Juan Irache
University of Navarra, Pharmacy and Pharmaceutical Technology, Faculty Member
Research Interests: Chemistry, Molecular Biology, Oxidative Stress, DNA damage, Medicine, and 15 moreCell line, Mutagenesis, Genotoxicity, Animals, Cell Death, Comet Assay, Biological markers, Cell Proliferation, Microbial Viability, Organometallic Compounds, Mutagens, Cricetinae, Mutagenicity tests, Pharmacology and pharmaceutical sciences, and microsomes
Ganciclovir is a nucleoside analogue widely used in the treatment of cytomegalovirus infections, which affects mainly immunocompromised patients. Recently, new pharmaceutical dosage forms based on the use of albumin nanoparticles have... more
Ganciclovir is a nucleoside analogue widely used in the treatment of cytomegalovirus infections, which affects mainly immunocompromised patients. Recently, new pharmaceutical dosage forms based on the use of albumin nanoparticles have been developed for improving the efficacy of this drug. The aim of this study was to develop an analytical HPLC method for the determination of ganciclovir in both pharmaceuticals
Research Interests: Engineering, Chemistry, Analytical Chemistry, Technology, Chromatography, and 12 moreMedicine, Humans, Albumin, Calibration, Cytomegalovirus, High Performance Liquid Chromatography, High Pressure Liquid Chromatography, CHEMICAL SCIENCES, Reproducibility of Results, Sensitivity and Specificity, Antiviral Agents, and Ganciclovir
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The aim was to evaluate the potential of nanocarriers, based on the coating of zein nanoparticles (ZNP) with a Gantrez® AN-PEG conjugate (GP), for the oral delivery of insulin. ZNP-GP displayed less negative surface charge and a 14-fold... more
The aim was to evaluate the potential of nanocarriers, based on the coating of zein nanoparticles (ZNP) with a Gantrez® AN-PEG conjugate (GP), for the oral delivery of insulin. ZNP-GP displayed less negative surface charge and a 14-fold higher diffusion coefficient in pig intestinal mucus than ZNP. Both nanoparticles showed a spherical shape and an insulin load of 77.5 µg/mg. Under simulated gastric conditions, ZNP-GP released significantly lower amount of insulin than ZNP, while under simulated intestinal conditions, both types of nanoparticles displayed similar behaviour. In Caenorhabditis elegans wild-type N2, grown under high glucose conditions, insulin treatments reduced glucose and fat accumulation without altering the growth rate, the worm length, or the pumping rate. The effect was significantly greater ( p < 0.001) when insulin was nanoencapsulated in ZNP-GP compared with that encapsulated in ZNP or formulated in solution. This would be related to the highest capability of ZNP-GP to diffuse in the dense peritrophic-like layer covering intestinal cells in worms. In daf-2 mutants, the effect on fat and glucose reduction by insulin treatment was suppressed, indicating a DAF-2 dependent mechanism. In summary, ZNP-GP is a promising platform that may offer new opportunities for the oral delivery of insulin and other therapeutic proteins. Graphical abstract
Research Interests: Biophysics, Chemistry, Caenorhabditis elegans, Medicine, Insulin, and 2 moreIn Vivo and Nanocarriers(In Vivo and Nanocarriers)
(In Vivo and Nanocarriers)
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Research Interests: Technology, Chitosan, Nanoparticles, Medicine, Biological Sciences, and 14 moreLeishmaniasis, Animals, Naphthoquinones, Drug Delivery Systems, Skin, CHEMICAL SCIENCES, Immune system, Topical Drug Administration, Dermis, Cutaneous Leishmaniasis, Topical Drug Delivery, Drug Carriers, Leishmania Major, and Scars
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Nimodipine may be of interest to treat behavioral alterations and memory deficits. However, its oral administration is hampered by a low bioavailability. The aim of this work was to develop pegylated nanoparticles as oral carriers of... more
Nimodipine may be of interest to treat behavioral alterations and memory deficits. However, its oral administration is hampered by a low bioavailability. The aim of this work was to develop pegylated nanoparticles as oral carriers of nimodipine and test their capability to both reverse the anxiety and protect against cognitive impairment of in stressed mice. Pegylated nanoparticles (NMD-NP/PEG), with a size of 190 nm and a payload of 68 µg/mg, significantly improve the oral bioavailability of nimodipine; about 7-times higher than for the control drug solution (62% vs 9%). The effect of oral nimodipine on the anxiety and cognitive capabilities in a model of stressed mice was also evaluated. NMD-NP/PEG displayed a poor effect on the anxiety-like behavior of animals. Nevertheless, only the treatment with NMD-NP/PEG exerted a protective effect against the memory impairments induced by chronic corticosterone administration, improving the cognitive capabilities of animals when compared wi...
