Multi-Approach Design and Fabrication of Hybrid Composites for Drug Delivery and Cancer Therapy

Drug delivery systems (DDS) have been developed in the last decades to improve the pharmacological properties of free drugs by modifying their pharmacokinetic profile and biodistribution. Major limitations for newly developed drug molecules are the poor water solubility and stability, which can be addressed by DDS. These can protect the drugs from the potentially harsh external conditions found in the biological fluids, and improve their dissolution rate by different strategies, overall increasing the therapeutic activity of the drugs. Additionally, chemotherapeutic agents are nonspecific in nature, leading to deleterious off-target side effects, and poor therapeutic efficacy. Therefore, targeted therapy plays a very important role in cancer treatment, although not without obstacles, since DDS have to overcome a number of biological barriers following their intravenous administration, including renal clearance or opsonization-mediated phagocytosis and efficient extravasation to the tumor. Mesoporous silicon (PSi) micro- and nanoparticles offer numerous benefits for biomedical applications, in particular for drug delivery. Along with a great biocompatibility and biodegradability, PSi possess mesopores (2‒50 nm), where the drugs can be easily loaded and confined in their amorphous state avoiding extensive crystallization, thus, increasing their dissolution rate. However, the release of drugs from this platform is uncontrolled and fast, necessitating the use of strategies to tune the drug release. In this thesis, multiple approaches were used for the design and fabrication of hybrid composites for drug delivery and cancer therapy, including PSi and polymer‒drug conjugate-based DDS produced by different modalities of the microfluidics technology and pH-switch nanoprecipitation. First, the loading and release of drugs with different solubility characteristics from PSi were investigated, and further PSi-lipid and polymer-composites were developed to control the drug release profiles. Overall, it was achieved both a sustained release of hydrophilic and hydrophobic molecules loaded on the PSi and also a reduced initial burst release from the bare PSi particles. Next, PSi-based nanovectors were envisaged for antitumoral applications. A smart PSi-based hybrid nanocomposite with stealth properties was developed, consisting of a pH-responsive polymeric structure assembled on the surface of drug-loaded PSi nanoparticles. This nanocomposite was extremely efficient avoiding drug release from PSi under physiological conditions, while allowing the release of the drug upon acidification of the medium. Remarkably, the nanocomposites avoided extensive macrophage recognition and phagocytosis. Thereupon, a tumor targeted theranostic nanoplatform with dual pH- and magnetic-response capacity was designed. The DDS consisted of a polymeric-drug conjugate nanoparticle containing an imaging agent and decorated with a tumor homing peptide for targeted drug delivery, which was successfully applied for intracellular triggered drug release. Overall, the hybrid composites based on PSi and a polymer-drug conjugate represented an advanced contribution to the field of drug delivery and cancer therapy, and in particular to the development of PSi as a platform for advanced drug delivery applications.Lähestymistapoja lääkeannosteluun ja syöpähoitoon tarkoitettujen yhdistelmävalmisteiden kehittämiseen ja valmistamiseen Uudet lääkeaineet ovat usein huonosti veteen liukenevia, mikä vaikeuttaa niiden annostelua potilaille tai saattaa jopa estää niiden pääsyn markkinoille. Tästä syystä on kehitetty erilaisia menetelmiä, joilla niukkaliukoisista lääkeaineista saadaan tehtyä lääkevalmiste. Valmisteet voivat kuitenkin joissakin tapauksissa sisältää myrkyllisiä apuaineita tai vaatia potilaalle mahdollisesti kivuliaan tai epämukavan annostelutavan. Lisäksi syöpälääkkeiden tapauksessa vaaditaan erityistä huomiota. On tunnettua, että solunsalpaajahoidoissa käytettävät kemoterapeuttiset aineet ovat luonteeltaan epätarkkoja mikä aiheuttaa haitallisia sivuvaikutuksia muualle kuin kohteena olevaan kudokseen sekä johtaa usein matalaan terapeuttiseen tehoon. Siksi viime vuosikymmeninä on kehitetty lääkeannostelumuotoja, joilla voisi parantaa vapaan lääkeaineen farmakologisia ominaisuuksia, muokkaammalla aineiden farmakokineettista profiilia sekä biologista jakautumista. Annostelumuodoilla voidaan eri tavoin parantaa lääkeaineiden liukenemisnopeutta sekä suojella näitä entsymaattiselta hajoamiselta tai hajoamiselta maha-suolikanavassa kulkeutumisen aikana. Lisäksi, kun käytetään edistyneitä lääkkeen annostelumuotoja syövän hoidossa, pystytään rajoittamaan syöpälääkkeiden sivuvaikutuksia ja lisäämään terapeuttista tehoa, välttämällä lääkeaineen ennenaikainen vapautuminen verenkierrossa sekä kohdentamalla aineet kasvainalueelle. Tässä väitöstyössä kehitettiin ja valmistettiin lääkeannosteluun sekä syöpähoitoon tarkoitettuja huokoinen pii- tai polymeeri-lääkeaine −pohjaisia yhdistelmävalmisteita. Valmistusmenetelmät perustuvat mikrofluidiikkaan tai pH-kytkin nanosaostukseen. Väitöstyön ensimmäisessä osassa hahmotellaan lääkeannostelumuotojen käyttöä veteen niukkaliukoisten lääkeaineiden liukenemisnopeuden parantamisessa, samalla kun aineiden vapautumista säädetään pitkäaikaisen terapeuttisen vaikutuksen aikaansaamiseksi. Väitöstyön toinen osa keskittyy kasvainten hoitoon.Siinä kuvataan lääkeannostelumuotojen kykyä estää syövänvastaisten aineiden vapautuminen verenkiertoa kuvastavissa fysiologisissa olosuhteissa sekä näiden kykyä kohdentaa vapautuminen kasvainympäristöön

