Nanomatrices mesoporosas estímulo-respuesta para la liberación de fármacos

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Química en Ciencias Farmacéuticas, leída el 29-10-2019The overall objective of this PhD thesis has been the design and production of engineered mesoporous nanoparticles for biomedical applications. In this sense, the efforts during this doctoral thesis have been headed towards the development of nanomatrices with potential applicability in the treatment of complex diseases, such as bone and wound healing and cancer. The initial context of this doctoral thesis was the European project “MOZART” (“MesopOrous matrices for localiZed pH-triggered releAse of theRapeuTic ions and drugs”), which included many different European partners (11) from both academic and industrial environments. The proposal involved the use of mesoporous materials to treat delayed bone healing and chronic wound healing. The objective was to load therapeutic agents and ions within the mesoporous framework that would be released in the affected areas, boosting the healing and improving the health of the patients. The use of a stimuli responsive gatekeeper for the pore entrances to minimize potential premature release was considered. In this sense, the acid pH that was expected to be found in those pathological scenarios was selected as stimulus to trigger the payload release...El objetivo principal de esta tesis ha sido el diseño y la producción de nanopartículas mesoporosas para aplicaciones biomédicas. En este sentido, los esfuerzos durante esta tesis doctoral han estado dirigidos hacia el desarrollo de nanomatrices con potencial aplicabilidad en el tratamiento de enfermedades complejas, como pueden ser la reparación de fracturas crónicas graves de hueso y de heridas piel o el cáncer. El contexto inicial de esta tesis doctoral fue el proyecto europeo “MOZART”(“MesopOrous matrices for localiZed pH-triggered releAse of theRapeuTic ions and drugs”), que incluía diferentes miembros europeos (11) del ámbito académico e industrial. La proposición implicaba el uso de materiales mesoporosos para tratar enfermedades de hueso y piel. El objetivo era cargar agentes e iones terapéuticos en la matriz mesoporosa, los cuales serían liberados en las zonas de interés, fomentando la curación y mejorando la vida de los pacientes. El uso de compuertas estimulo-respuesta para cerrar los mesoporoso fue considerada. En ese sentido, el pH ácido que se esperaba encontrar en estas patologías fue considerado como estímulo para iniciar la liberación dela carga...Depto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEunpu

Influence of the Surface Functionalization on the Fate and Performance of Mesoporous Silica Nanoparticles.

Mesoporous silica nanoparticles have been broadly applied as drug delivery systems 14 owing to their exquisite features, such as excellent textural properties or biocompatibility. However, 15 there are various biological barriers that prevent their proper translation into the clinic, including 16 (1) lack of selectivity toward tumor tissues, (2) lack of selectivity for tumoral cells and (3) endosomal 17 sequestration of the particles upon internalization. In addition, their open porous structure may 18 lead to premature drug release, consequently affecting healthy tissues and decreasing the efficacy 19 of the treatment. First, this review will provide a comprehensive and systematic overview of the 20 different approximations that have been implemented into mesoporous silica nanoparticles to 21 overcome each of such biological barriers. Afterward, the potential premature and non-specific drug 22 release from these mesoporous nanocarriers will be addressed by introducing the concept of stimuli23 responsive gatekeepers, which endow the particles with on-demand and localized drug delivery

Mesoporous Silica Nanoparticles for the Treatment of Complex Bone Diseases: Bone Cancer, Bone Infection and Osteoporosis

Bone diseases, such as bone cancer, bone infection and osteoporosis, constitute a major issue for modern societies as a consequence of their progressive ageing. Even though these pathologies can be currently treated in the clinic, some of those treatments present drawbacks that may lead to severe complications. For instance, chemotherapy lacks of great tumor tissue selectivity, affecting healthy and diseased tissues. In addition, the inappropriate use of antimicrobials is leading to the appearance of drug-resistance bacteria and persistent biofilms, rendering current antibiotics useless. Furthermore, current antiosteoporotic treatments present many side effects as a consequence of their poor bioavailability and the need to use higher doses. In view of the exposed evidences, the encapsulation and selective delivery to the diseased tissues of the different therapeutic compounds seem highly convenient. In this sense, silica-based mesoporous nanoparticles offer great loading capacity within their pores, the possibility of modifying the surface to target the particles to the malignant areas and great biocompatibility. This manuscript is intended to be a comprehensive review of the available literature on complex bone diseases treated with silica-based mesoporous nanoparticles, whose further development and eventual translation into the clinic could bring significant benefits for our future society