Research Interests: Pharmacology, Cognition, Locomotion, Nanoparticles, Medicine, and 15 moreAnxiety, Pharmaceutics, Animals, Corticosterone, Male, Bioavailability, Elevated Plus Maze, ANXIETY, Drug Carriers, Maze Learning, NIMODIPINE, Nanocarriers, Neuroprotective Agents, Calcium Channel Blockers, and Pharmacology and pharmaceutical sciences
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Oral administration is the most commonly used and accepted route for drug administration. However, two of the main concerns are the poor intestinal epithelium permeability and rapid degradation, which limit absorption of drugs. In this... more
Oral administration is the most commonly used and accepted route for drug administration. However, two of the main concerns are the poor intestinal epithelium permeability and rapid degradation, which limit absorption of drugs. In this context, nanocarriers have shown great potential for oral drug delivery. Nevertheless, special importance should be given to the possible toxic effect of these nanocarriers, such as their bioaccumulation in different tissues of the body, as well as, the different physicochemical parameters influencing their properties and so their potential toxic effect. This review describes first some aspects related to the behavior of nanosystems within the gastrointestinal tract and then some aspects of nanotoxicology and its evaluation, including the most popular techniques and approaches used for in vitro and in vivo toxicity studies. It also reviews the physicochemical characteristics of polymeric nanoparticles that may influence the development of toxicological effects, and finally it summarizes the toxicity results that have been published regarding polymeric nanocarriers.
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Abstract Inflammatory bowel disease (IBD) is a chronic condition with symptoms such as diarrhea, abdominal pain, weight loss, rectal bleeding and anemia, represented by Crohn's disease (CD) and ulcerative colitis (UC). One of the main... more
Abstract Inflammatory bowel disease (IBD) is a chronic condition with symptoms such as diarrhea, abdominal pain, weight loss, rectal bleeding and anemia, represented by Crohn's disease (CD) and ulcerative colitis (UC). One of the main problems in the treatment of IBD is the low capacity of the drugs to reach the inflamed colon, which generates the need for administration of high doses of medicines and, consequently, the occurrence of several adverse effects. A possible alternative to overcome this limitation is the encapsulation of drugs in polymeric nanocarriers. Nanosystems have shown utility in increasing the absorption of drugs in the colon, improving the effectiveness of treatment and decreasing the necessary doses. Based on the above, this review aims to perform a prospective study related to the development of nanostructures obtained from natural polymers to optimize the treatment of IBD with a focus on the colon. All searches were carried out in the scientific databases (VHL, PubMed, Science Direct, and Scopus) and patents (EPO, USPTO, WIPO, and INPI) using as keywords the main natural polymers AND “Inflammatory bowel diseases" AND "nano". In this study, 44 articles and 4 patents were included. We observed that the main focus of the studies are the polymeric nanoparticles from polysaccharide with properties programmed to overcome several obstacles to the efficient release and delivery of the drug in the colon. Chitosan was the most cited polymer in the development of nanosystems, due to its resistance to enzymatic degradation and mucoadhesive properties that optimize the treatment of IBD. This polymer showed greater capacity to reach the inflamed colon and promote sustained release of the drug. However, studies are still recent.
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The burden of dysentery due to shigellosis among children in the developing world is still a major concern. A safe and efficacious vaccine against this disease is a priority, since no licensed vaccine is available. This review provides an... more
The burden of dysentery due to shigellosis among children in the developing world is still a major concern. A safe and efficacious vaccine against this disease is a priority, since no licensed vaccine is available. This review provides an update of vaccine achievements focusing on subunit vaccine strategies and the forthcoming strategies surrounding this approach. In particular, this review explores several aspects of the pathogenesis of shigellosis and the elicited immune response as being the basis of vaccine requirements. The use of appropriate Shigella antigens, together with the right adjuvants, may offer safety, efficacy and more convenient delivery methods for massive worldwide vaccination campaigns.
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... Page 184. Nanoparticules for Oral Vaccination 171 access of antigens and pathogens through the intercellular tight junctions that restrict the passage from the lumen to the submucosa [Miyoshi and Takai, 2005]. ... In fact,... more
... Page 184. Nanoparticules for Oral Vaccination 171 access of antigens and pathogens through the intercellular tight junctions that restrict the passage from the lumen to the submucosa [Miyoshi and Takai, 2005]. ... In fact, conventional nanoparticles are rapidly eliminated from ...