Reusable platform for assembling glass capillaries for micro fluids (machine-translation by google translate, not legally binding)

La presente invención se trata de un dispositivo reusable que sirve de plataforma para capilares de vidrio usados en micro-fluidos. El dispositivo comprende tres partes: una plataforma, un inyector, y un sistema de sellado. La plataforma sirve de sujeción y guía a los capilares de vidrio. Además, esta y el inyector constan de una cámara de inyección que aloja el capilar de vidrio y recibe el fluido inyectado desde el exterior a través de una aguja insertada en el inyector. Ambas cámaras de inyección junto con el capilar de vidrio que sale de ellas, están selladas mediante el sistema de sellado, que comprende dos arandelas de goma, cada una rodeando una cámara, cuya presión es adecuada mediante el sistema de ajuste de presión, un tornillo con una tuerca palometa. El dispositivo es fácil de usar, reusable y permite trabajar con flujos de fluidos elevados.The present invention is a reusable device serving as a platform for glass capillaries used in micro-fluids. The device comprises three parts: a platform, an injector, and a sealing system. The platform serves as a support and guide to the glass capillaries. In addition, this and the injector consist of an injection chamber that houses the glass capillary and receives the fluid injected from the outside through a needle inserted in the injector. Both injection chambers together with the glass capillary that comes out of them, are sealed by the sealing system, which comprises two rubber washers, each surrounding a chamber, whose pressure is adequate through the pressure adjustment system, a screw with a thumb nut. The device is easy to use, reusable and allows to work with high fluid flows. (Machine-translation by Google Translate, not legally binding

Effect of vanadium carbide on dry sliding wear behavior of powder metallurgy AISI M2 high speed steel processed by concentrated solar energy

Mixtures of AISI M2 high speed steel and vanadium carbide (3, 6 or 10 wt.%) were prepared by powder metallurgy and sintered by concentrated solar energy (CSE). Two different powerful solar furnaces were employed to sinter the parts and the results were compared with those obtained by conventional powder metallurgy using a tubular electric furnace. CSE allowed significant reduction of processing times and high heating rates. The wear resistance of compacts was studied by using rotating pin-on-disk and linearly reciprocating ball-on-flat methods. Wear mechanisms were investigated by means of scanning electron microscopy (SEM) observations and chemical inspections of the microstructures of the samples. Better wear properties than those obtained by conventional powder metallurgy were achieved. The refinement of the microstructure and the formation of carbonitrides were the reasons for this.JCCM in the Spanish National Programme (Project PPIC10-0052-5968

Application of electric fields to clean ultrafiltration membranes fouled with whey model solutions

