Nuestros investigadores

María José Blanco Prieto

Facultad de Farmacia y Nutrición. Universidad de Navarra
Líneas de investigación
Nanotecnología aplicadas a biomateriales de interés farmacéutcio y biomédico. Vehículos transportadores de fármacos, proteínas y péptidos. Vectorización de medicamentos, nuevas formas de liberación controlada de fármacos. Micropartículas, scaffolds, fibr
Índice H
46, (Google Scholar, 08/10/2020)

Publicaciones científicas más recientes (desde 2010)

Autores: Torres Ortega, Pablo Vicente; Smerdou Picazo, Cristian; Ansorena Artieda, Eduardo; et al.
ISSN 0928-0987  Vol. 159  2021  págs. 105726
Human glial cell line-derived neurotrophic factor (hGDNF) is the most potent dopaminergic factor described so far, and it is therefore considered a promising drug for Parkinson's disease (PD) treatment. However, the production of therapeutic proteins with a high degree of purity and a specific glycosylation pattern is a major challenge that hinders its commercialization. Although a variety of systems can be used for protein production, only a small number of them are suitable to produce clinical-grade proteins. Specifically, the baby hamster kidney cell line (BHK-21) has shown to be an effective system for the expression of high levels of hGDNF, with appropriate post-translational modifications and protein folding. This system, which is based on the electroporation of BHK-21 cells using a Semliki Forest virus (SFV) as expression vector, induces a strong shut-off of host cell protein synthesis that simplify the purification process. However, SFV vector exhibits a temperature-dependent cytopathic effect on host cells, which could limit hGDNF expression. The aim of this study was to improve the expression and purification of hGDNF using a biphasic temperature cultivation protocol that would decrease the cytopathic effect induced by SFV. The protocol described constitutes an efficient and highly scalable method to produce highly pure hGDNF.
Autores: Puig Rigall, Joan; Blanco Prieto, María José (Autor de correspondencia); Radulescu, A.; et al.
ISSN 0021-9797  Vol. 582  2021  págs. 353-363
Hypothesis: The combination of polymeric surfactants into mixed micelles is expected to improve properties relevant to their use in drug delivery, such as micellar size, gelation, and toxicity. We investigated synergistic effects in mixtures of D-¿-Tocopheryl polyethylene glycol succinate (TPGS), an FDA-approved PEGylated derivative of vitamin E, and Tetronic surfactants, pH-responsive and thermogelling polyethylene oxide (PEO)-polypropylene oxide (PPO) 4-arm block copolymers. We hypothesized that mixed micelles would form under specific conditions and provide a handle to tune formulation characteristics. Experiments: We examined the morphology of the self-assembled structures in mixtures of TPGS with two Tetronic: T1107 and T908, using a combination of dynamic light scattering (DLS), small-angle neutron scattering (SANS), NMR spectroscopy (NOESY and diffusion NMR) and oscillatory rheology, over a range of compositions, temperatures and pH. Cell viability was assessed in NIH/3T3 fibroblasts. Findings: The combination of TPGS with either of the two Tetronic produces spherical core-shell micelles that comprise both surfactants in their structure (mixed micelles). T1107 unimers incorporate into TPGS aggregates below the critical micelle temperature of the poloxamine, while mixed micelles only form under limited conditions with T908. At high concentration/temperature, small proportions of TPGS extend the gel phase, more markedly with T1107, with similar elastic moduli (30-50 kPa) and a BCC crystalline structure. Cell viability of NIH/3T3 fibroblasts grown in the hydrogels increases significantly when the poloxamine gels are doped with TPGS, making the combination of poloxamines and TPGS a promising platform for drug delivery.
Autores: Puig Rigall, Joan; Blanco Prieto, María José; Aydillo Miguel, Carlos; et al.
ISSN 0167-7322  Vol. 324  2021 
The combination of polymeric surfactants with different features into mixed micelles give access to properties that may be superior to the single-component micelles. In this work, we investigated synergistic effects in mixtures of D-alpha-Tocopheryl polyethylene glycol succinate (TPGS) with poloxamines (also known as Tetronic), pH-responsive and thermogelling polyethylene oxide (PEO)-polypropylene oxide (PPO) 4-arm block copolymers. We examined the morphology of the self-assembled micelles of TPGS with Tetronic 1107 (T1107) and 908 (T908) in the presence of naproxen (NA), used as a model drug, and assessed the capacity of the single and mixed micelles to trap the guest, using a combination of small-angle neutron scattering (SANS) and NMR spectroscopy (1D, 2D-NOESY and diffusion NMR), over a range of compositions and temperatures, in the dilute regime and gel state. NA did not interact with T1107 or T908 in their unimer form, but it was incorporated into the hydrophobic core of the micelles above the critical micellar temperature (CMT). In contrast, TPGS dissolved NA at any temperature, mainly in the tocopherol core, with some partitioning in the PEG-shell. The micellar structure was not altered by the presence of NA, except for an expansion of the core size, a result of the preferential accumulation of NA in that compartment. The solubility of the drug in single component micelles increased markedly with temperature, while mixed micelles produced an intermediate enhancement o
Autores: Aparicio Blanco, Juan; Sanz-Arriazu, L.; Lorenzoni, Ricardo; et al.
ISSN 0378-5173  Vol. 581  2020  págs. 119283
Even though substantial advances in understanding glioma pathogenesis have prompted a more rational design of potential therapeutic strategies, glioblastoma multiforme remains an incurable disease with the lowest median overall survival among all malignant brain tumours. Therefore, there is a dire need to find novel drug delivery strategies to improve the current dismal survival outcomes. In this context, nanomedicine offers an appealing alternative as it shows potential to improve brain drug delivery. Accordingly, we here review nanomedicine-based drug delivery strategies tested in orthotopic animal models of glioblastoma intended to improve the efficacy of the drug candidates that are currently used in the clinical setting or that have entered clinical trials for the treatment of glioblastoma multiforme. We also outline the future perspectives of nanotechnology to provide emerging glioblastoma treatment with broad translational clinical potential based on the nanocarriers that have already entered the clinical trials stage for the treatment of malignant glioma.
Autores: Rodríguez Nogales, Carlos; Moreno, H.; Zandueta Pascual, Carolina; et al.
Revista: CANCERS
ISSN 2072-6694  Vol. 12  Nº 7  2020  págs. 1895
Due to chemoresistance and a high propensity to form lung metastasis, survival rates in pediatric osteosarcoma (OS) are poor. With the aim to improve anticancer activity in pediatric OS, a multidrug nanomedicine was designed using the alkyl-lysophospholipid edelfosine (EF) co-assembled with squalenoyl-gemcitabine (SQ-Gem) to form nanoassemblies (NAs) of 50 nm. SQ-Gem/EF NAs modified the total Gem pool exposure in the blood stream in comparison with SQ-Gem NAs, which correlated with a better tolerability and a lower toxicity profile after multiple intravenous administrations in mice. For in vivo preclinical assessment in an orthotopic OS tumor model, P1.15 OS cells were intratibially injected in athymic nude mice. SQ-Gem/EF NAs considerably decreased the primary tumor growth kinetics and reduced the number of lung metastases. Our findings support the candidature of this anticancer nanomedicine as a potential pediatric OS therapy.
Autores: Rodríguez Nogales, Carlos; Mura, S.; Couvreur, P., (Autor de correspondencia); et al.
ISSN 0378-5173  Vol. 582  2020 
Despite the great advances accomplished in the treatment of pediatric cancers, recurrences and metastases still exacerbate prognosis in some aggressive solid tumors such as neuroblastoma and osteosarcoma. In view of the poor efficacy and toxicity of current chemotherapeutic treatments, we propose a single multitherapeutic nanotechnology-based strategy by co-assembling in the same nanodevice two amphiphilic antitumor agents: squalenoyl-gemcitabine and edelfosine. Homogeneous batches of nanoassemblies were easily formulated by the nanoprecipitation method. Their anticancer activity was tested in pediatric cancer cell lines and pharmacokinetic studies were performed in mice. In vitro assays revealed a synergistic effect when gemcitabine was co-administered with edelfosine. Squalenoyl-gemcitabine/edelfosine nanoassemblies were found to be capable of intracellular translocation in patient-derived metastatic pediatric osteosarcoma cells and showed a better antitumor profile than squalenoyl-gemcitabine nanoassemblies alone. The intravenous administration of this combinatorial nanomedicine in mice exhibited a controlled release behavior of gemcitabine and diminished edelfosine plasma peak concentrations. These findings make it a suitable pre-clinical candidate for childhood cancer therapy.
Autores: Garbayo Atienza, Elisa; Pascual Gil de Gómez, Simón; Rodríguez Nogales, Carlos; et al.
ISSN 1939-5116  Vol. 12  Nº 5  2020  págs. e1637
Nanomedicine and drug delivery technologies play a prominent role in modern medicine, facilitating better treatments than conventional drugs. Nanomedicine is being increasingly used to develop new methods of cancer diagnosis and treatment, since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs, thereby reducing their toxicity. Regenerative medicine provides another area where innovative drug delivery technology is being studied for improved tissue regeneration. Drug delivery systems can protect therapeutic proteins and peptides against degradation in biological environments and deliver them in a controlled manner. Similarly, the combination of drug delivery systems and stem cells can improve their survival, differentiation, and engraftment. The present review summarizes the most important steps carried-out by the group of Prof Blanco-Prieto in nanomedicine and drug delivery technologies. Throughout her scientific career, she has contributed to the area of nanomedicine to improve anticancer therapy. In particular, nanoparticles loaded with edelfosine, doxorubicin, or methotrexate have demonstrated great anticancer activity in preclinical settings of lymphoma, glioma, and pediatric osteosarcoma. In regenerative medicine, a major focus has been the development of drug delivery systems for brain and cardiac repair. In this context, several microparticle-based technologies loaded with biologics have demonstrated efficacy in clinically relevant animal models such as monkeys and pigs. The latest research by this group has shown that drug delivery systems combined with cell therapy can achieve a more complete and potent regenerative response. Cutting-edge areas such as noninvasive intravenous delivery of cardioprotective nanomedicines or extracellular vesicle-based therapies are also being explored. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Autores: Saludas Echauri, Laura; Garbayo Atienza, Elisa; Mazo Vega, Manuel María; et al.
ISSN 0022-3565  Vol. 370  Nº 3  2019  págs. 761 - 771
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are a promising cell source for cardiac repair after myocardial infarction (MI) because they offer several advantages such as potential to remuscularize infarcted tissue, integration in the host myocardium, and paracrine therapeutic effects. However, cell delivery issues have limited their potential application in clinical practice, showing poor survival and engraftment after transplantation. In this work, we hypothesized that the combination of hiPSC-CMs with microparticles (MPs) could enhance long-term cell survival and retention in the heart and consequently improve cardiac repair. CMs were obtained by differentiation of hiPSCs by small-molecule manipulation of the Wnt pathway and adhered to biomimetic poly(lactic-co-glycolic acid) MPs covered with collagen and poly(D-lysine). The potential of the system to support cell survival was analyzed in vitro, demonstrating a 1.70-fold and 1.99-fold increase in cell survival after 1 and 4 days, respectively. The efficacy of the system was tested in a mouse MI model. Interestingly, 2 months after administration, transplanted hiPSC-CMs could be detected in the peri-infarct area. These cells not only maintained the cardiac phenotype but also showed in vivo maturation and signs of electrical coupling. Importantly, cardiac function was significantly improved, which could be attributed to a paracrine effect of cells. These findings suggest that MPs represent an excellent platform for cell delivery in the field of cardiac repair, which could also be translated into an enhancement of the potential of cell-based therapies in other medical applications.
Autores: Luque Michel, Edurne; Sebastian, V., (Autor de correspondencia); Larrea, A. ; et al.
ISSN 0939-6411  Vol. 145  2019  págs. 65 - 75
With a very poor prognosis and no clear etiology, glioma is the most aggressive cancer in the brain. Thanks to its versatility, nanomedicine is a promising option to overcome the limitations on chemotherapy imposed by the blood brain barrier (BBB). The objective of this paper was to obtain monitored tumor-targeted therapeutic nanoparticles (NPs). To that end, theranostic surfactant-coated polymer poly-Lactic-co-Glycolic Acid (PLGA) nanoplatform encapsulating doxorubicin hydrochloride (DOX) and superparamagnetic iron oxide NPs (SPIONs) were developed. Different non-ionic surfactants known as BBB crossing enhancers (Tween 80, Brij-35, Pluronic F68 or Vitamin E-TPGS) were used to develop 4 types of theranostic nanoplatforms, which were characterized in terms of size and morphology by DLS, TEM and STEM-HAADF analyses. Moreover, the 3-month stability test, the therapeutic efficacy against different glioma cell lines (U87-MG, 9L/LacZ and patient derived-neuronal stem cells) and the Magnetic Resonance Imaging (MRI) relaxivity were studied. Results showed that the synthesised nanoplatforms were stable at 4 degrees C after their lyophilization, being that of paramount importance to ensure a long-term stability in a future in vivo application. Furthermore, the theranostic nanoplatforms were efficient in the in vitro treatment of glioma cells, proving to have imaging efficacy as MRI contrast agents. Our results show an efficient loading of drugs and good value of the relaxivity. Therefore, the efficient theranostic hybrid nanoplatform developed here could be used to perform MRI-guided delivery of hydrophobic drugs.
