Gisbert Garzarán, Miguel

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Gisbert Garzarán
Universidad Complutense de Madrid
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Now showing 1 - 10 of 15
  • Publication
    Antibiotic delivery from bone-targeted mesoporous silica nanoparticles for the treatment of osteomyelitis caused by methicillin-resistant Staphylococcus aureus
    (Elsevier, 2022-10-28) Aguilera Correa, John Jairo; Gisbert Garzarán, Miguel; Mediero, A.; Pablo Velasco, David de; Fernández Aceñero, María Jesús; Lozano Borregón, Daniel; Esteban, J.; Vallet Regí, María
    Osteomyelitis is a hard-to-treat infection of the bone and bone marrow that is mainly caused by Staphylococcus aureus, with an increasing incidence of methicillin-resistant S. aureus (MRSA). Owing to the aggressiveness of these bacteria in colonizing and destroying the bone, systemic antibiotic treatments fail to eradicate the infection. Instead, it normally entails surgery to remove the dead or infected bone. In this work, we report bone-targeted mesoporous silica nanoparticles for the treatment of osteomyelitis. The nanoparticles have been engineered with a functional gelatine/colistin coating able to hamper premature release from the mesopores while effectively disaggregating the bacterial biofilm. Because antibiotic resistance is a global emergency, we have designed two sets of identical nanoparticles, carrying each of them a clinically relevant antibiotic, that have demonstrated to have synergistic effect. The bone-targeted nanoparticles have been thoroughly evaluated in vitro and in vivo, obtaining a notable reduction of the amount of bacteria in the bone in just 24 h after only one dose, and paving the way for localized, nanoparticle-mediated treatment of MRSA-caused osteomyelitis. Statement of significance In this work, we propose the use of bone-targeted mesoporous silica nanoparticles to address S. aureus-caused osteomyelitis that render synergistic therapeutic effect via multidrug delivery. Because the bacterial biofilm is responsible for an aggressive surgical approach and prolonged antibiotic treatment, the nanoparticles have been functionalized with a functional coating able to both disaggregate the biofilm, hamper premature antibiotic release and protect the intact bone. These engineered nanoparticles are able to effectively target bone tissue both in vitro and in vivo, showing high biocompatibility and elevated antibacterial effect.
  • Publication
    Targeting Agents in Biomaterial-Mediated Bone Regeneration
    (MDPI, 2023-01-19) Gisbert Garzarán, Miguel; Gómez-Cerezo, Natividad; Vallet Regí, María
    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.
  • Publication
    Stimuli-responsive mesoporous nanomatrices for drug delivery
    (Universidad Complutense de Madrid, 2019-12-19) Gisbert Garzarán, Miguel; Manzano García, Miguel
    The 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...
  • Publication
    Mesoporous Silica Nanoparticles for Targeting Subcellular Organelles.
    (MDPI, 2020-12-18) Gisbert Garzarán, Miguel; Lozano Borregón, Daniel; Vallet Regí, María
    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.
  • Publication
    Arabic gum plus colistin coated moxifloxacin-loaded nano particles forthe treatment of bone infection caused by Escherichia coli
    (Elsevier, 2021-10-13) Aguilera Correa, John Jairo; Gisbert Garzarán, Miguel; Mediero Muñoz, Aránzazu; Carias Calix, R.A; Jiménez Jiménez, Carla; Esteban, Jaime; Vallet Regí, María
    Osteomyelitis is an inflammatory process of bone and bone marrow that may even lead topatient death. Even though this disease is mainly caused by Gram-positive organisms, the proportion of bone infections caused by Gram-negative bacteria, such as Escherichia coli, has significantly increased in recent years. In this work, mesoporous silica nanoparticles have been employed as a platform to engineer a nanomedicine able to eradicate E. coli- related bone infections. For that purpose, the nanoparticles have been loaded with moxifloxacin and further functionalized with Arabic gum and colistin (AG+CO-coated MX-loaded MSNs). The nanosystem demonstrated high affinity toward E. coli biofilm matrix, thanks to AG coating, and marked antibacterial effect because of the bactericidal effect of moxifloxacin and the disaggregating effect of colistin. AG+CO-coated MX-loaded MSNs were able to eradicate the infection developed on a trabecular bone in vitro and showed pronounced antibacterial efficacy in vivo against an osteomyelitis provoked by E. coli. Furthermore, AG+CO-coated MX-loaded MSNs were shown to be essentially non-cytotoxic with only slight effect on cell proliferation and mild hepatotoxicity, which might be attributed to the nature of both antibiotics. In view of these results, these nanoparticles may be considered as a promising treatment for bone infections caused by enterobacteria, such as E. coli, and introduce a general strategy against bone infections based on the implementation of antibiotics with different but complementary activity into a single nanocarrier.
  • Publication
    Mesoporous Silica Nanoparticles for the Treatment of Complex Bone Diseases: Bone Cancer, Bone Infection and Osteoporosis
    (MDPI, 2020-01-20) Gisbert Garzarán, Miguel; Manzano García, Miguel; Vallet Regí, María
    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.
  • Publication
    Influence of the Surface Functionalization on the Fate and Performance of Mesoporous Silica Nanoparticles.
