Nanoparticles from Gantrez® AN-poly(ethylene glycol) conjugates as carriers for oral delivery of docetaxel

The oral delivery of docetaxel (DTX) is challenging due to a low bioavailability, related to an important pre-systemic metabolism. With the aim of improving the bioavailability of this cytotoxic agent, nanoparticles from conjugates based on the copolymer of methyl vinyl ether and maleic anhydride (poly(anhydride)) and two different types of PEG, PEG2000 (PEG2) or methoxyPEG2000 (mPEG2), were evaluated. Nanoparticles, with a DTX loading close to 10%, were prepared by desolvation and stabilized with calcium, before purification and lyophilization. For the pharmacokinetic study, nanoparticles were orally administered to mice at a single dose of 30 mg/kg. The plasma levels of DTX were high, prolonged in time and, importantly, quantified within the therapeutic window. The relative oral bioavailability was calculated to be up to 56% when DTX was loaded in nanoparticles from poly(anhydride)-mPEG2000 conjugate (DTX-NP-mPEG2). Finally, a comparative toxicity study between equitoxic doses of free iv DTX and oral DTX-NP-mPEG2 was conducted in mice. Animals orally treated with DTX-loaded nanoparticles displayed less severe signs of hypersensitivity reactions, peripheral neurotoxicity, myelosuppression and hepatotoxicity than free iv docetaxel. In summary, poly(anhydride)-PEG conjugate nanoparticles appears to be adequate carries for the oral delivery of docetaxel

Modulation of the fate of zein nanoparticles by their coating with a Gantrez® AN-thiamine polymer conjugate

The aim of this work was to evaluate the mucus-permeating properties of nanocarriers using zein nanoparticles (NPZ) coated with a Gantrez® AN-thiamine conjugate (GT). NPZ were coated by incubation at different GT-tozein ratios: 2.5% coating with GT (GT-NPZ1), 5% (GT-NPZ2) and 10% (GT-NPZ3). During the process, the GT conjugate formed a polymer layer around the surface of zein nanoparticles. For GT-NPZ2, the thickness of this corona was estimated between 15 and 20 nm. These nanocarriers displayed a more negative zeta potential than uncoated NPZ. The diffusivity of nanoparticles was evaluated in pig intestinal mucus by multiple particle tracking analysis. GT-NPZ2 displayed a 28-fold higher diffusion coefficient within the mucus layer than NPZ particles. These results align with in vivo biodistribution studies in which NPZ displayed a localisation restricted to the mucus layer, whereas GT-NPZ2 were capable of reaching the intestinal epithelium. The gastro-intestinal transit of mucoadhesive (NPZ) and mucus-permeating nanoparticles (GT-NPZ2) was also found to be different. Thus, mucoadhesive nanoparticles displayed a significant accumulation in the stomach of animals, whereas mucus-penetrating nanoparticles appeared to exit the stomach more rapidly to access the small intestine of animal

The effect of thiamine-coating nanoparticles on their biodistribution and fate following oral administration

Thiamine-coated nanoparticles were prepared by two different preparative methods and evaluated to compare their mucus-penetrating properties and fate in vivo. The first method of preparation consisted of surface modification of freshly poly(anhydride) nanoparticles (NP) by simple incubation with thiamine (T-NPA). The second procedure focused on the preparation and characterization of a new polymeric conjugate between the poly(anhydride) backbone and thiamine prior the nanoparticle formation (T-NPB). The resulting nanoparticles displayed comparable sizes (about 200 nm) and slightly negative surface charges. For T-NPA, the amount of thiamine associated to the surface of the nanoparticles was 15 µg/mg. For in vivo studies, nanoparticles were labeled with either 99mTc or Lumogen® Red. T-NPA and T-NPB moved faster from the stomach to the small intestine than naked nanoparticles. Two hours post-administration, for T-NPA and T-NPB, more than 30% of the given dose was found in close contact with the intestinal mucosa, compared with a 13.5% for NP. Interestingly, both types of thiamine-coated nanoparticles showed a greater ability to cross the mucus layer and interact with the surface of the intestinal epithelium than NP, which remained adhered in the mucus layer. Four hours post-administration, around 35% of T-NPA and T-NPB were localized in the ileum of animals. Overall, both preparative processes yielded thiamine decorated carriers with similar physico-chemical and biodistribution properties, increasing the versatility of these nanocarriers as oral delivery systems for a number of biologically active compounds