Autores: Pascual Gil de Gómez, Simón; Abizanda Sarasa, Gloria María; Iglesias López, Elena; et al.
ISSN 1061-186X  Vol. 27  Nº 43987  2019  págs. 573 - 581
Neuregulin-1 loaded poly(lactic-co-glycolic acid) (PLGA) microparticles hold great promise for treating acute myocardial infarction, as they have been proved to recover heart function and induce positive heart remodelling in preclinical studies. More recently, the inflammatory response of the heart after acute myocardial infarction (AMI) has been identified as one of the major mechanisms in cardiac tissue remodelling and repair. However, the connection between neuregulin-1 PLGA microparticles and inflammation is still not well characterised. In the present study we assessed this relationship in a mouse AMI model. First, in vitro evidence indicated that neuregulin-1 PLGA microparticles induced a macrophage polarisation toward a regenerative phenotype (CD206+ cells), preventing macrophages from evolving toward the inflammatory phenotype (B7-2+ cells). This correlated with in vivo experiments, where neuregulin-1 PLGA microparticles locally improved the CD206+/B7-2+ ratio. Moreover, neuregulin-1 PLGA microparticles were administered at different time points (15¿min, 24, 72 and 168¿h) after infarction induction without causing secondary inflammatory issues. The time of treatment administration did not alter the inflammatory response. Taken together, these results suggest that neuregulin-1 PLGA microparticles can be administered depending on the therapeutic window of the encapsulated drug and that they enhance the heart's reparative inflammatory response after acute myocardial infarction, helping cardiac tissue repair.
Autores: Rodríguez Nogales, Carlos; Sebastian, V.; Irusta, S. ; et al.
ISSN 0939-6411  Vol. 144  2019  págs. 165 - 173
Among anticancer nanomedicines, squalenoyl nanocomposites have obtained encouraging outcomes in a great variety of tumors. The prodrug squalenoyl-gemcitabine has been chosen in this study to construct a novel multidrug nanosystem in combination with edelfosine, an alkyl-lysophopholipid with proven anticancer activity. Given their amphiphilic nature, it was hypothesized that both anticancer compounds, with complementary molecular targets, could lead to the formation of a new multitherapy nanomedicine. Nanoassemblies were formulated by the nanoprecipitation method and characterized by dynamic light scattering, transmission electron microscopy and X-ray photoelectron spectroscopy. Because free edelfosine is highly hemolytic, hemolysis experiments were performed using human blood erythrocytes and nanoassemblies efficacy was evaluated in a patient-derived metastatic pediatric osteosarcoma cell line. It was observed that these molecules spontaneously self-assembled as stable and monodisperse nanoassemblies of 51 +/- 1 nm in a surfactant/polymer free-aqueous suspension. Compared to squalenoyl-gemcitabine nanoassemblies, the combination of squalenoyl-gemcitabine with edelfosine resulted in smaller pArtículo size and a new supramolecular conformation, with higher stability and drug content, and ameliorated antitumor profile.
Autores: Torres Ortega, Pablo Vicente; Saludas Echauri, Laura; Hanafy, A. S. ; et al.
ISSN 0168-3659  Vol. 295  2019  págs. 201 - 213
Current therapies for Parkinson's disease are symptomatic and unable to regenerate the brain tissue. In recent years, the therapeutic potential of a wide variety of neuroprotective and neuroregenerative molecules such as neurotrophic factors, antioxidants and RNA-based therapeutics has been explored. However, drug delivery to the brain is still a challenge and the therapeutic efficacy of many drugs is limited. In the last decade, micro- and nanoparticles have proved to be powerful tools for the administration of these molecules to the brain, enabling the development of new strategies against Parkinson's disease. The list of encapsulated drugs and the nature of the particles used is long, and numerous studies have been carried out supporting their efficacy in treating this pathology. This review aims to give an overview of the latest advances and emerging frontiers in micro- and nanomedical approaches for repairing dopaminergic neurons. Special emphasis will be placed on offering a new perspective to link these advances with the most relevant clinical trials and with the real possibility of transferring micro- and nanoformulations to industrial scale-up processes. This review is intended as a contribution towards facing the challenges that still exist in the clinical translation of micro- and nanotechnologies to administer therapeutic agents in Parkinson's disease.
Autores: Rodríguez Nogales, Carlos; Noguera, R.; Couvreur, P. , (Autor de correspondencia); et al.
ISSN 0022-3565  Vol. 370  Nº 3  2019  págs. 625 - 635
Neuroblastoma (NB) is the most common extracranial solid tumor preferentially occurring in preschoolers. Its characteristic aggressiveness and heterogeneous clinical behavior are especially visible in relapsed or refractory cases and hamper therapeutic success. Although the introduction of novel antitumor agents, such as dinutuximab, isotretinoin, irinotecan, or I-131- metaiodobenzylguanidine, has increased survival rates, the situation in high-risk NB remains dismal. Moreover, treatment is particularly aggressive in these patients, leading to short- and long-term toxicities. The extensive research performed using nanotechnology in recent decades has prompted its application as a therapeutic alternative to overcome some of the common limitations of conventional chemotherapy. Nevertheless, the therapeutic role of nanomedicine in pediatric tumors like NB is not fully elucidated, and to date, only albumin-bound paclitaxel nanoparticles have reached clinic stages. In this review, we summarize the current therapeutic strategies for NB with special attention to the use of nanomedicine. We also highlight the preclinical studies on passive and active targeting nanodelivery of therapeutics in experimental NB models.
Autores: Puig Rigall, Joan; Obregon-Gomez, I.; Monreal-Perez, P. ; et al.
ISSN 0021-9797  Vol. 524  2018  págs. 42 - 51
Tetronics are X-shaped block-copolymers of polyethylene oxide and polypropylene oxide, which self-assemble into micelles and can undergo a sol-gel transition; these transitions are dependent on temperature, concentration but also pH, due to the central diamine group of the tetrablock. We report the nanoscale morphologies underlying these different phases and the rheology of the systems for a very large, highly hydrophilic block copolymer, Tetronic 908, through the combined use of oscillatory rheology, steadyblock-state and time-resolved fluorescence, small-angle neutron scattering (SANS), dynamic light scattering (DLS) and Fourier transform infrared attenuated total reflectance (FTIR-ATR). At low concentrations, SANS reveal core-shell micelles of ca. 10 nm radius, presenting a dehydrated core and a highly hydrated shell, with relatively small aggregation numbers (N-agg approximate to 13). The micelles are notably affected by the pH, due to the protonation of the central amine spacer at low pH (pH approximate to 2), which shifts micellization to higher temperature, with smaller micelles than at natural pH. In the intermediate concentration regime (10-15%), micelles become smaller (N-agg approximate to 5), and present a higher hydration of the core. In the high concentration regime, Tetronic 908 undergoes a sol-gel transition above a threshold temperature, which is fully inhibited at acidic pH. SANS data from the gel phase reveal a BCC order of tightly packed spheres. Temperature sweeps in oscillatory rheology show a shift of the onset of gelation towards lower temperatures as concentration increases, an increase in the elastic modulus G' and an expansion of gel region over a larger range of temperatures. SANS and rheology reveal that at pH below the natural pH (ca. 8), gelation is shifted to higher temperatures, but the morphology of the gels is similar, while under highly acidic conditions the gelation is fully suppresed. (C) 2018 Elsevier Inc. All rights reserved.
Autores: Unamuno Iñurritegui, Xabier; Imbuluzqueta Iturburua, Edurne; Salles, F. ; et al.
ISSN 0939-6411  Vol. 132  2018  págs. 11-18
Due to their high porosity and versatile composition and structure, nanoscaled Metal-Organic Frameworks (nanoMOFs) have been recently proposed as novel drug delivery systems, and have been demonstrated to have important capacities and potential for controlled release of different active ingredients. Gentamicin (GM; a broad spectrum aminoglycoside antibiotic indicated in bacterial septicemia therapy) has great therapeutic interest, but the associated bioavailability and toxicity drawbacks accompanying high doses and repeated administration of this free drug make its encapsulation inside new nanocarriers necessary. GM encapsulation within two different porous biofriendly Fe and Zr-carboxylates nanoMOFs was performed by a simple impregnation method, with full characterization of the resulting GM-containing solid using a large panel of techniques (X ray powder diffraction-XRPD, Fourier transform infrared spectroscopy-FTIR, thermogravimetric analysis-TGA, N-2 sorption, scanning electron microscopy-SEM, dynamic light scattering-DLS, zeta-potential, fluorescence spectroscopy and molecular simulations). High reproducible encapsulation rates, reaching 600 mu g of GM per mg of formulation, were obtained using the biocompatible mesoporous iron(III) trimesate nanoparticles (NPs) MIL-100(Fe) (MIL: Materials from Institut Lavoisier). In vitro GM delivery studies were also carried out using different oral and intravenous simulated physiological conditions, with complete antibiotic release within 8 h when using protein free media, but lower release rates in the presence of proteins. Furthermore, in vitro toxicity of GM-containing MIL-100(Fe) NPs was investigated on two different cell lines: a monocyte from leukemia (THP-1) and adherent fibroblastoid cells (NIH/3T3). These nanoMOFs had a low cytotoxic profile with IC50 values up to 1 mg.mL(-1), ensuring adequate cell proliferation after 24 h. Finally, antibacterial activity studies were carried out on two Gram-positive bacteria and one Gram-negative bacterium: S. aureus, S. epidermidis and P. aeruginosa, respectively. GM-loaded MIL-100(Fe) NPs exhibited the same activity as free GM, confirming that the antibiotic activity of the released GM was conserved.
Autores: Saludas Echauri, Laura; Pascual Gil de Gómez, Simón; Roli, F.; et al.
ISSN 0378-5122  Vol. 110  2018  págs. 1 - 9
The capacity of the heart to heal after a myocardial infarction is not enough to restore normal cardiac function. Fortunately, delivery of therapeutics such as stem cells, growth factors, exosomes and small interfering ribonucleic acid (siRNA), among other bioactive molecules, has been shown to enhance heart repair and improve cardiac function. Furthermore, new delivery systems for these therapeutic agents have enhanced their regenerative and cardioprotective potential. In particular, nano- and microparticles (NPs and MPs) are promising. These systems may be administered directly in the infarcted myocardium or reach the heart after intravenous injection due to the enhanced permeability and retention effect or active targeting. Thus, NPs and MPs have made it possible to administer a wide range of potential drugs, including therapeutic molecules and/or stem cells, and evidence in favor of their use has been reported in several preclinical studies. Here, we review the studies done over the last 5 years using NPs and MPs loaded with therapeutics for repairing cardiac tissue after a myocardial infarction, and discuss some of the advances, challenges and future prospects in this field. In addition, we address the application of NPs and MPs for cardioprotective purposes.
Autores: González Fernández, Yolanda; Brown, H. K.; Patiño García, Ana; et al.
ISSN 0304-3835  Vol. 430  2018  págs. 193 - 200
Osteosarcoma (OS) is the most frequent paediatric bone cancer, responsible for 9% of all cancer-related deaths in children. In this paper, a new strategy based on delivering edelfosine (ET) in lipid nanoparticles (LN) was explored in order to target the primary tumour and eliminate metastases. The in vitro and in vivo efficacy of the free drug, drug loaded into lipid nanoparticles (ET-LN) and doxorubicin (DOX) against osteosarcoma (OS) cells was analysed. ET and ET-LN decreased the growth of OS cells in vitro in a time- and dose-dependent manner. Interestingly, the uptake of ET and ET-LN was lower when OS cells were pre-treated with DOX. In vivo studies revealed that ET and ET-LN slowed down the primary tumour growth in two OS models. However, the combination of both drugs showed no additional anti-tumour effect. Importantly, ET-LN successfully prevented the metastatic spread of OS cells from the primary tumour to the lungs. On the whole, ET-LN are a promising candidate for OS chemotherapy.
Autores: Rodríguez Nogales, Carlos; González Fernández, Yolanda; Aldaz Pastor, Azucena; et al.
