos biofarmacéuticos y farmacocinéticos.La internalización o paso de los nanosistemas al interior celular es un procesocuyo conocimiento es cada vez mas imprescindible, resaltándose algunos de losaspectos mas novedosos como el papel de los llamados péptidos fusógenos. Igualmentetiene cada vez mas relevancia el conocimiento de los procesos que protejenal fármaco de su degradación en los endolisosomas (por ejemplo el efecto esponjade protones de las polietileniminas y los factores que controlan la rápida liberacióndel nanosistema de los endolisosomas (vectores lisosomotrópicos); con vistas a lautilización de fármacos cuya diana se encuentra en el interior del núcleo celular,interesa destacar el transporte activo por medio del complejo poro nuclear.Finalmente se expone el papel de los llamados excipientes funcionales, los cualeshan hecho cambiar el concepto clásico de un excipiente farmacéutico, ya que cada vez existen mayores evidencias de que polímeros como poloxamer, poloxaminasy polietielinglicoles pueden modificar señales de trasducción intracelular eincrementar la eficacia de ciertos principios activos (AU)

The use of various pharmaceutical nanocarriers has become one of the mostimportant areas of Nanomedicine. Ideally, such carriers should be specificallydeliver the drug to the pathological area to provide the maximum therapeuticefficacy. The concept of «magic bullets» given by Ehrlich has now emerged in theform of targeted drug delivery systems and polymeric nanopartyicles, liposomes,micelles, dendrimers and polymer-drug conjugates are the vanguards of this everevolvingfield. The specific targeting ligands which guide the drug carriers to themolecular targets be it on cell surface or nulear membranes implies new biopharmaceuticalaspects such us a better understanding of the physiological barriers,half-life of the nanosystems in the blood stream, the presence of receptors on cellmembranes, the different mechanisms of internalization of nanostructures, intracelulartrafficking and interactions.It is conceivable, that dispite all the formidable challenges, interplay of differentdisciplines ranging from engineering to biology will make a new promissingfield in Pharmaceutical Technology: the Pharmaceutical Nanotechnology (AU)

Low molecular weight chitosan nanoparticles as new carriers for nasal vaccine delivery in mice.

High molecular weight (Mw) chitosan (CS) solutions have already been proposed as vehicles for nasal immunization. The aim of the present work was to investigate the potential utility of low Mw CS in the form of nanoparticles as new long-term nasal vaccine delivery vehicles. For this purpose, CS of low Mws (23 and 38 kDa) was obtained previously by a depolymerization process of the commercially available CS (70 kDa). Tetanus toxoid (TT), used as a model antigen, was entrapped within CS nanoparticles by an ionic cross-linking technique. TT-loaded nanoparticles were first characterized for their size, electrical charge, loading efficiency and in vitro release of antigenically active toxoid. The nanoparticles were then administered intranasally to conscious mice in order to study their feasibility as vaccine carriers. CS nanoparticles were also labeled with FITC-BSA and their interaction with the rat nasal mucosa examined by confocal laser scanning microcopy (CLSM). Irrespective of the CS Mw, the nanoparticles were in the 350 nm size range, and exhibited a positive electrical charge (+40 mV) and associated TT quite efficiently (loading efficiency: 50-60%). In vitro release studies showed an initial burst followed by an extended release of antigenically active toxoid. Following intranasal administration, TT-loaded nanoparticles elicited an increasing and long-lasting humoral immune response (IgG concentrations) as compared to the fluid vaccine. Similarly, the mucosal response (IgA levels) at 6 months post-administration of TT-loaded CS nanoparticles was significantly higher than that obtained for the fluid vaccine. The CLSM images indicated that CS nanoparticles can cross the nasal epithelia and, hence, transport the associated antigen. Interestingly, the ability of these nanoparticles to provide improved access to the associated antigen to the immune system was not significantly affected by the CS Mw. Indeed, high and long-lasting responses could be obtained using low Mw CS molecules. Furthermore, the response was not influenced by the CS dose (70-200 microg), achieving a significant response for a very low CS dose. In conclusion, nanoparticles made of low Mw CS are promising carriers for nasal vaccine delivery.