Fotoactivación de precursors sol-gel para la preparación de láminas delgadas ferroeléctricas de PbTiO₃ a baja temperatura

En la presente tesis doctoral se han preparado y caracterizado, desde un punto de vista estructural, microestructural y eléctrico, láminas delgadas ferroeléctricas de titanato de plomo (PbTiO3, PT) a tan sólo 400°C mediante PCSD, diseñando para ello una nueva estrategia de síntesis de las disoluciones precursoras. La fabricación de las láminas se ha llevado a cabo mediante el depósito de las disoluciones por spin-coating sobre substratos de Pt/TiO2/SiO2/(100)Si seguido de un secado y un tratamiento térmico en un horno RTP combinado con irradiación UV para favorecer la eliminación de los orgánicos y la cristalización del óxido a baja temperatura. El titanato de plomo cristaliza con estructura perovsquita y es el ferroeléctrico por excelencia, presentando un alto valor de polarización espontánea Ps~50μC/cm2. Por este motivo, este óxido ha sido elegido como objeto de este estudio. El responsable de una reducción tan significativa en la temperatura de procesado de las películas de PT es un compuesto fotosensible, N-metildietanolamina (MDEA), utilizado por primera vez en la fabricación de láminas con este fin, que no presenta toxicidad y con un máximo de absorción muy próximo a la longitud de onda de la lámpara utilizada en la irradiación (222 nm). La caracterización de los soles pone de manifiesto que el MDEA forma complejos con los cationes metálicos presentes en el sistema, que son los responsables de una alta absorción en el UV a través de un proceso de transferencia de carga, un tipo de transición electrónica con coeficientes de absortividad molar muy superiores a los que presentan las transiciones π-π*, que son las que experimentan habitualmente las disoluciones precursoras fotoactivadas en la técnica PCSD. La reducción en la temperatura de cristalización del óxido se debe tanto al aumento de la fotosensibilidad de las disoluciones precursoras debido a la existencia de transferencias de carga en los complejos que forma el compuesto MDEA, como a un fenómeno de autoignición que tiene lugar en el sistema debido a la presencia del nitrógeno del MDEA junto a un alto contenido de orgánicos, que origina una gran cantidad de energía que el sistema consume en la cristalización del óxido, reduciéndose así la temperatura. De esta forma, MDEA proporciona unos resultados que otros fotoactivadores no permiten obtener. De este modo, se esperarían los mismos efectos para cualquier composición que contuviera al menos un catión de configuración d0 o d10, puesto que son los complejos que forma el MDEA con los cationes metálicos de este tipo los responsables del aumento de la fotosensibilidad de las disoluciones precursoras a través de las transferencias de carga. Como las principales familias de ferroeléctricos contienen cationes de este tipo, esta nueva estrategia de síntesis abre las puertas a la preparación de una gran variedad de composiciones de óxidos mixtos funcionales con gran interés aplicativo en dispositivos electrónicos

Modulation of the fate of zein nanoparticles by their coating with a Gantrez® AN-thiamine polymer conjugate

The aim of this work was to evaluate the mucus-permeating properties of nanocarriers using zein nanoparticles (NPZ) coated with a Gantrez® AN-thiamine conjugate (GT). NPZ were coated by incubation at different GT-tozein ratios: 2.5% coating with GT (GT-NPZ1), 5% (GT-NPZ2) and 10% (GT-NPZ3). During the process, the GT conjugate formed a polymer layer around the surface of zein nanoparticles. For GT-NPZ2, the thickness of this corona was estimated between 15 and 20 nm. These nanocarriers displayed a more negative zeta potential than uncoated NPZ. The diffusivity of nanoparticles was evaluated in pig intestinal mucus by multiple particle tracking analysis. GT-NPZ2 displayed a 28-fold higher diffusion coefficient within the mucus layer than NPZ particles. These results align with in vivo biodistribution studies in which NPZ displayed a localisation restricted to the mucus layer, whereas GT-NPZ2 were capable of reaching the intestinal epithelium. The gastro-intestinal transit of mucoadhesive (NPZ) and mucus-permeating nanoparticles (GT-NPZ2) was also found to be different. Thus, mucoadhesive nanoparticles displayed a significant accumulation in the stomach of animals, whereas mucus-penetrating nanoparticles appeared to exit the stomach more rapidly to access the small intestine of animal