Revista: ACS NANO
ISSN 1936-0851  Vol. 12  Nº 8  2018  págs. 7482 - 7496
Chemotherapy protocols for childhood cancers are still problematic due to the high toxicity associated with chemotherapeutic agents and incorrect dosing regimens extrapolated from adults. Nanotechnology has demonstrated significant ability to reduce toxicity of anticancer compounds. Improvement in the therapeutic index of cytostatic drugs makes this strategy an alternative to common chemotherapy in adults. However, the lack of nanomedicines specifically for pediatric cancer care raises a medical conundrum. This review highlights the current state and progress of nanomedicine in pediatric cancer and discusses the real clinical challenges and opportunities.
Autores: Rodríguez Nogales, Carlos; González Fernández, Yolanda; Aldaz Pastor, Azucena; et al.
Revista: ACS NANO
ISSN 1936-0851  Vol. 12  Nº 8  2018  págs. 7482-7496
Chemotherapy protocols for childhood cancers are stillproblematic due to the high toxicity associated with chemotherapeuticagents and incorrect dosing regimens extrapolated from adults.Nanotechnology has demonstrated significant ability to reduce toxicityof anticancer compounds. Improvement in the therapeutic index ofcytostatic drugs makes this strategy an alternative to commonchemotherapy in adults. However, the lack of nanomedicinesspecifically for pediatric cancer care raises a medical conundrum.This review highlights the current state and progress of nanomedicinein pediatric cancer and discusses the real clinical challenges andopportunities.
Autores: Del Rey, N. L. G.; Quiroga Varela, Ana; Garbayo Atienza, Elisa; et al.
ISSN 1662-5129  Vol. 12  Nº 113  2018 
When James Parkinson described the classical symptoms of the disease he could hardly foresee the evolution of our understanding over the next two hundred years. Nowadays, Parkinson's disease is considered a complex multifactorial disease in which genetic factors, either causative or susceptibility variants, unknown environmental cues, and the potential interaction of both could ultimately trigger the pathology. Noteworthy advances have been made in different fields from the clinical phenotype to the decoding of some potential neuropathological features, among which are the fields of genetics, drug discovery or biomaterials for drug delivery, which, though recent in origin, have evolved swiftly to become the basis of research into the disease today. In this review, we highlight some of the key advances in the field over the past two centuries and discuss the current challenges focusing on exciting new research developments likely to come in the next few years. Also, the importance of pre-motor symptoms and early diagnosis in the search for more effective therapeutic options is discussed.
Autores: Díaz Herráez, Paula; Saludas, L.; Pascual Gil de Gómez, Simón; et al.
ISSN 0168-3659  Vol. 249  2017  págs. 23 - 31
Tissue engineering is a promising strategy to promote heart regeneration after a myocardial infarction (MI). In this study, we investigated the reparative potential of a system that combines adipose-derived stem cells (ADSCs) with microparticles (MPs) loaded with neuregulin (NRG), named ADSC-NRG-MPs, on a rat MI model. First, cells were attached to the surface of MPs encapsulating NRG and coated with a 1:1 mixture of collagen and poly-D-lysine. One week after in vivo administration, the system favored the shift of macrophage expression from a pro-inflammatory to a regenerative phenotype. At long-term, the adhesion of ADSCs to MPs resulted in an increased cell engraftment, with cells being detectable in the tissue up to three months. In consonance, better tissue repair was observed in the animals treated with cells attached to MPs, which presented thicker left ventricles than the animals treated with ADSCs alone. Moreover, the presence of NRG in the system promoted a more complete regeneration, reducing the infarct size and stimulating cardiomyocyte proliferation. Regarding vasculogenesis, the presence of ADSCs and NRG-MPs alone stimulated vessel formation when compared to the control group, but the combination of both induced the largest vasculogenic effect, promoting the formation of both arterioles and capillaries. Importantly, only when ADSCs were administered adhered to MPs, they were incorporated into newly formed vessels. Collectively, these findings demonstrate that the combination of ADSCs, MPs and NRG favored a synergy for inducing a greater and more complete improvement in heart regeneration and provided strong evidence to move forward with preclinical studies with this strategy. (C) 2017 Elsevier B.V. All rights reserved.
Autores: Mitxelena Iribarren, Oihane; Hisey, C. L.; Errazquin Irigoyen, M. ; et al.
ISSN 1387-2176  Vol. 19   Nº 2  2017  págs. 35
Cancer is a leading cause of mortality in the world, with osteosarcoma being one of the most common types among children between 1 and 14 years old. Current treatments including preoperative chemotherapy, surgery and postoperative chemotherapy produce several side effects with limited effectiveness. The use of lipid nanoparticles as biodegradable shells for controlled drug delivery shows promise as a more effective and targeted tumor treatment. However, in vitro validation of these vehicles is limited due to fluid stagnation in current techniques, in which nanoparticles sediment onto the bottom of the wells killing the cells by asphyxiation. In the current series of experiments, results obtained with methotrexate-lipid nanoparticles under dynamic assay conditions are presented as a promising alternative to current free drug based therapies. Effects on the viability of the U-2 OS osteosarcoma cell line of recirculation of cell media, free methotrexate and blank and methotrexate containing lipid nanoparticles in a 11 mu M concentration were successfully assessed. In addition, several designs for the microfluidic platform used were simulated using COMSOL-Multiphysics, optimized devices were fabricated using soft-lithography and simulated parameters were experimentally validated. Nanoparticles did not sediment to the bottom of the platform, demonstrating the effectiveness of the proposed system. Moreover, encapsulated methotrexate was the most effective treatment, as after 72 h the cell population was reduced nearly 40% while under free methotrexate circulation the cell population doubled. Overall, these results indicate that methotrexate-lipid nanoparticles are a promising targeted therapy for osteosarcoma treatment.
Autores: Pascual Gil de Gómez, Simón; Simón Yarza, María Teresa; Garbayo Atienza, Elisa; et al.
ISSN 0378-5173  Vol. 523  Nº 2  2017  págs. 531 - 533
Neuregulin (NRG1) and fibroblast growth factor (FGF1) are well known growth factors implicated in cardiomyocyte proliferation and survival, as well as in angiogenesis, the development of adult heart and the maintenance of cardiac function. NRG1 and FGF1 have become promising therapeutic agents to treat myocardial infarction (MI) disorder. Unfortunately, clinical trials performed so far reported negative efficacy results, because growth factors are rapidly degraded and eliminated from the biological tissues once administered. In order to increase their bioavailability and favour their therapeutic effects, they have been combined with poly(lactic-co-glycolic acid) and polyethylene glycol microparticles (PLGA MPs and PEG-PLGA MPs). Here we compare both types of microparticles loaded with NRG1 or FGF1 in terms of efficacy in a rat MI model. Our results showed that intramyocardial injection of NRG1 or FGF1-loaded PLGA and PEG-PLGA MPs brought about similar improvements in the ejection fraction, angiogenesis and arteriogenesis after administration into the infarcted hearts. PEG coating did not add any effect regarding MP efficacy. Both PLGA and PEG-PLGA MPs were equally phagocyted in the heart. To our knowledge, this is the first study analysing the opsonisation process in heart tissue. The results allow us to conclude that the opsonisation process is different in heart tissue compared to blood. (C) 2016 Elsevier B.V. All rights reserved.
Autores: Saludas, L.; Pascual Gil de Gómez, Simón; Prosper Cardoso, Felipe; et al.
ISSN 0378-5173  Vol. 523  Nº 2  2017  págs. 454 - 475
Heart failure still represents the leading cause of death worldwide. Novel strategies using stem cells and growth factors have been investigated for effective cardiac tissue regeneration and heart function recovery. However, some major challenges limit their translation to the clinic. Recently, biomaterials have emerged as a promising approach to improve delivery and viability of therapeutic cells and proteins for the regeneration of the damaged heart. In particular, hydrogels are considered one of the most promising vehicles. They can be administered through minimally invasive techniques while maintaining all the desirable characteristics of drug delivery systems. This review discusses recent advances made in the field of hydrogels for cardiac tissue regeneration in detail, focusing on the type of hydrogel (conventional, injectable, smart or nano-and micro-gel), the biomaterials used for its manufacture (natural, synthetic or hybrid) and the therapeutic agent encapsulated (stem cells or proteins). We expect that these novel hydrogel-based approaches will open up new possibilities in drug delivery and cell therapies. (C) 2016 Elsevier B.V. All rights reserved.
Autores: González Fernández, Yolanda; Imbuluzqueta Iturburua, Edurne; Zalacain Díez, Marta; et al.
ISSN 0304-3835  Vol. 388  2017  págs. 262 - 268
Despite the great advances that have been made in osteosarcoma therapy during recent decades, recurrence and metastases are still the most common outcome of the primary disease. Current treatments include drugs such as doxorubicin (DOX) that produce an effective response during the initial exposure of tumor cells but sometimes induce drug resistance within a few cycles of chemotherapy. New therapeutic strategies are therefore needed to overcome this resistance. To this end, DOX was loaded into lipid nanoparticles (LN) and its efficacy was evaluated in commercial and patient-derived metastatic osteosarcoma cell lines. DOX efficacy was heavily influenced by passage number in metastatic cells, in which an overexpression of P-gp was observed. Notably, DOX-LN overcame the resistance associated with cell passage and improved DOX efficacy fivefold. Moreover, when DOX was co-administered with either free or encapsulated edelfosine (ET), a synergistic effect was observed. This higher efficacy of the combined treatment was found to be at least partially due to an increase in caspase-dependent cell death. The combination of DOX and ET is thus likely to be effective against osteosarcoma. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
Autores: Luque Michel, Edurne; Sebastian, V.; Szczupak, B.; et al.
ISSN 1773-2247  Vol. 42  2017  págs. 315 - 320
Nanotechnology is growing quickly, with great advances in the area of nanomedicine. Opening the door to personalized medicine, a considerable number of nanosystems have been synthetized for the diagnosis, treatment and monitoring of diseases. Specifically, gold nanoparticles (AuNPs) have been shown to be good contrast agents. However, they have a limited surface area for the transport of active molecules. In this paper, polymeric nanoparticles encapsulating AuNPs have been synthetized by the double emulsion method (w/o/w) and solvent evaporation technique. This approach opens up the possibility of encapsulating hydrophilic and/or lipophilic thermostable biomolecules. The nanoparticles could be monitored in macrophage cells by simple scanning electron microscopy (SEM). Nevertheless, a micro computed tomography (micro-CT) study revealed that they would not be detected in future in vivo studies. In short, this paper explains the difficulty of obtaining nanovehicles that are trackable from early investigation stages to their clinical use, and discusses the controversy surrounding the concentration of AuNPs needed to obtain enough X-ray attenuation with safe doses. (C) 2017 Elsevier B.V. All rights reserved.
Autores: Alvarez-Lorenzo, C., (Autor de correspondencia); Alonso, M. J.; Blanco Prieto, María José; et al.
Título: Editorial
ISSN 1773-2247  Vol. 42  2017  págs. 1 - 1
Autores: Blanco Prieto, María José; Garbayo Atienza, Elisa
ISSN 0378-5173  Vol. 523  Nº 2  2017  págs. 439 - 440
Autores: Wen, M. M.; El-Salamouni, N. S.; El-Refaie, W. M.; et al.
ISSN 0168-3659  Vol. 245  2017  págs. 95 - 107
Alzheimer's disease (AD) is a neurodegenerative disease with high prevalence in the rapidly growing elderly population in the developing world. The currently FDA approved drugs for the management of symptomatology of AD are marketed mainly as conventional oral medications. Due to their gastrointestinal side effects and lack of brain targeting, these drugs and dosage regiments hinder patient compliance and lead to treatment discontinuation. Nanotechnology-based drug delivery systems (NTDDS) administered by different routes can be considered as promising tools to improve patient compliance and achieve better therapeutic outcomes. Despite extensive research, literature screening revealed that clinical activities involving NTDDS application in research for AD are lagging compared to NTDDS for other diseases such as cancers. The industrial perspectives, processability, and cost/benefit ratio of using NTDDS for AD treatment are usually overlooked. Moreover, active and passive immunization against AD are by far the mostly studied alternative AD therapies because conventional oral drug therapy is not yielding satisfactorily results. NTDDS of approved drugs appear promising to transform this research from 'paper to clinic' and raise hope for AD sufferers and their caretakers. This review summarizes the recent studies conducted on NTDDS for AD treatment, with a primary focus on the industrial perspectives and processability. Additionally, it highlights the ongoing clinical trials for AD management.
Autores: Garbayo Atienza, Elisa; Ansorena Artieda, Eduardo; Lana Vega, Hugo; et al.