    (MDPI, 2020-05-09) Gisbert Garzarán, Miguel; Vallet Regí, María
    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.
  • Publication
    Designing Mesoporous Silica Nanoparticles to Overcome Biological Barriers by Incorporating Targeting and Endosomal Escape.
    (ACS PUBLICATIONS, 2021-02-17) Gisbert Garzarán, Miguel; Lozano Borregón, Daniel; Matsumoto, Kotaro; Komcatsu, Aoi; Manzano García, Miguel; Tamanoi, Fuyuhiko; Vallet Regí, María
    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.
  • Publication
    Hybrid injectable sol-gel systems based on thermo-sensitive polyurethane hydrogels carrying pH-sensitive mesoporous silica nanoparticles for the controlled and triggered release of therapeutic agents.
    (Frontiers Media, 2020-02-15) Boffito, Monica; Torchio, Alessandro; Tonda-Turro, Chiara; Laurano, Rosella; Gisbert Garzarán, Miguel; Berckmann, Julia C; Cassino, Claudio; Manzano García, Miguel; Duda, Georg; Vallet Regí, María; Schmidt-Bleek, Katharina; Ciardelli, Gianluca
    Injectable therapeutical formulations locally releasing their cargo with tunable kinetics in response to external biochemical/physical cues are gaining interest in the scientific community, with the aim to overcome the cons of traditional administration routes. In this work, we proposed an alternative solution to this challenging goal by combining thermosensitive hydrogels based on custom-made amphiphilic poly(ether urethane)s (PEUs) and mesoporous silica nanoparticles coated with a self-immolative polymer sensitive to acid pH (MSN-CS-SIP). By exploiting PEU chemical versatility, Boc-protected amino groups were introduced as PEU building block (PEU-Boc), which were then subjected to a deprotection reaction to expose pendant primary amines along the polymer backbone (PEU-NH2, 3E18 NH2/gPEU-NH2) with the aim to accelerate system response to external acid pH environment. Then, thermo-sensitive hydrogels were designed (15% w/v) showing fast gelation in physiological conditions (approximately 5 min), while no significant changes in gelation temperature and kinetics were induced by the Boc-deprotection. Conversely, free amines in PEU-NH2 effectively enhanced and accelerated acid pH transfer (pH 5) through hydrogel thickness (PEU-Boc and PEUNH2 gels covered approximately 42 and 52% of the pH delta between their initial pH and the pH of the surrounding buffer within 30 min incubation, respectively). MSN-CS-SIP carrying a fluorescent cargo as model drug (MSN-CS-SIP-Ru) were then encapsulated within the hydrogels with no significant effects on their thermo-sensitivity. Injectability and in situ gelation at 37�C were demonstrated ex vivo through sub-cutaneous injection. Hybrid Hydrogels for pH-Triggered Release in rodents. Moreover, MSN-CS-SIP-Ru-loaded gels turned out to be detectable through the skin by IVIS imaging. Cargo acid pH-triggered delivery from PEU-Boc and PEUNH2 gels was finally demonstrated through drug release tests in neutral and acid pH environments (in acid pH environment approximately 2-fold higher cargo release). Additionally, acid-triggered payload release from PEU-NH2 gels was significantly higher compared to PEU-Boc systems at 3 and 4 days incubation. The herein designed hybrid injectable formulations could thus represent a significant step forward in the development of multi-stimuli sensitive drug carriers. Indeed, being able to adapt their behavior in response to biochemical cues from the surrounding physio-pathological environment, these formulations can effectively trigger the release of their payload according to therapeutic needs.
  • Publication
    Engineered pH-Responsive Mesoporous Carbon Nanoparticles for Drug Delivery
    (ACS PUBLICATIONS, 2020-03-05) Gisbert Garzarán, Miguel; Berkmann, Julia; Giasafaki, Dimitra; Lozano Borregón, Daniel; Spyrou, Konstantinos; Manzano García, Miguel; Steriotis, Theodore A; Duda, Georg; Schmidt-Bleek, Katharina; Charalambopoulou, Georgia; Vallet Regí, María
    In this work, two types of mesoporous carbon particles with different morphology, size and pore structure have been functionalized with a self-immolative polymer sensitive to changes in pH and tested as drug nanocarriers. It is shown that their textural properties allow significantly higher loading capacity compared to typical mesoporous silica nanoparticles. In vial release experiments of a model Ru dye at pH 7.4 and 5 confirm the pH-responsiveness of the hybrid systems, showing that only small amounts of the cargo are released at physiological pH, whereas at slightly acidic pH (e.g. that of lysosomes) self-immolation takes place and a significant amount of the cargo is released. Cytotoxicity studies using human osteosarcoma cells show that the hybrid nanocarriers are not cytotoxic by themselves but induce significant cell growth inhibition when loaded with a chemotherapeutic drug such as doxorubicin. In preparation of an in vivo application, in vial responsiveness of the hybrid system to short-term pH-triggering is confirmed. The consecutive in vivo study shows no substantial cargo release over a period of 96 hours under physiological pH conditions. Short-term exposure to acidic pH releases an experimental fluorescent cargo during and continuously after the triggering period over 72 hours.