Nanoparticles for Bio-Medical Applications

RESEARCHER ID M-3378-2014 (María Vallet Regí) ORCID 0000-0002-6104-4889 (María Vallet Regí)The Special Issue of Nanomaterials “Nanoparticles for Bio‐medical applications” high‐ 13 lights the use of different types of nanoparticles for biomedical applications, including magnetic nanoparticles, mesoporous carbon nanoparticles, mesoporous bioactive glass nanoparticles, and mesoporous silica nanoparticles, among others. The wide variety of applications covered by the 16 articles published here are proof of the growing attention that the use of nanoparticles has received in recent years.Depto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEUnión Europea. Horizonte 2020pu

Self-Immolative Polymers as novel pH-responsive gate keepers for drug delivery

A novel pH-sensitive nanocarrier based on mesoporous silica nanoparticles with self-immolative polymers blocking the pore openings is presented. Triggered release by acid pH is demonstrated, together with their in vitro biocompatibility and effective cell internalisation, which makes this new material a promising candidate for future applications in cancer treatment

Self-immolative chemistry in nanomedicine

Self-immolative chemistry is based on the cascade of disassembling reactions triggered by the adequate stimulation and leading to the sequential release of the smaller constituent elements. This review will focus on the possibilities that this type of chemistry offers to nanomedicine research, which is an area where the stimuli responsive behavior is always targeted. There are some examples on the use of self-immolative chemistry for prodrugs or nanoparticles for drug delivery, but there is still an exciting land of opportunities waiting to be explored. This review aims at revising what has been done so far, but, most importantly, it aims at inspiring new research of self-immolative chemistry on nanomedicine

Mesoporous Silica Nanoparticles for Targeting Subcellular Organelles.

Current chemotherapy treatments lack of great selectivity towards tumoral cells, which 13 leads to nonspecific drug distribution and subsequent side effects. In this regard, the use of 14 nanoparticles able to encapsulate and release therapeutic agents has attracted growing attention. In 15 this sense, mesoporous silica nanoparticles (MSNs) have been widely employed as drug carriers 16 owing to their exquisite physico-chemical properties. Because MSNs present a surface full of silanol 17 groups, they can be easily functionalized to endow the nanoparticles with many different 18 functionalities, including the introduction of moieties with affinity for the cell membrane or relevant 19 compartments within the cell, thus increasing the efficacy of the treatments. This review manuscript 20 will provide the state-of-the-art on MSNs functionalized for targeting subcellular compartments, 21 focusing on the cytoplasm, the mitochondria and the nucleus

Targeting Agents in Biomaterial-Mediated Bone Regeneration

Bone diseases are a global public concern that affect millions of people. Even though current treatments present high efficacy, they also show several side effects. In this sense, the development of biocompatible nanoparticles and macroscopic scaffolds has been shown to improve bone regeneration while diminishing side effects. In this review, we present a new trend in these materials, reporting several examples of materials that specifically recognize several agents of the bone microenvironment. Briefly, we provide a subtle introduction to the bone microenvironment. Then, the different targeting agents are exposed. Afterward, several examples of nanoparticles and scaffolds modified with these agents are shown. Finally, we provide some future perspectives and conclusions. Overall, this topic presents high potential to create promising translational strategies for the treatment of bone-related diseases. We expect this review to provide a comprehensive description of the incipient state-of-the-art of bone-targeting agents in bone regeneration

Designing Mesoporous Silica Nanoparticles to Overcome Biological Barriers by Incorporating Targeting and Endosomal Escape.

The several biological barriers that nanoparticles might encounter when administered to a patient constitute the major bottleneck of nanoparticle7 mediated tumor drug delivery, preventing their successful translation into the clinic and reducing their therapeutic profile. In this work, mesoporous silica nanoparticles have been employed as a platform to engineer a versatile nanomedicine able to address such barriers, achieving (a) excessive premature drug release control, (b) accumulation in tumor tissues, (c) selective internalization in tumoral cells, and (d) endosomal escape. The nanoparticles have been decorated with a self-immolative redox-responsive linker to prevent excessive premature release, to which a versatile and polyvalent peptide that is able to recognize tumoral cells and induce the delivery of the nanoparticles to the cytoplasm via endosomal escape has been grafted. The excellent biological performance of the carrier has been demonstrated using 2D and 3D in vitro cell cultures and a tumor-bearing chicken embryo model, demonstrating in all cases high biocompatibility and cytotoxic effect, efficient endosomal escape and tumor penetration, and accumulation in tumors grown on the chorioallantoic membrane of chicken embryos