ISSN 0142-9612  Vol. 110  2016  págs. 11-23
Glial cell line-derived neurotrophic factor (GDNF) remains the most potent neurotrophic factor for dopamine neurons. Despite its potential as treatment for Parkinson's disease (PD), its clinical application has been hampered by safety and efficacy concerns associated with GDNF's short in vivo half-life and with significant brain delivery obstacles. Drug formulation systems such as microparticles (MPs) may overcome these issues providing protein protection from degradation and sustained drug release over time. We therefore sought to evaluate the efficacy and safety of GDNF delivered via injectable biodegradable MPs in a clinically relevant model of PD and to investigate the mechanism contributing to their beneficial effects. MPs were injected unilaterally into the putamen of parkinsonian monkeys with severe nigrostriatal degeneration. Notably, a single administration of the microencapsulated neurotrophic factor achieved sustained GDNF levels in the brain, providing motor improvement and dopaminergic function restoration. This was reflected by a bilateral increase in the density of striatal dopaminergic neurons 9 months after treatment. Moreover, GDNF was retrogradely transported to the substantia nigra increasing bilaterally the number of dopaminergic and total neurons, regardless of the severe degeneration. GDNF-MP injection within the putamen elicited no adverse effects such as immunogenicity, cerebellar degeneration or weight loss. MPs are therefore a safe, efficient vehicle for sustained protein delivery to the brain, supporting the therapeutic benefit of GDNF when encapsulated within MPs for brain repair. Overall, these findings constitute important groundwork for GDNF-MP clinical development.
Autores: Guada Ramírez, Melissa; Lasa Saracíbar, Beatriz; Lana Vega, Hugo; et al.
ISSN 0378-5173  Vol. 500  Nº 1 - 2  2016  págs. 154 - 161
In the present work, the feasibility of cyclosporine A lipid nanoparticles (CsA LN) for oral administration was investigated. Three CsA LN formulations were developed using Precirol as lipid matrix, one stabilized with Tween(®) 80 (Tw) and the other two with mixtures of phosphatidylcholine or Pluronic(®) F127 with taurocholate (Lec:TC and PL:TC, respectively). The physical characteristics of the LN were studied under gastrointestinal pH and their integrity was found to be dependent on the stabilizers. The in vitro intestinal permeability was assessed with a human colon adenocarcinoma cell model and in vivo pharmacokinetic and biodistribution studies were performed in Balb/c mice using Sandimmune Neoral(®) as reference. In vitro results showed the highest CsA permeability with the LN containing Lec:TC. In contrast, the best in vivo performance was achieved from the LN containing Tw. The bioavailability of CsA was matched and even enhanced with Precirol nanoparticles. This study suggests the suitability of LN as promising vehicles for CsA oral delivery.
Autores: Garbayo Atienza, Elisa; Gavira Gómez, Juan José; García de Yébenes Castro, Manuel; et al.
ISSN 2045-2322  Vol. 6  2016  págs. 25932
Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials.
Autores: Guada Ramírez, Melissa; Beloqui, A.; Alhouayek, M.; et al.
ISSN 0378-5173  Vol. 503  Nº 1 - 2  2016  págs. 196 - 198
Cyclosporine A (CsA) is a well-known immunosuppressive agent used as rescue therapy in severe steroid-refractory ulcerative colitis (UC). However, toxicity issues associated with CsA when administered in its commercially available formulations have been reported in clinical practice. Since nanotechnology has been proposed as a promising strategy to improve safety and efficacy in the treatment of inflammatory bowel disease (IBD), the main purpose of this study was to evaluate the effect of oral administration of CsA-loaded lipid nanoparticles (LN) in the dextran sodium sulfate (DSS)-induced colitis mouse model using Sandimmune Neoral (R) as reference. The results showed that the formulations used did not decrease colon inflammation in terms of myeloperoxidase activity (MPO), tumor necrosis factor (TNF)-alpha expression, or histological scoring in the acute stage of the disease. However, further studies are needed in order to corroborate the efficacy of these formulations in the chronic phase of the disease.
Autores: Guada Ramírez, Melissa; Lana Vega, Hugo; Gil Royo, Ana Gloria; et al.
ISSN 0939-6411  Vol. 101  2016  págs. 112 - 118
The pharmacodynamic effect and the safety of cyclosporine A lipid nanoparticles (CsA LN) for oral administration were investigated using Sandimmune Neoral as reference. First, the biocompatibility of the unloaded LN on Caco-2 cells was demonstrated. The pharmacodynamic response and blood levels of CsA were studied in Balb/c mice after 5 and 10days of daily oral administration equivalent to 5 and 15mg/kg of CsA in different formulations. The in vivo nephrotoxicity after 15days of treatment at the high dose was also evaluated. The results showed a significant decrease in lymphocyte count (indicator of immunosuppression) for the CsA LN groups which was not observed with Sandimmune Neoral. CsA blood levels remained constant over the time after treatment with LN, whereas a proportional increase in drug blood concentration was observed with Sandimmune Neoral. Therefore, CsA LN exhibited a better pharmacological response along with more predictable pharmacokinetic information, diminishing the risk of toxicity. Moreover, a nephroprotective effect against CsA related toxicity was observed in the histopathological evaluation when LN containing Tween 80 were administered. Therefore, our preliminary findings suggest LN formulations would be a good alternative for CsA oral delivery, enhancing efficacy and reducing the risk of nephrotoxicity.
Autores: Guada Ramírez, Melissa; Beloqui, A.; Kumar, M. N. ; et al.
ISSN 0168-3659  Vol. 225  2016  págs. 269 - 282
Cyclosporine A (CsA) is a well-known immunosuppressive agent that gained considerable importance in transplant medicine in the late 1970s due to its selective and reversible inhibition of T-lymphocytes. While CsA has been widely used to prevent graft rejection in patients undergoing organ transplant it was also used to treat several systemic and local autoimmune disorders. Currently, the neuro-and cardio-protective effects of CsA (CiCloMulsion (R); NeuroSTAT (R)) are being tested in phase II and III trials respectively and NeuroSTAT (R) received orphan drug status from US FDA and Europe in 2010. The reformulation strategies focused on developing Cremophor (R) EL free formulations and address variable bioavailability and toxicity issues of CsA. This reviewis an attempt to highlight the progressmade so far and the roomavailable for further improvements to realize the maximum benefits of CsA.
Autores: González Fernández, Yolanda; Imbuluzqueta Iturburua, Edurne; Patiño García, Ana; et al.
ISSN 1381-6128  Vol. 21  Nº 42  2015  págs. 6104-24
Osteosarcoma is the most frequent primary bone tumor in the pediatric age group. Its aggressive local growth pattern and its high propensity to metastasize, mainly to the lungs, give the disease an unfavorable prognosis that has situated this disease as one of the leading causes of pediatric cancer death. Current protocols for osteosarcoma treatment are based on neo-adjuvant (pre-operatory) chemotherapy followed by surgical resection of the tumor and a new phase of adjuvant chemotherapy. Despite the progress that these protocols have made in improving the outcome of the disease, the limited access of drugs to bone tumor and metastases, their indiscriminate distribution in the organism, the high required doses that cause intolerable toxicity and the development of multidrug resistance, still represent a major challenge. Nanotechnology has emerged as a new strategy to successfully address these problems by the development of nanoscaled drug carriers that present the ability to target the drug to the tumor cells, achieving high drug concentrations in the tumor area, while decreasing its presence in healthy tissues and therefore its potential systemic toxicity. This review summarizes the different lipid nanocarriers developed to deliver first and second-line anti-osteosarcoma drugs as well as emerging agents in the treatment of this disease. Moreover, it also discusses the potential of these nanocarriers for the treatment of osteosarcoma.
Autores: Pascual Gil de Gómez, Simón; Simon-Yarza, T.; Garbayo Atienza, Elisa; et al.
ISSN 0168-3659  Vol. 220  2015  págs. 388 - 396
The growth factor neuregulin (NRG) is one of the most promising candidates in protein therapy as potential treatment for myocardial infarction (MI). In the last few years, biomaterial based delivery systems, such as polymeric microparticles (MPs) made of poly(lactic co glycolic acid) and polyethylene glycol (PLGA and PEG-PLGA MPs), have improved the efficacy of protein therapy in preclinical studies. However, no cardiac treatment based on MPs has yet been commercialized since this is a relatively new field and total characterization of polymeric MPs remains mandatory before they reach the clinical arena. Therefore, the objective of this study was to characterize the in vivo release, bioactivity and biodegradation of PLGA and PEG-PLGA MPs loaded with biotinylated NRG in a rat model of MI. The effect of PEGylation in the clearance of the particles from the cardiac tissue was also evaluated. Interestingly, MPs were detected in the cardiac tissue for up to 12 weeks after administration. In vivo release analysis showed that bNRG was released in a controlled manner throughout the twelve week study. Moreover, the biological cardiomyocyte receptor (ErbB4) for NRG was detected in its activated form only in those animals treated with bNRG loaded MPs. On the other hand, the PEGylation strategy was effective in diminishing phagocytosis of these MPs compared to noncoated MPs in the long term(12 weeks after injection). Taking all this together, we report new evidence in favor of the use of polymeric PLGA and PEG-PLGA MPs as delivery systems for treating MI, which could be soon included in clinical trials. (C) 2015 Elsevier B.V. All rights reserved.
Autores: Guada Ramírez, Melissa; Sebastian, V.; Irusta, S.; et al.
ISSN 1176-9114  Vol. 10  2015  págs. 6541 - 6553
Cyclosporine A (CsA) is an immunosuppressant commonly used in transplantation for prevention of organ rejection as well as in the treatment of several autoimmune disorders. Although commercial formulations are available, they have some stability, bioavailability, and toxicity related problems. Some of these issues are associated with the drug or excipients and others with the dosage forms. With the aim of overcoming these drawbacks, lipid nanoparticles (LN) have been proposed as an alternative, since excipients are biocompatible and also a large amount of surfactants and organic solvents can be avoided. CsA was successfully incorporated into LN using the method of hot homogenization followed by ultrasonication. Three different formulations were optimized for CsA oral administration, using different surfactants: Tween(®) 80, phosphatidylcholine, taurocholate and Pluronic(®) F127 (either alone or mixtures). Freshly prepared Precirol nanoparticles showed mean sizes with a narrow size distribution ranging from 121 to 202 nm, and after freeze-drying were between 163 and 270 nm, depending on the stabilizer used. Surface charge was negative in all LN developed. High CsA entrapment efficiency of approximately 100% was achieved. Transmission electron microscopy was used to study the morphology of the optimized LN. Also, the crystallinity of the nanoparticles was studied by X-ray powder diffraction and differential scanning calorimetry. The presence of the drug in LN surfaces was confirmed by X-ray photoelectron spectroscopy. The CsA LN developed preserved their physicochemical properties for 3 months when stored at 4°C. Moreover, when the stabilizer system was composed of two surfactants, the LN formulations were also stable at room temperature. Finally, the new CsA formulations showed in vitro dose-dependent immuno-suppressive effects caused by the inhibition of IL-2 levels secreted from stimulated Jurkat cells. The findings obtained in this paper suggest that new lipid nanosystems are a good alternative to produce physicochemically stable CsA formulations for oral administration.
Autores: Simón Yarza, María Teresa; Rossi, A.; Heffels, K. H.; et al.
ISSN 1076-3279  Vol. 21  Nº 9-10  2015  págs. 1654 - 1661
Cardiovascular disease represents one of the major health challenges in modern times and is the number one cause of death globally. Thus, numerous studies are under way to identify effective cell- and/or growth factor-based therapies for repairing damaged cardiac tissue. In this regard, improving the engraftment or survival of regenerative cells and prolonging growth factor exposure have become fundamental goals in advancing these therapeutic approaches. Therefore, biomaterials have emerged as innovative scaffolds for the delivery of both cells and proteins in tissue engineering applications. In the present study, electrospinning was used to generate smooth homogenous polymeric fibers, which consisted of a PLGA/NCO-sP(EO-stat-PO) polymer blend encapsulating the cardioactive growth factor, Neuregulin-1 (Nrg). We evaluated the biocompatibility and degradation of this Nrg-containing biomaterial in a rat model of myocardial ischemia. Following implantation, histological analysis revealed the presence of an initial acute inflammatory response, which was followed by a chronic inflammatory phase, characterized by the presence of giant cells. Notably, the scaffold remained in the heart after 3 months. Furthermore, increase in the M2:M1 macrophage ratio following implantation suggested the induction of constructive tissue remodeling. Taken together, the combination of Nrg-encapsulating scaffolds with cells capable of inducing cardiac regeneration could represent an ambitious and promising therapeutic strategy for repairing diseased or damaged myocardial tissue.
Autores: Tamames Tabar, Cristina; Imbuluzqueta Iturburua, Edurne; Guillou, N.; et al.