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Este estudio utiliza C. elegans para evaluar la toxicidad de los nanogeles (NG) copoliméricos de N-isopropilacrilamida (NIPAAm) y metacrilato de 2-(dietilamino)etilo (DEAEM), preparados mediante polimerización en emulsión sin tensoactivo... more
Este estudio utiliza C. elegans para evaluar la toxicidad de los nanogeles (NG) copoliméricos de N-isopropilacrilamida (NIPAAm) y metacrilato de 2-(dietilamino)etilo (DEAEM), preparados mediante polimerización en emulsión sin tensoactivo utilizando polietilenglicol monometil éter metacrilato (PEGMA) como estabilizador reactivo. Los nematodos ingirieron NG marcados con fluoresceína, como se demostró mediante microscopía de fluorescencia. Se utilizaron dos iniciadores diferentes, catiónicos y aniónicos para iniciar la síntesis de los NG. Los resultados demuestran que ambos tipos de NG afectan el tamaño y la reproductividad de los nematodos. C. elegans es un modelo pluricelular potencial para evaluar la toxicidad de los NG sensibles, evitando el uso de mamíferos para las evaluaciones.
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Fil: Lopez Hiriart, Milagros. Universidad Nacional de Rosario. Facultad de Ciencias Bioquimicas y Farmaceuticas; Argentina.
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OBJECTIVE To optimize radiolabeling with 99mTc and 67Ga of albumin nanoparticles coated with 4 differents synthetic polymers and to evaluate their stability in vivo and in vitro, as well as their biodistribution in vivo after intravenous... more
OBJECTIVE To optimize radiolabeling with 99mTc and 67Ga of albumin nanoparticles coated with 4 differents synthetic polymers and to evaluate their stability in vivo and in vitro, as well as their biodistribution in vivo after intravenous administration. MATERIAL AND METHODS The nanoparticles were prepared using albumin and NOTA-modified albumin by the desolvation method and coated with 4 different polymers; HPMC, GMN2, GPM2 and GTM2. They were purified, lyophilized and characterized. Radiolabelling with 99mTc was perfomed with 74 MBq of 99mTc sodium pertechnetate, previously reduced with and acid solution of tin chloride at different concentrations (0.003, 0.005, 0.007, 0.01, 0.05 and 0.1mg/ml) and at different times (5, 10, 15, 30 and 60minutes) and temperatures (room temperature, 40°C and 60°C). Radiolabelling with 67Ga was perfomed by incubation of the nanoparticles with 37 MBq of 67Gallium chloride (obtained from commercial gallium-67 citrate) at different times (10 and 30minutes) and temperatures (room temperature, 30°C and 60°C), and posterior purification with microconcentrators. The radiochemical purity was evaluated by TLC. Stability studies of radiolabeled nanoparticles in physiological serum and blood plasma were perfomed. Biodistribution studies of nanoparticles coated with GPM2 polymer were carried out in Wistar rats after intravenous administration of the nanoparticles. Control animals were carried out with 99mTc sodium pertechnetate and 67Ga chloride. To do so, the animals were killed and activity in organs was measured in a gamma counter. RESULTS 99mTc labeling was carried out optimally with a tin concentration of 0.007mg/ ml for the GPM2 nanoparticles and 0.005mg / ml for the rest of the formulations, with a radiolabelling time of 10minutes at room temperature. In the case of 67Ga the label was optimized at 30° C temperature and 30minutes of incubation. In both cases the radiochemical purity obtained was greater than 97%. The nanoparticles showed high stability in vitro after 48hours of labeling (70% nanoparticles labeled with 99mTc and 90% those labeled with 67Ga). Biodistribution studies of nanoparticles 99mTc -GPM2 and 67Ga -NOTA-GPM2 showed a high accumulation of activity in the liver at 2 and 24hours after intravenous administration. CONCLUSION The labeling procedure with 99mTc and 67Ga of albumin and albumin modified with NOTA nanoparticles allows obtaining nanoparticles with high labeling yields and adequate in vitro stability, allowing their use for in vivo studies.