In this work, the effectiveness of electric fields to clean two ZrO2 TiO2 ultrafiltration (UF) membranes fouled with three types of whey model solutions was investigated. Membranes tested had different molecular weight cut-offs (MWCOs) (15 and 50 kDa). Whey model solutions consisted of aqueous solutions of bovine serum albumin (BSA) at 10 g/L, a mixture of BSA (10 g/L) and CaCl2 (1.65 g/L) and whey protein concentrate (WPC) (total protein content 45%) solutions at different concentrations (22.2, 33.3 and 150.0 g/L). The hydraulic cleaning efficiency (HCE) achieved by means of the application of the electric fields was evaluated as a function of the membrane MWCO and the operating conditions of the cleaning technique (applied potential, temperature of the cleaning solution and concentration of NaCl). The results demonstrated that the presence of NaCl favoured the removal of protein deposits on the membrane layer. On the other hand, the higher the temperature of the cleaning solution and the applied potential were, the higher HCE was achieved. Regarding the membrane MWCO, the permselective properties of the 15 kDa membrane were completely recovered after the cleaning procedure by electric field for all the feed fouling solutions tested, whereas this technique could not completely remove the protein deposits on the 50 kDa membrane when BSA solutions were used as feed.The authors of this work wish to gratefully acknowledge the financial support from the Spanish Ministry of Science and Innovation through the project CTM2010-20186 and the company MAGNETO Special Anodes B.V. for supplying the Ti-Ir electrode.Corbatón Báguena, MJ.; Alvarez Blanco, S.; Vincent Vela, MC.; Ortega Navarro, EM.; Pérez-Herranz, V. (2016). Application of electric fields to clean ultrafiltration membranes fouled with whey model solutions. Separation and Purification Technology. 159:92-99. https://doi.org/10.1016/j.seppur.2015.12.039S929915

Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain

More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use. In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6 hours of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6 hours seems to have some neuroprotective efficacy. TH duration longer than 72 hours or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Unclarified aspects are the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects. TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for cooling devices for the transfer of these patients and their centralisationSe cumple ahora más de una década del inicio de la hipotermia terapéutica (HT) en España, la única intervención neuroprotectora que ha venido a ser práctica estándar en el tratamiento de la encefalopatía hipóxico-isquémica perinatal (EHI). El objetivo de este artículo es ofrecer un panorama actual y presentar las controversias surgidas alrededor de la aplicación de esta terapia. En esta década se ha implantado con éxito la HT en la gran mayoría de los hospitales terciarios de España y más del 85% de los recién nacidos con EHI moderada-grave reciben esta terapia. Entre los aspectos que pueden mejorar la eficacia de la HT están su inicio precoz dentro de las primeras 6 horas de vida y el control de factores comórbidos asociados a la asfixia perinatal. En los pacientes con EHI moderada el inicio después de las 6 horas parece mantener cierta eficacia neuroprotectora. Una duración de la HT mayor de 72 horas o un enfriamiento más profundo no ofrecen mayor eficacia neuroprotectora y aumentan el riesgo de efectos adversos. Persiste la controversia acerca de la sedación durante la HT, la aplicación de esta intervención a los neonatos con EHI leve y en otros escenarios. La información pronóstica y su marco temporal es uno de los aspectos más desafiantes. La HT es universal en países con recursos económicos, aunque existen puntos de controversia no resueltos. Si bien es un tratamiento generalizado en nuestro país, falta disponer de dispositivos para el traslado de estos pacientes y su centralizació

In vivo dual-delivery of glucagon like peptide -1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the most promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding nanosystems for oral protein delivery is from in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems has been studied before, but the simultaneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model, induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the therapeutic efficacy of GLP-1. Four hours after the oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4 h, representing half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6 h after the oral administration of the dual-drug composite system and, although no statistically significant differences existed, the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study.Peer reviewe

Microfluidic assembly of multistage porous silicon-lipid vesicles for controlled drug release

A reliable microfluidic platform for the generation of stable and monodisperse multistage drug delivery systems is reported. A glass-capillary flow-focusing droplet generation device was used to encapsulate thermally hydrocarbonized porous silicon (PSi) microparticles into the aqueous cores of double emulsion drops, yielding the formation of a multistage PSi–lipid vesicle. This composite system enables a large loading capacity for hydrophobic drugs.Peer reviewe