ISSN 1466-8033  Vol. 17  2015  págs. 456 - 462
A novel biocompatible and bioactive Metal¿Organic Framework (BioMOF), named BioMIL-5 (Bioactive Materials from Institut Lavoisier), was hydrothermally synthesized from a Zn2+ salt and azelaic acid, both with interesting antibacterial and dermatological properties. Its structure was determined by high resolution X-ray powder diffraction, and further characterized by infrared spectroscopy, thermogravimetric analysis and elemental analysis. The determination of the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values of BioMIL-5 in Staphylococcus aureus and Staphylococcus epidermidis demonstrated that the antimicrobial activity of the individual components of BioMIL-5 were maintained after its synthesis. Moreover, BioMIL-5 was found to be stable in water and in bacterial culture medium, especially in water, leading to the subsequent progressive release of its active constituents, AzA and Zn2+ ions. Interestingly, this slow active delivery allowed control of the growth of a S. epidermidis suspension over 7 days. The high stability of this material and the maintenance of its antibacterial properties make BioMIL-5 a good candidate for future bioapplications, for skin care and in cosmetics.
Autores: Estella Hermoso de Mendoza, Ander; Castelló Cros, Remedios; Imbuluzqueta Iturburua, Edurne; et al.
ISSN 1550-7033  Vol. 11  Nº 4  2015  págs. 691 - 701
Protein phosphatase 2A (PP2A) is a serin-threonin phosphatase that regulates many proteins critical for malignant cell behavior; therefore, PP2A is considered to be a human tumor suppressor. In this study, we assessed the pharmacokinetic profile and the antileukemic effects of the PP2A activator FTY720, free or encapsulated in lipid nanoparticles, in in vitro and in vivo models of acute myeloid leukemia. FTY720 lipid nanoparticles presented diameters around 210 nm, with an encapsulation efficiency up to 75% and significantly increased FTY720 oral bioavailability. In addition, FTY720 restores PP2A phosphatase activity and decreases phosphorylation of PP2A and its targets Akt, ERK1/2 and STAT5, all implicated in the pathogenesis of acute myeloid leukemia. Moreover, FTY720 exerts an additive anti-leukemic effect in combination with drugs used in standard induction therapy. Importantly, FTY720 lipid nanoparticles were more efficient at inducing cell growth arrest and apoptosis than FTY720 solution. Finally, oral administration of FTY720 lipid nanoparticles to mice every three days was as effective in reducing acute myeloid leukemia xenograft tumor growth as daily oral administration of FTY720. These results provide the first evidence for the potential use of FTY720 lipid nanoparticles as an oral therapeutic agent in acute myeloid leukemia.
Autores: Pascual-Gil, S.; Garbayo Atienza, Elisa; Díaz Herráez, Paula; et al.
ISSN 0168-3659  Vol. 203  2015  págs. 23 - 38
Myocardial infarction causes almost 7.3 million deaths each year worldwide. However, current treatments are more palliative than curative. Presently, cell and protein therapies are considered the most promising alternative treatments. Clinical trials performed until now have demonstrated that these therapies are limited by protein short half¿life and by low transplanted cell survival rate, prompting the development of novel cell and protein delivery systems able to overcome such limitations. In this review we discuss the advances made in the last 10 years in the emerging field of cardiac repair using biomaterial¿based delivery systems with focus on the progress made on preclinical in vivo studies. Then, we focus in cardiac tissue engineering approaches, and how the incorporation of both cells and proteins together into biomaterials has opened new horizons in the myocardial infarction treatment. Finally, the ongoing challenges and the perspectives for future work in cardiac tissue engineering will also be discussed.
Autores: Rocha Formiga, Fabio; Pelacho Samper, Beatriz; Garbayo Atienza, Elisa; et al.
ISSN 0168-3659  Vol. 173  2014  págs. 132 - 139
Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1- and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment were detected. Our data support the therapeutic benefit ofNRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in pre-clinical and clinical studies. (C) 2013 Elsevier B.V. All rights reserved.
Autores: Sadaba Díaz de Rada, María Belén; Del Barrio Diaz Aldagalan, Anabel; Campanero Martínez, Miguel Ángel; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 9  Nº 2  2014  págs. e89747
Palonosetron is a potent second generation 5- hydroxytryptamine-3 selective antagonist which can be administered by either intravenous (IV) or oral routes, but subcutaneous (SC) administration of palonosetron has never been studied, even though it could have useful clinical applications. In this study, we evaluate the bioavailability of SC palonosetron. PATIENTS AND METHODS: Patients treated with platinum-based chemotherapy were randomized to receive SC or IV palonosetron, followed by the alternative route in a crossover manner, during the first two cycles of chemotherapy. Blood samples were collected at baseline and 10, 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 h after palonosetron administration. Urine was collected during 12 hours following palonosetron. We compared pharmacokinetic parameters including AUC0-24h, t1/2, and Cmax observed with each route of administration by analysis of variance (ANOVA). RESULTS: From October 2009 to July 2010, 25 evaluable patients were included. AUC0-24h for IV and SC palonosetron were respectively 14.1 and 12.7 ng × h/ml (p¿=¿0.160). Bioavalability of SC palonosetron was 118% (95% IC: 69-168). Cmax was lower with SC than with IV route and was reached 15 minutes following SC administration. CONCLUSIONS: Palonosetron bioavailability was similar when administered by either SC or IV route. This new route of administration might be specially useful for outpatient management of emesis and for administration of oral chemotherapy.
Autores: Lasa Saracíbar, Beatriz; Aznar Gómez, María Ángela; Lana Vega, Hugo; et al.
ISSN 0378-5173  Vol. 474  Nº 1 - 2  2014  págs. 1 - 5
Edelfosine, an alkyl-lysophospholipid antitumor drug with severe side-effects, has previously been encapsulated into lipid nanoparticles (LN) with the purpose of improving their toxicity profile. LN are made of lipids recognized as safe by the Food and Drug Administration (FDA) and, therefore, these systems are generally considered as nontoxic vehicles. However, toxicity studies regarding the use of LN as vehicles for drug administration are limited. In the present study, we investigated the in vivo toxicity of free edelfosine, and the protection conferred by LN. The free drug, non-loaded LN and edelfosine-loaded LN were orally administered to mice. Our results show that the oral administration of the free drug at 4 times higher than the therapeutic dose caused the death of the animals within 72 h. Moreover, histopathology revealed gastrointestinal toxicity and an immunosuppressive effect. In contrast, LN showed a protective effect against edelfosine toxicity even at the higher dose and were completely safe. LN are, therefore, a safe vehicle for the administration of edelfosine by the oral route. The nanosystems developed could be further used for the administration of other drugs.
Autores: Aznar Gómez, María Ángela; Lasa Saracíbar, Beatriz; Blanco Prieto, María José
ISSN 1543-8384  Vol. 11  Nº 8  2014  págs. 2650 - 2658
The antitumor ether lipid edelfosine is the prototype of a novel generation of promising anticancer drugs that has been shown to be an effective antitumor agent in numerous malignancies. However, several cancer types display resistance to different antitumoral compounds due to multidrug resistance (MDR). Thus, MDR is a major drawback in anticancer therapy. In that sense, the leukemic cell line K-562 shows resistance to edelfosine. This resistance is overcome by the use of nanotechnology. The present work describes the rate and mechanism of internalization of free and nanoencapsulated edelfosine. The molecular mechanisms underlying cell death are described in the present paper by characterization of several molecules implied in the apoptosic and autophagic pathways (PARP, LC3IIB, caspases-3, -9 and -7), and their pattern of expression is compared with the cell induction in a sensitive cell line HL-60. Results showed different internalization patterns in both cells. Clathrin and lipid raft mediated endocytosis were observable in edelfosine uptake, whereas these mechanism were not visible in the uptake of lipid nanoparticles, which might suffer phagocytosis and macropinocytosis. Both treatments induced caspase-mediated apoptosis in HL-60 cells, whereas this cell death mechanism was unnoticeable in K-562 cells. Moreover, an important increase in autophagic vesicles was visible in K-562 cells. Thus, this mechanism might be implicated in overcoming K-562 resistance with the treatment by lipid nanoparticles.
Autores: Garbayo Atienza, Elisa; Estella Hermoso de Mendoza, Ander; Blanco Prieto, María José
ISSN 0929-8673  Vol. 21  Nº 36  2014  págs. 4100 - 4131
Nanomedicine has recently emerged as an exciting tool able to improve the early diagnosis and treatment of a variety of intractable or age-related brain disorders. The most relevant properties of nanomaterials are that they can be engineered to cross the blood brain barrier, to target specific cells and molecules and to act as vehicles for drugs. Potentially beneficial properties of nanotherapeutics derived from its unique characteristics include improved efficacy, safety, sensitivity and personalization compared to conventional medicines. In this review, recent advances in available nanostructures and nanomaterials for brain applications will be described. Then, the latest applications of nanotechnology for the diagnosis and treatment of neurological disorders, in particular brain tumors and neurodegenerative diseases, will be reviewed. Recent investigations of the neurotoxicity of the nanomaterial both in vitro and in vivo will be summarized. Finally, the ongoing challenges that have to be meet if new nanomedical products are to be put on the market will be discussed and some future directions will be outlined.
Autores: Tamames Tabar, Cristina; Cunha, D.; Imbuluzqueta Iturburua, Edurne; et al.
ISSN 0959-9428  Vol. 2  Nº 3  2014  págs. 262 - 271
A series of fourteen porous Metal¿Organic Frameworks (MOFs) with different compositions (Fe, Zn, and Zr; carboxylates or imidazolates) and structures have been successfully synthesised at the nanoscale and fully characterised by XRPD, FTIR, TGA, N2 porosimetry, TEM, DLS and z-potential. Their toxicological assessment was performed using two different cell lines: human epithelial cells from foetal cervical carcinoma (HeLa) and murine macrophage cell line (J774). It appears that MOF nanoparticles (NPs) exhibit low cytotoxicity, comparable to those of other commercialised nanoparticulate systems, the less toxic being the Fe carboxylate and the more toxic being the zinc imidazolate NPs. The cytotoxicity values, higher in J774 cells than in HeLa cells, are mainly function of their composition and cell internalisation capacity. Finally, cell uptake of one of the most relevant Fe-MOF-NPs for drug vectorisation has been investigated by confocal microscopy studies, and indicates a faster kinetics of cell penetration within J774 compared to HeLa cells.
Autores: Lasa Saracíbar, Beatriz; Guada Ramírez, Melissa; Sebastián, V.; et al.
ISSN 1568-0266  Vol. 14  Nº 9  2014  págs. 1124 - 1132
Nanotechnology is providing a new therapeutic paradigm by enhancing drug efficacy and preventing side-effects. Edelfosine is a synthetic ether lipid analogue of platelet activating factor with high antitumor activity. The encapsulation of this potent antitumor drug in lipid nanoparticles increases its oral bioavailability; moreover, it prevents the hemolytic and gastrointestinal side-effects of the free drug. The literature points towards lymphatic absorption of lipid nanoparticles after oral administration, and previous in vitro and in vivo studies stress the protection against toxicity that these nanosystems provide. The present study is intended to assess the permeability of lipid nanoparticles across the intestinal barrier. Caco-2 monoculture and Caco-2/Raji co-culture were used as in vitro models of enterocytes and Microfold cells respectively. Results showed that free drug is internalized and possibly metabolized in enterocytes. These results do not correlate with those observed in vivo when edelfosine-lipid nanoparticles were administered orally in mice, which suggests that the microfold model is not a good model to study the absorption of edelfosine-lipid nanoparticles across the intestinal barrier in vitro.
Autores: des Rieux, A.; De Berdt, P.; Ansorena Artieda, Eduardo; et al.
ISSN 1549-3296  Vol. 102  Nº 7  2014  págs. 2345 - 2355
We hypothesized that vascular endothelial growth factor (VEGF)-containing hydrogels that gelify in situ after injection into a traumatized spinal cord, could stimulate spinal cord regeneration. Injectable hydrogels composed of 0.5% Pronova UPMVG MVG alginate, supplemented or not with fibrinogen, were used. The addition of fibrinogen to alginate had no effect on cell proliferation in vitro but supported neurite growth ex vivo. When injected into a rat spinal cord in a hemisection model, alginate supplemented with fibrinogen was well tolerated. The release of VEGF that was incorporated into the hydrogel was influenced by the VEGF formulation [encapsulated in microspheres or in nanoparticles or in solution (free)]. A combination of free VEGF and VEGF-loaded nanoparticles was mixed with alginate:fibrinogen and injected into the lesion of the spinal cord. Four weeks post injection, angiogenesis and neurite growth were increased compared to hydrogel alone. The local delivery of VEGF by injectable alginate:fibrinogen-based hydrogel induced some plasticity in the injured spinal cord involving fiber growth into the lesion site.