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Research Interests: Pharmacology, Nanoparticles, Medicine, Dexamethasone, Neovascularization, and 11 moreOcular Delivery, CIENCIAS DE LA SALUD, In Vivo, Optometry and Ophthalmology, Bevacizumab, Neurosciences, Corneal neovascularization, PEGylated, Choroidal Neovascularization, Human serum albumin, and Medical biochemistry and metabolomics
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Under many circumstances, prophylactic immunizations are considered as the only possible strategy to control infectious diseases. Considerable efforts are typically invested in immunogen selection but, erroneously, the route of... more
Under many circumstances, prophylactic immunizations are considered as the only possible strategy to control infectious diseases. Considerable efforts are typically invested in immunogen selection but, erroneously, the route of administration is not usually a major concern despite the fact that it can strongly influence efficacy. The skin is now considered a key component of the lymphatic system with tremendous potential as a target for vaccination. The purpose of this review is to present the immunological basis of the skin-associated lymphoid tissue, so as to provide understanding of the skin vaccination strategies. Several strategies are currently being developed for the transcutaneous delivery of antigens. The classical, mechanical or chemical disruptions versus the newest approaches based on microneedles for antigen delivery through the skin are discussed herein.
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Quercetin has been identified as a promising compound with a neuroprotective potential against age-related neurodegenerative diseases such as Alzheimer's disease (AD). Nevertheless, the clinical application of quercetin is hampered by... more
Quercetin has been identified as a promising compound with a neuroprotective potential against age-related neurodegenerative diseases such as Alzheimer's disease (AD). Nevertheless, the clinical application of quercetin is hampered by its low oral bioavailability. The aim of this work was to evaluate the capability of nanoencapsulated quercetin in zein nanoparticles (NPQ), that significantly improves the oral absorption and bioavailability of the flavonoid, as potential oral treatment for AD. For this purpose, SAMP8 mice were orally treated for two months with either NPQ (25mg/kg every 48h) or a solution of quercetin (Q; 25mg/kg daily). NPQ displayed a size of 260nm and a payload of about 70μg/mg. For Q, no significant effects were observed in animals. On the contrary, the oral administration of NPQ improved the cognition and memory impairments characteristics of SAMP8 mice. These observations appeared to be related with a decreased expression of the hippocampal astrocyte marker...
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Understanding how nanoparticles are formed and how those processes ultimately determine the nanoparticles' properties and their impact on their capture by immune cells is key in vaccination studies. Accordingly, we wanted to evaluate... more
Understanding how nanoparticles are formed and how those processes ultimately determine the nanoparticles' properties and their impact on their capture by immune cells is key in vaccination studies. Accordingly, we wanted to evaluate how the previously described poly (anhydride)-based nanoparticles of the copolymer of methyl vinyl ether and maleic anhydride (NP) interact with macrophages, and how this process depends on the physicochemical properties derived from the method of preparation. First, we studied the influence of the desolvation and drying processes used to obtain the nanoparticles. NP prepared by the desolvation of the polymers in acetone with a mixture of ethanol and water yielded higher mean diameters than those obtained in the presence of water (250nm vs. 180nm). In addition, nanoparticles dried by lyophilization presented higher negative zeta potentials than those dried by spray-drying (-47mV vs. -35mV). Second, the influence of the NP formulation on the phagocytosis by J774 murine macrophage-like cell line was investigated. The data indicated that NPs prepared in the presence of water were at least three-times more efficiently internalized by cells than NPs prepared with the mixture of ethanol and water. Besides, lyophilized nanoparticles appeared to be more efficiently taken up by J744 cells than those dried by spray-drying. To further understand the specific mechanisms involved in the cellular internalization of NPs, different pharmacological inhibitors were used to interfere with specific uptake pathways. Results suggest that the NP formulations, particularly, nanoparticles prepared by the addition of ethanol:water, are internalized by the clathrin-mediated endocytosis, rather than caveolae-mediated mechanisms, supporting their previously described vaccine adjuvant properties.