Autores: Pippa, Raffaella; Domínguez, A.; Christensen, D. J.; et al.
ISSN 0887-6924  Vol. 28  Nº 9  2014  págs. 1915 - 1918
Autores: Lasa Saracíbar, Beatriz; Estella Hermoso de Mendoza, Ander; Mollinedo, F. ; et al.
ISSN 0304-3835  Vol. 334  Nº 2  2013  págs. 302 - 310
Although current therapies have improved leukemia survival rates, adverse drug effects and relapse are frequent. Encapsulation of edelfosine (ET) in lipid nanoparticles (LNs) improves its oral bioavailability and decreases its toxicity. Here we evaluated the efficacy of ET-LN in myeloid leukemia cell lines. Drug-loaded LN were as effective as free ET in sensitive leukemia cell lines. Moreover, the encapsulated drug overcame the resistance of the K562 cell line to the drug. LN containing ET might be used as a promising drug delivery system in leukemia due to their capacity to overcome the in vivo pitfalls of the free drug and their efficacy in vitro in leukemia cell lines.
Autores: Ansorena Artieda, Eduardo; De-Berdt, P.; Ucakar, B.; et al.
ISSN 0378-5173  Vol. 455  Nº 1-2  2013  págs. 148 - 158
We hypothesized that local delivery of GDNF in spinal cord lesion via an injectable alginate hydrogel gelifying in situ would support spinal cord plasticity and functional recovery. The GDNF release from the hydrogel was slowed by GDNF encapsulation in microspheres compared to non-formulated GDNF (free GDNF). When injected in a rat spinal cord hemisection model, more neurofilaments were observed in the lesion when the rats were treated with free GDNF-loaded hydrogels. More growing neurites were detected in the tissues surrounding the lesion when the animals were treated with GDNF microsphere-loaded hydrogels. Intense GFAP (astrocytes), low betaIII tubulin (neural cells) and RECA-1 (endothelial cells) stainings were observed for non-treated lesions while GDNF-treated spinal cords presented less GFAP staining and more endothelial and nerve fiber infiltration in the lesion site. The animals treated with free GDNF-loaded hydrogel presented superior functional recovery compared with the animals treated with the GDNF microsphere-loaded hydrogels and non-treated animals.
Autores: Aznar Gómez, María Ángela; Lasa Saracíbar, Beatriz; Estella Hermoso de Mendoza, Ander; et al.
ISSN 0378-5173  Vol. 454  Nº 2  2013  págs. 720 - 726
Breast cancer is a heterogeneous group of neoplasms predominantly originating in the terminal duct lobular units. It represents the leading cause of cancer death in women and the survival frequencies for patients at advanced stages of the disease remain low. New treatment options need to be researched to improve these rates. The anti-tumor ether lipid edelfosine (ET) is the prototype of a novel generation of promising anticancer drugs. However, it presents several drawbacks for its use in cancer therapy, including gastrointestinal and hemolytic toxicity and low oral bioavailability. To overcome these obstacles, ET was encapsulated in Precirol ATO 5 lipid nanoparticles (ET-LN), and its anti-tumor potential was in vitro tested in breast cancer. The formulated ET-LN were more effective in inhibiting cell proliferation and notably decreased cell viability, showing that the cytotoxic effect of ET was considerably enhanced when ET was encapsulated. In addition, ET and ET-LN were able to promote cell cycle arrest at G1 phase. Moreover, although both treatments provoked an apoptotic effect in a time-dependent manner, such anti-tumor effects were noticeably improved with ET-LN treatment. Therefore, our results indicate that encapsulating ET in LN played an essential role in improving the efficacy of the drug.
Autores: Guada Ramírez, Melissa; Imbuluzqueta Iturburua, Edurne; Estella Hermoso de Mendoza, Ander; et al.
ISSN 1570-0232  Vol. 927  2013  págs. 164 - 172
Cyclosporine A (CyA) is an immunosuppressant cyclic undecapeptide used for the prevention of organ transplant rejection and in the treatment of several autoimmune disorders. An ultra high performance liquid chromatography tandem mass spectrometry method (UHPLC-MS/MS) to quantify CyA in lipid nanosystems and mouse biological matrices (whole blood, kidneys, lungs, spleen, liver, heart, brain, stomach and intestine) was developed and fully validated. Chromatographic separation was performed on an Acquity UPLC (R) BEH C18 column with a gradient elution consisting of methanol and 2 mM ammonium acetate aqueous solution containing 0.1% formic acid at a flow rate of 0.6 mL/min. Amiodarone was used as internal standard (IS). Retention times of IS and CyA were 0.69 min and 1.09 min, respectively. Mass spectrometer operated in electrospray ionization positive mode (ESI+) and multiple reaction monitoring (MRM) transitions were detected, m/z 1220.69 -> 1203.7 for CyA and m/z 646 -> 58 for IS. The extraction method from biological samples consisted of a simple protein precipitation with 10% trichloroacetic acid aqueous solution and acetonitrile and 5 mu L of supernatant were directly injected into the UHPLC-MS/MS system. Linearity was observed between 0.001 mu g/mL-2.5 mu g/mL (r >= 0.99) in all matrices. The precision expressed in coefficient of variation (CV) was below 11.44% and accuracy in bias ranged from -12.78% to 7.99% including methanol and biological matrices. Recovery in all cases was above 70.54% and some matrix effect was observed. CyA was found to be stable in post-extraction whole blood and liver homogenate samples exposed for 6h at room temperature and 72 h at 4 degrees C. The present method was successfully applied for quality control of lipid nanocarriers as well as in vivo studies in BALB/c mice.
Autores: Simón Yarza, María Teresa; Tamayo Revuelta, Esther; Benavides Vallvé, Carolina; et al.
ISSN 0378-5173  Vol. 454  Nº 2  2013  págs. 784 -790
Autores: Ansorena Artieda, Eduardo; Casales Zoco, Erkuden; Aranda, Alejandro Mario; et al.
ISSN 0378-5173  Vol. 440  Nº 1  2013  págs. 19-26
Human glial cell line-derived neurotrophic factor (hGDNF) is a very promising protein for the treatment of Parkinson's disease and other neurodegenerative disorders. The present work describes a quick and simple method to obtain a high amount of purified hGDNF using a mammalian cell-derived system. The method is based on the high expression level provided by a Semliki Forest virus vector and its ability to induce a strong shut-off of host-cell protein synthesis in mammalian cells. As a result, hGDNF is the only protein present in the supernatant and can be efficiently purified by a single chromatographic step. Using this system it was possible to eliminate other secreted proteins from the culture medium, like insulin-like growth factor-5, which are hard to remove using other hGDNF production methods. Purified hGDNF presents a complex glycosylation pattern typical of mammalian expression systems and is biologically active. This protocol could be extended to other secreted proteins and could be easily scaled up for industrial purposes. (C) 2012 Elsevier B.V. All rights reserved.
Autores: Simón Yarza, María Teresa; Rocha Formiga, Fabio; Tamayo Revuelta, Esther; et al.
ISSN 0378-5173  Vol. 440  Nº 1  2013  págs. 13 - 18
The potential of poly(lactic-co-glycolic) acid (PLGA) microparticles as carriers for vascular endothelial growth factor (VEGF) has been demonstrated in a previous study by our group, where we found improved angiogenesis and heart remodeling in a rat myocardial infarction model (Formiga et al., 2010). However, the observed accumulation of macrophages around the injection site suggested that the efficacy of treatment could be reduced due to particle phagocytosis. The aim of the present study was to decrease particle phagocytosis and consequently improve protein delivery using stealth technology. PEGylated microparticles were prepared by the double emulsion solvent evaporation method using TROMS (Total Recirculation One Machine System). Before the uptake studies in monocyte-macrophage cells lines (J774 and Raw 264.7), the characterization of the microparticles developed was carried out in terms of particle size, encapsulation efficiency, protein stability, residual poly(vinyl alcohol) (PVA) and in vitro release. Microparticles of suitable size for intramyocardial injection (5 mu m) were obtained by TROMS by varying the composition of the formulation and TROMS conditions with high encapsulation efficiency (70-90%) and minimal residual PVA content (0.5%). Importantly, the bioactivity of the protein was fully preserved. Moreover, PEGylated microparticles released in phosphate buffer 50% of the entrapped protein within 4 h, reaching a plateau within the first day of the in vitro study. Finally, the use of PLGA microparticles coated with PEG resulted in significantly decreased uptake of the carriers by macrophages, compared with non PEGylated microparticles, as shown by flow cytometry and fluorescence microscopy. On the basis of these results, we concluded that PEGylated microparticles loaded with VEGF could be used for delivering growth factors in the myocardium. (C) 2012 Elsevier B.V. All rights reserved.
Autores: Rocha Formiga, Fabio; Garbayo Atienza, Elisa; Díaz Herráez, Paula; et al.
ISSN 0939-6411  Vol. 85  Nº 3  2013  págs. 665 - 672
Poly-lactide-co-glycolide (PLGA) microparticles emerged as one of the most promising strategies to achieve site-specific drug delivery. Although these microparticles have been demonstrated to be effective in several wound healing models, their potential in cardiac regeneration has not yet been fully assessed. The present work sought to explore PLGA microparticles as cardiac drug delivery systems. PLGA microparticles were prepared by Total Recirculation One-Machine System (TROMS) after the formation of a multiple emulsion. Microparticles of different size were prepared and characterized to select the most suitable size for intramyocardial administration. Next, the potential of PLGA microparticles for administration in the heart was assessed in a MI rat model. Particle biodegradation over time and myocardial tissue reaction were studied by routine staining and confocal microscopy. Results showed that microparticles with a diameter of 5¿m were the most compatible with intramyocardial administration in terms of injectability through a 29-gauge needle and tissue response. Particles were present in the heart tissue for up to 3months post-implantation and no particle migration toward other solid organs was observed, demonstrating good myocardial retention. CD68 immunolabeling revealed 31%, 47% and below 4% microparticle uptake by macrophages 1week, 1month, and 3months after injection, respectively (P<0.001). Taken together, these findings support the feasibility of the developed PLGA microparticles as vehicles for delivering growth factors in the infarcted myocardium.
Autores: Imbuluzqueta Iturburua, Edurne; Gamazo de la Rasilla, Carlos Manuel; Lana Vega, Hugo; et al.
ISSN 0066-4804  Vol. 57  Nº 7  2013  págs. 3326 - 3333
The clinical management of human brucellosis is still challenging and demands in vitro active antibiotics capable of targeting the pathogen-harboring intracellular compartments. A sustained release of the antibiotic at the site of infection would make it possible to reduce the number of required doses and thus the treatment-associated toxicity. In this study, a hydrophobically modified gentamicin, gentamicin-AOT [AOT is bis(2-ethylhexyl) sulfosuccinate sodium salt], was either microstructured or encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles. The efficacy of the formulations developed was studied both in vitro and in vivo. Gentamicin formulations reduced Brucella infection in experimentally infected THP-1 monocytes (>2-log10 unit reduction) when using clinically relevant concentrations (18 mg/liter). Moreover, in vivo studies demonstrated that gentamicin-AOT-loaded nanoparticles efficiently targeted the drug both to the liver and the spleen and maintained an antibiotic therapeutic concentration for up to 4 days in both organs. This resulted in an improved efficacy of the antibiotic in experimentally infected mice. Thus, while 14 doses of free gentamicin did not alter the course of the infection, only 4 doses of gentamicin-AOT-loaded nanoparticles reduced the splenic infection by 3.23 logs and eliminated it from 50% of the infected mice with no evidence of adverse toxic effects. These results strongly suggest that PLGA nanoparticles containing chemically modified hydrophobic gentamicin may be a promising alternative for the treatment of human brucellosis.
Autores: Díaz Herráez, Paula; Garbayo Atienza, Elisa; Simón Yarza, María Teresa; et al.
ISSN 0939-6411  Vol. 85  Nº 1  2013  págs. 143 - 150
Myocardial infarction (MI) is the leading cause of death worldwide, and extensive research has therefore been performed to find a cure. Neuregulin-1 (NRG) is a growth factor involved in cardiac repair after MI. We previously described how biocompatible and biodegradable microparticles, which are able to release NRG in a sustained manner, represent a valuable approach to avoid problems related to the short half-life after systemic administration of proteins. The effectiveness of this strategy could be improved by combining NRG with several cytokines involved in cardiac regeneration. The present study investigates the potential feasibility of using NRG-releasing particle scaffold combined with adipose-derived stem cells (ADSC) as a multiple growth factor delivery-based tissue engineering strategy for implantation in the infarcted myocardium. NRG-releasing particle scaffolds with a suitable size for intramyocardial implantation were prepared by TROMS. Next, ADSC were adhered to particle scaffolds and their potential for heart administration was assessed in a MI rat model. NRG was successfully encapsulated reaching encapsulation efficiencies of 92.58±3.84%. NRG maintained its biological activity after the microencapsulation process. ADSCs adhered efficiently to particle scaffolds within a few hours. The ADSC-cytokine delivery system developed proved to be compatible with intramyocardial administration in terms of injectability through a 23-gauge needle and tissue response. Interestingly, ADSC-scaffolds were present in the peri-infarted tissue 2weeks after implantation. This proof of concept study provides important evidence required for future effectiveness studies and for the translation of this approach.
Autores: Tamames Tabar, Cristina; Imbuluzqueta Iturburua, Edurne; Campanero Martínez, Miguel Ángel; et al.
ISSN 1387-2273  Vol. 935  2013  págs. 47 - 53
A simple liquid-liquid extraction procedure and quantification by high-performance liquid chromatography (HPLC) method coupled to a diode-array detector (DAD) of genistein (GEN) was developed in various mouse biological matrices. 7-ethoxycoumarin was used as internal standard (IS) and peaks were optimally separated using a Kinetex C18 column (2.6 mu m. 150 mm x 2.10 mm I.D.) at 40 degrees C with an isocratic elution of mobile phase with sodium dihydrogen phosphate 0.01 M in water at pH 2.5 and methanol (55:45, v/v), at a flow rate of 0.25 mL/min. The injection volume was 10 mu L. In all cases, the range of GEN recovery was higher than 61%. The low limit of quantification (LLOQ) was 25 ng/mL. The linearity of the calibration curves was satisfactory in all cases as shown by correlation coefficients >0.996. The within-day and between-day precisions were <15% and the accuracy ranged in all cases between 90.14% and 106.05%. This method was successfully applied to quantify GEN in liver, spleen, kidney and plasma after intravenous administration of a single dose (30 mg/kg) in female BALB/C mice
Autores: Ravi-Kumar, M. N.; Blanco Prieto, María José; Waterhouse, D. N.;
ISSN 0304-3835  Vol. 334  Nº 2  2013  págs. 153 - 154
Autores: Blanco Prieto, María José
Título: Editorial
ISSN 0378-5173  Vol. 440  Nº 1  2013  págs. 1 - 2
Autores: Ravi-Kumar, M. N.; Blanco Prieto, María José; Waterhouse, D. N.;
Título: Nanotherapeutics
ISSN 0304-3835  Vol. 334  Nº 2  2013  págs. 155 - 156
Autores: Garbayo Atienza, Elisa; Ansorena Artieda, Eduardo; Blanco Prieto, María José
ISSN 0378-5122  Vol. 76  Nº 3  2013  págs. 272 - 278
Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease. Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood-brain barrier and target a specific region are still needed. Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly targeted drugs. The advent of new molecular and cellular targets like ¿-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients.
Autores: Imbuluzqueta Iturburua, Edurne; Lemaire, S; Gamazo de la Rasilla, Carlos Manuel; et al.
ISSN 0305-7453  Vol. 67  Nº 9  2012  págs. 2158-2164
The aim of this study was to investigate different hydrophobic gentamicin formulations [gentamicin-bis(2-ethylhexyl) sulfosuccinate (GEN-AOT), microstructured GEN-AOT (PCA GEN-AOT) and GEN-AOT-loaded poly(lactide-co-glycolide) acid (PLGA) nanoparticles (NPs)] in view of improving its therapeutic index against intracellular bacteria. The intracellular accumulation, subcellular distribution and intracellular activity of GEN-AOT and NPs in different monocyticmacrophagic cell lines were studied. Human THP-1 and murine J774 phagocytic cells were incubated with GEN-AOT formulations at relevant extracellular concentrations [from 1 MIC to 18 mg/L (human C-max)], and their intracellular accumulation, subcellular distribution and toxicity were evaluated and compared with those of conventional unmodified gentamicin. Intracellular activity of the formulations was determined against bacteria showing different subcellular localizations, namely Staphylococcus aureus (phagolysosomes) and Listeria monocytogenes (cytosol). GEN-AOT formulations accumulated 2-fold (GEN-AOT) to 8-fold (GEN-AOT NPs) more than gentamicin in phagocytic cells, with a predominant subcellular localization in the soluble fraction (cytosol) and with no significant cellular toxicity. NP formulations allowed gentamicin to exert its intracellular activity after shorter incubation times and/or at lower concentrations. With an extracellular concentration of 10 MIC, a 1 log(10) decrease in S. aureus intracellular inoculum was obtained after 12 h instead of 24 h for NPs versus free gentamicin, and a static effect was observed against L. monocytogenes at 24 h with NPs, while free gentamicin was ineffective. GEN-AOT formulations yielded a high cellular accumulation, especially in the cytosol, which resulted in improved efficacy against both intracellular S. aureus and L. monocytogenes.
Autores: Estella Hermoso de Mendoza, Ander; Campanero Martínez, Miguel Ángel; Lana Vega, Hugo; et al.
ISSN 1743-5889  Vol. 7  Nº 5  2012  págs. 679 - 690
Background: Lipid nanoparticles (LNs) made of synthetic lipids Compritol (R) 888 ATO and Precirol (R) ATO 5 were developed with an average size of 110.4 +/- 2.1 and 103.1 +/- 2.9 nm, and an encapsulation efficiency above 85% for both type of lipids. These LNs decrease the hemolytic toxicity of the drug by 90%. Materials & methods: Pharmacokinetic and biodistribution profiles of the drug were studied after intravenous and oral administration of edelfosine-containing LNs. Results: This provided an increase in relative oral bioavailability of 1500% after a single oral administration of drug-loaded LNs, maintaining edelfosine plasma levels over 7 days in contrast to a single oral administration of edelfosine solution, which presented a relative oral bioavailability of 10%. Moreover, edelfosine-loaded LNs showed a high accumulation of the drug in lymph nodes and resulted in slower tumor growth than the free drug in a murine lymphoma xenograft model, as well as potent extranodal dissemination inhibition.
Autores: Vilas Zornoza, Amaia; Aguirre Ena, Xabier; Abizanda Sarasa, Gloria María; et al.
ISSN 0887-6924  Vol. 26  Nº 7  2012  págs. 1517 - 1526
Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I - II HDAC inhibitor, in acute lymphoblastic leukemia ( ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)gamma c(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)gamma c(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.
Autores: Estella Hermoso de Mendoza, Ander; Calvo, P.; Bishop, A.; et al.
ISSN 1550-7033  Vol. 8  Nº 4  2012  págs. 703-708
PM02734 is a chemically synthesized depsipeptide derived from the marine kahalalides family with a broad spectrum of activity against solid tumors in vitro and in vivo, but presenting low bioavailability. In this work, solid lipid nanoparticles made of Precirol(R) ATO 5 have been developed using a hot homogenization method followed by high shear homogenization and ultrasonication. These solid lipid nanoparticles show suitable size (around 150 nm) and encapsulation efficiency (nearly 70%) for the oral administration of the compound PM02734. A physical-chemical stability study was performed after 6 months of storage at different thermical conditions, concluding that solid lipid nanoparticles stored at 4 00 were more stable than solid lipid nanoparticles stored at 25 degrees C. The pharmacokinetic profile of drug-loaded solid lipid nanoparticles was also evaluated in Beagle dogs and compared with that of a cyclodextrin-based delivery system by means of AUC, C-max, and T-max parameter estimation. Solid lipid nanoparticle based formulation provided a sustained release of the drug for a longer period of time than the cyclodextrins.
Autores: Simón Yarza, María Teresa; Rocha Formiga, Fabio; Tamayo Revuelta, Esther; et al.
ISSN 1838-7640  Vol. 2  Nº 6  2012  págs. 541 - 552
Since the discovery of the Vascular Endothelial Growth Factor (VEGF) and its leading role in the angiogenic process, this has been seen as a promising molecule for promoting neovascularization in the infarcted heart. However, even though several clinical trials were initiated, no therapeutic effects were observed, due in part to the short half life of this factor when administered directly to the tissue. In this context, drug delivery systems appear to offer a promising strategy to overcome limitations in clinical trials of VEGF.The aim of this paper is to review the principal drug delivery systems that have been developed to administer VEGF in cardiovascular disease. Studies published in the last 5 years are reviewed and the main features of these systems are explained. The tissue engineering concept is introduced as a therapeutic alternative that holds promise for the near future.
Autores: Garbayo Atienza, Elisa; Ansorena Artieda, Eduardo; Blanco Prieto, María José
ISSN 1389-2010  Vol. 13  Nº 12  2012  págs. 2388 - 2402
Neurodegenerative disorders (NDs) are rapidly increasing as population ages. However, successful treatments for NDs have so far been limited and drug delivery to the brain remains one of the major challenges to overcome. There has recently been growing interest in the development of drug delivery systems (DDS) for local or systemic brain administration. DDS are able to improve the pharmacological and therapeutic properties of conventional drugs and reduce their side effects. The present review provides a concise overview of the recent advances made in the field of brain drug delivery for treating neurodegenerative disorders. Examples include polymeric micro and nanoparticles, lipidic nanoparticles, pegylated liposomes, microemulsions and nanogels that have been tested in experimental models of Parkinson's, Alzheimer's and Hungtinton's disease. Overall, the results reviewed here show that DDS have great potential for NDs treatment.
Autores: Lasa Saracíbar, Beatriz; Estella Hermoso de Mendoza, Ander; Guada Ramírez, Melissa; et al.
ISSN 1742-5247  Vol. 9  Nº 10  2012  págs. 1245 - 1261
Introduction: Cancer is a leading cause of death worldwide and it is estimated that deaths from this disease will rise to over 11 million in 2030. Most cases of cancer can be cured with surgery, radiotherapy or chemotherapy if they are detected at an early stage. However, current cancer therapies are commonly associated with undesirable side effects, as most chemotherapy treatments are cytotoxic and present poor tumor targeting. Areas covered: Lipid nanoparticles (LN) are one of the most promising options in this field. LN are made up of biodegradable generally recognized as safe (GRAS) lipids, their formulation includes different techniques, and most are easily scalable to industrial manufacture. LN overcome the limitations imposed by the need for intravenous administration, as they are mainly absorbed via the lymphatic system when they are administered orally, which improves drug bioavailability. Furthermore, depending on their composition, LN present the ability to cross the blood-brain barrier, thus opening up the possibility of targeting brain tumors. Expert opinion: The drawbacks of chemotherapeutic agents make it necessary to invest in research to find safer and more effective therapies. Nanotechnology has opened the door to new therapeutic options through the design of formulations that include a wide range of materials and formulations at the nanometer range, which improve drug efficacy through direct or indirect tumor targeting, increased bioavailability and diminished toxicity.
Autores: Rocha Formiga, Fabio; Tamayo Revuelta, Esther; Simón Yarza, María Teresa; et al.
ISSN 1382-4147  Vol. 17  Nº 3  2012  págs. 449 - 473
Cardiovascular diseases remain the first cause of morbidity and mortality in the developed countries and are a major problem not only in the western nations but also in developing countries. Current standard approaches for treating patients with ischemic heart disease include angioplasty or bypass surgery. However, a large number of patients cannot be treated using these procedures. Novel curative approaches under investigation include gene, cell, and protein therapy. This review focuses on potential growth factors for cardiac repair. The role of these growth factors in the angiogenic process and the therapeutic implications are reviewed. Issues including aspects of growth factor delivery are presented in relation to protein stability, dosage, routes, and safety matters. Finally, different approaches for controlled growth factor delivery are discussed as novel protein delivery platforms for cardiac regeneration.
Autores: Aguirre Ena, Xabier; Vilas Zornoza, Amaia; Abizanda Sarasa, Gloria María; et al.
Revista: BLOOD
ISSN 0006-4971  Vol. 118  Nº 21  2011  págs. 660
Autores: Estella Hermoso de Mendoza, Ander; Préat, V.; Mollinedo, F.; et al.
ISSN 0168-3659  Vol. 156  Nº 3  2011  págs. 421 - 426
Edelfosine is the prototype molecule of a family of anticancer drugs collectively known as synthetic alkyl-lysophospholipids. This drug holds promise as a selective antitumor agent, and a number of preclinical assays are in progress. In this study, we observe the accumulation of edelfosine in brain tissue after its oral administration in Compritol (R) and Precirol (R) lipid nanoparticles (LN). The high accumulation of edelfosine in brain was due to the inhibition of P-glycoprotein by Tween (R) 80, as verified using a P-glycoprotein drug interaction assay. Moreover, these LN were tested in vitro against the C6 glioma cell line, which was later employed to establish an in vivo xenograft mouse model of glioma. In vitro studies revealed that edelfosine-loaded LN induced an antiproliferative effect in C6 glioma cell line. In addition, in vivo oral administration of drug-loaded LN in NMRI nude mice bearing a C6 glioma xenograft tumor induced a highly significant reduction in tumor growth (p<0.01) 14 days after the beginning of the treatment. Our results showed that Tween (R) 80 coated Compritol (R) and Precirol (R) LN can effectively inhibit the growth of C6 glioma cells in vitro and suggest that edelfosine-loaded LN represent an attractive option for the enhancement of antitumor activity on brain tumors in vivo.
Autores: Imbuluzqueta Iturburua, Edurne; Elizondo, E.; Gamazo de la Rasilla, Carlos Manuel; et al.
ISSN 1742-7061  Vol. 7  Nº 4  2011  págs. 1599 - 1608
Autores: Garbayo Atienza, Elisa; Ansorena Artieda, Eduardo; Lanciego Pérez, José Luis; et al.
ISSN 0885-3185  Vol. 26  Nº 10  2011  págs. 1943 - 1947
Background: Glial cell-derived neurotrophic factor is a survival factor for dopaminergic neurons and a promising candidate for the treatment of Parkinson's disease. However, the delivery issue of the protein to the brain still remains unsolved. Our aim was to investigate the effect of long-term delivery of encapsulated glial cell-derived neurotrophic factor within microspheres. Methods: A single dose of microspheres containing 2.5 mu g of glial cell-derived neurotrophic factor was implanted intrastriatally in animals 2 weeks after a 6-hydroxydopamine lesion. Results: The amphetamine test showed a complete behavioral recovery after 16 weeks of treatment, which was maintained until the end of the study (week 30). This effect was accompanied by an increase in dopaminergic striatal terminals and neuroprotection of dopaminergic neurons. Conclusions: The main achievement was the long-term neurorestoration in parkinsonian animals induced by encapsulated glial cell-derived neurotrophic factor, suggesting that microspheres may be considered as a means to deliver glial cell-derived neurotrophic factor for Parkinson's disease treatment.
Autores: Elizondo, E.; Sala, S.; Imbuluzqueta Iturburua, Edurne; et al.
ISSN 0724-8741  Vol. 28  Nº 2  2011  págs. 309 - 321
PURPOSE: To investigate, for the first time, the viability of compressed antisolvent methodologies for the preparation of drug-loaded particles of the biodegradable and bioadhesive polymer poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA), utilizing gentamicin (Gm) as a model drug. METHODS: Precipitation with a Compressed Antisolvent (PCA) method was used for the preparation of PVM/MA particles loaded with gentamicin. Before encapsulation, gentamicin was modified into a hydrophobic complex, GmAOT, by exchanging its sulphate ions with an anionic surfactant. GmAOT:PVM/MA composites were fully characterized in terms of size, morphology, composition, drug distribution, phase composition, in vitro activity and drug release. RESULTS: Homogeneous nanostructured microparticles of PVM/MA loaded with high and uniformly distributed quantities of GmAOT were obtained by PCA. The drug loading factors could be tuned at will, improving up to ten times the loadings obtained by other precipitation techniques. Gentamicin retained its bioactivity after being processed, and, according to its release profiles, after an initial burst it experienced a sustained release over 30 days. CONCLUSIONS: Compressed antisolvent methods are suitable technologies for the one-step preparation of highly loaded nanostructured PVM/MA matrices with promising application in the delivery of low bioavailable drugs.
Autores: Estella Hermoso de Mendoza, Ander; Imbuluzqueta Iturburua, Izaskun; Campanero Martínez, Miguel Ángel; et al.
ISSN 1570-0232  Vol. 879  Nº 30  2011  págs. 3490-6
An ultra high performance liquid chromatography tandem mass spectrometry method (UHPLC-MS/MS) was developed and validated for the quantitation of LBH589, a novel histone deacetylase inhibitor (HDACi), in mouse plasma and tissues (liver, spleen, kidney and lung). Tobramycin was employed as the internal standard. Separation was performed on an Acquity UPLC¿ BEH column, with a mobile phase consisting of 10% water (with 0.1% of trifluoroacetic acid) and 90% methanol (with 0.1% trifluoroacetic acid). LBH589 and tobramycin were determined using an electrospray ionization (ESI) interface. Detection was performed on electrospray positive ionization mass spectrometry by multiple reaction monitoring of the transitions of LBH589 at m/z 349.42¿157.95 and of tobramycin at 468.2¿163. Calibration curves for the UHPLC method (0.0025-1 ¿g/mL for plasma and tissue homogenates, equivalent to 0.0357-14.2857 ¿g/g for tissue samples) showed a linear range of detector responses (r>0.998). Intra-batch and inter-batch precision expressed as coefficient of variation (CV) ranged from 0.92 to 8.40%. Accuracy expressed as bias, ranged from -2.41 to 2.62%. The lower limit of quantitation (LLOQ) was 0.0025 ¿g/mL for both plasma and tissue homogenate samples, equivalent to 0.0357 ¿g/g tissue. This method was successfully applied to quantify LBH589 in plasma and tissue samples obtained after the intraperitoneal administration of a single dose of 20 mg/kg of LBH589 in BALB/c mice.
Autores: Mollinedo, F; De la Iglesia-Vicente, J; Gajate, C; et al.
ISSN 1078-0432  Vol. 16  Nº 7  2010  págs. 2046 - 2054
Our data indicate that edelfosine accumulates and kills MCL and CLL cells in a rather selective way, and set coclustering of Fas/CD95 and lipid rafts as a new framework in MCL and CLL therapy. Our data support a selective antitumor action of edelfosine.
Autores: Imbuluzqueta Iturburua, Edurne; Gamazo de la Rasilla, Carlos Manuel; Ariza, Javier; et al.
ISSN 1093-9946  Vol. 15  2010  págs. 397 - 417
Autores: Ansorena Artieda, Eduardo; Garbayo Atienza, Elisa; Lanciego Pérez, José Luis; et al.
ISSN 0378-5173  Vol. 385  Nº 1-2  2010  págs. 6 - 11
The administration of glial cell line-derived neurotrophic factor (GDNF) has emerged as a promising strategy for the treatment of several diseases of the nervous system as Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury and nerve regeneration as well as ocular diseases and drug addictions. A procedure for the purification of human recombinant glycosylated GDNF using a mammalian expression system as the source of the protein is discussed in the present paper. The neurotrophic factor was purified using cation exchange chromatography and gel filtration. A human cell line was chosen as the source of therapeutic protein, since a recombinant protein with a structure and glycosylation pattern equivalent to the native form is desirable for its prospective therapeutic utilization. The activity of the highly pure protein obtained was confirmed with a cell-based bioassay. The purified protein is suitable for its in vivo evaluation in animals and for possible subsequent clinical application.
Autores: Rocha Formiga, Fabio; Pelacho Samper, Beatriz; Garbayo Atienza, Elisa; et al.
ISSN 0168-3659  Vol. 147  Nº 1  2010  págs. 30 - 37
The use of pro-angiogenic growth factors in ischemia models has been associated with limited success in the clinical setting, in part owing to the short lived effect of the injected cytokine. The use of a microparticle system could allow localized and sustained cytokine release and consequently a prolonged biological effect with induction of tissue revascularization. To assess the potential of VEGF(165) administered as continuous release in ischemic disease, we compared the effect of delivery of poly(lactic-co-glycolic acid) (PLGA) microparticles (MP) loaded with VEGF(165) with free-VEGF or control empty microparticles in a rat model of ischemia-reperfusion. VEGF165 loaded microparticles could be detected in the myocardium of the infarcted animals for more than a month after transplant and provided sustained delivery of active protein in vitro and in vivo. One month after treatment, an increase in angiogenesis (small caliber caveolin-1 positive vessels) and arteriogenesis (alpha-SMA-positive vessels) was observed in animals treated with VEGF microparticles (p < 0.05), but not in the empty microparticles or free-VEGF groups. Correlating with this data, a positive remodeling of the heart was also detected in the VEGF-microparticle group with a significantly greater LV wall thickness (p < 0.01). In conclusion, PICA microparticle is a feasible and promising cytokine delivery system for treatment of myocardial ischemia. This strategy could be scaled up and explored in pre-clinical and clinical studies. (C) 2010 Elsevier B.V. All rights reserved.
Autores: Mollinedo, F.; De la Iglesia-Vicente, J.; Gajate, C.; et al.
ISSN 0950-9232  Vol. 29  Nº 26  2010  págs. 3748 - 3757
Despite recent advances in treatment, multiple myeloma (MM) remains an incurable malignancy. By using in vitro, ex vivo and in vivo approaches, we have identified here that lipid rafts constitute a new target in MM. We have found that the phospholipid ether edelfosine targets and accumulates in MM cell membrane rafts, inducing apoptosis through co-clustering of rafts and death receptors. Raft disruption by cholesterol depletion inhibited drug uptake by tumor cells as well as cell killing. Cholesterol replenishment restored MM cell ability to take up edelfosine and to undergo drug-induced apoptosis. Ceramide addition displaced cholesterol from rafts, and inhibited edelfosine-induced apoptosis. In an MM animal model, edelfosine oral administration showed a potent in vivo antimyeloma activity, and the drug accumulated preferentially and dramatically in the tumor. A decrease in tumor cell cholesterol, a major raft component, inhibited the in vivo antimyeloma action of edelfosine and reduced drug uptake by the tumor. The results reported here provide the proof-of-principle and rationale for further clinical evaluation of edelfosine and for this raft-targeted therapy to improve patient outcome in MM. Our data reveal cholesterol-containing lipid rafts as a novel and efficient therapeutic target in MM, opening a new avenue in cancer treatment. Lipid raft-targeted therapy in multiple myeloma. - ResearchGate. Available from: [accessed Mar 25, 2015].
Autores: Garbayo Atienza, Elisa; Gil-Pascual S; Prosper Cardoso, Felipe; et al.
Libro:  Bioresorbable polymers for biomedical applications : from fundamentals to translational medicine
Vol. 120  2017  págs. 445-467
However, although cardiac tissue engineering approaches have been shown to improve heart recovery after MI, there is still no approved treatment available on the market. More research is needed on cardiac tissue engineering strategies to optimize these promising treatments.
Autores: Díaz Herráez, Paula; Pascual Gil de Gómez, Simón; Garbayo Atienza, Elisa; et al.
Libro:  Drug delivery: An integrated Clinical and Engineering Approach
2016  págs. 437 - 478
Emphasizing an integrated clinical and engineering approach, this book explores the FDA regulatory and bioethical challenges involved in advancing drug delivery. It examines special clinical states requiring innovative drug delivery modifications, such as hypercoagulability often seen in pregnancy, cancer, and autoimmune diseases. It discusses methods for improved drug delivery in clinical settings using clinical end points, clinical trials, simulations, and other venues. It also describes the latest drug delivery advances involving nanomaterials, NEMS and MEMS devices, hydrogels, microencapsulation, lipids, stem cells, patches, ultrasound, and more.
Autores: Zapata Linares, Natalia María; Garbayo Atienza, Elisa; Blanco Prieto, María José; et al.
Libro:  Biointerfaces: where material meets biology
2015  págs. 74 - 104
Autores: Tamames Tabar, Cristina; García-Márquez, A.; Blanco Prieto, María José; et al.
Libro:  Bio- and Bioinspired Nanomaterials
2014  págs. 83 - 112
Autores: Pelacho Samper, Beatriz; Mazo Vega, Manuel María; Montori Pina, Sheyla; et al.
Libro:  Regenerative medicine and cell therapy
Vol. 316  2013  págs. 65 - 112
Autores: Simón Yarza, María Teresa; Garbayo Atienza, Elisa; Tamayo Revuelta, Esther; et al.
Libro:  Nanostructured biomaterials for overcoming biological barriers
2012  págs. 501 - 526
Autores: Estella Hermoso de Mendoza, Ander; Lasa Saracíbar, Beatriz; Campanero Martínez, Miguel Ángel; et al.
Libro:  Encyclopedia of Nanoscience and Nanotechnology / editor, Hari Singh Nalwa
Vol. 15  2011  págs. 455-478



Formulacion magistral (F. Farmacia). 
Universidad de Navarra - Facultad de Farmacia y Nutrición.

Tecnología Farmacéutica III (F. Farmacia). 
Universidad de Navarra - Facultad de Farmacia y Nutrición.

Nanotecnología e Ingeniería Biomédica (MIB). 
Universidad de Navarra - Escuela de Ingeniería.