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Research Interests: Chemistry, Analytical Chemistry, Chromatography, Nanoparticle, Nanoparticles, and 13 moreMedicine, HPLC, Calibration, High Performance Liquid Chromatography, High Pressure Liquid Chromatography, Solutions, Reproducibility of Results, Side Effect, Antineoplastic Agents, Ammonium Acetate, therapeutic index, fluorouracil, and Pharmacology and pharmaceutical sciences
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The study addresses Enterotoxigenic Escherichia coli (ETEC), a significant concern in low-income countries. Despite its prevalence, there is no licensed vaccine against ETEC. Bacterial vesicle-based vaccines are promising due to their... more
The study addresses Enterotoxigenic Escherichia coli (ETEC), a significant concern in low-income countries. Despite its prevalence, there is no licensed vaccine against ETEC. Bacterial vesicle-based vaccines are promising due to their safety and diverse virulence factors. However, cost-effective production requires enhancing vesicle yield while considering altered properties due to isolation methods. The proposed method involves heat treatment and ultrafiltration to recover vesicles from bacterial cultures. Two vesicle types, collected from heat-treated (HT-OMV) or untreated (NT-OMV) cultures, were compared. Vesicles were isolated via ultrafiltration alone (“complete”) or with ultracentrifugation (“sediment”). Preliminary findings suggest complete HT-OMV vesicles are suitable for an ETEC vaccine. They express important proteins (OmpA, OmpX, OmpW) and virulence factors (adhesin TibA). Sized optimally (50–200 nm) for mucosal vaccination, they activate macrophages, inducing marker expr...
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Research Interests: Biophysics, Chemistry, Nanoparticle, Medicine, Insulin, and 4 moreBiodistribution, In Vivo, Mucus, and Nanocarriers
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Zein, the major storage protein from corn, has a GRAS (Generally Regarded as Safe) status and may be easily transformed into nanoparticles, offering significant payloads for protein materials without affecting their stability. In this... more
Zein, the major storage protein from corn, has a GRAS (Generally Regarded as Safe) status and may be easily transformed into nanoparticles, offering significant payloads for protein materials without affecting their stability. In this work, the capability of bare zein nanoparticles (mucoadhesive) and nanoparticles coated with poly(ethylene glycol) (mucus-permeating) was evaluated as oral carriers of insulin (I-NP and I-NP-PEG, respectively). Both nanocarriers displayed sizes of around 270 nm, insulin payloads close to 80 µg/mg and did not induce cytotoxic effects in Caco-2 and HT29-MTX cell lines. In Caenorhabditis elegans, where insulin decreases fat storage, I-NP-PEG induced a higher reduction in the fat content than I-NP and slightly lower than the control (Orlistat). In diabetic rats, nanoparticles induced a potent hypoglycemic effect and achieved an oral bioavailability of 4.2% for I-NP and 10.2% for I-NP-PEG. This superior effect observed for I-NP-PEG would be related to their...
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The aim of this work was to evaluate oral nanocarriers, prepared from zein nanoparticles coated with a poly(anhydride)-thiamine conjugate (GT), for the delivery of insulin. Nanoparticles displayed a size of 250 nm with a negative surface... more
The aim of this work was to evaluate oral nanocarriers, prepared from zein nanoparticles coated with a poly(anhydride)-thiamine conjugate (GT), for the delivery of insulin. Nanoparticles displayed a size of 250 nm with a negative surface charge, and an insulin loading of 80 μg/mg. Under simulated gastric conditions, GT-coated nanoparticles released a significantly lower amount of insulin than bare ones; whereas in simulated intestinal conditions, both types of nanoparticles displayed a similar behavior. The effect of insulin on the lipid metabolism of C. elegans under high glucose conditions, characterized by a reduction of the fat content, was also investigated. The effect was significantly higher for the nanoencapsulated forms of insulin than for the free protein ( p < 0.001). This effect was two times higher for GT-coated nanoparticles than for bare ones. In rats, the hypoglycemic effect and the pharmacokinetic profile of insulin-loaded nanoparticles orally administered (50 IU/kg) were evaluated. The glycemia of animals slowly decreased reaching a minimum 6–10-h post-administration, with a maximum decrease of about 60%. The pharmacological availability of nanoencapsulated insulin was 13.5%. In serum, nanoparticles provided a maximum of insulin 4-h post-administration, and its relative oral bioavailability was 5.2% (compared with a sc formulation of insulin). Graphical abstract
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Enterotoxigenic Escherichia coli (ETEC) represents a major cause of morbidity and mortality in the human population. In particular, ETEC infections affect children under the age of five from low-middle income countries. However, there is... more
Enterotoxigenic Escherichia coli (ETEC) represents a major cause of morbidity and mortality in the human population. In particular, ETEC infections affect children under the age of five from low-middle income countries. However, there is no licensed vaccine against this pathogen. ETEC vaccine development is challenging since this pathotype expresses a wide variety of antigenically diverse virulence factors whose genes can be modified due to ETEC genetic plasticity. To overcome this challenge, we propose the use of outer membrane vesicles (OMVs) isolated from two ETEC clinical strains. In these OMVs, proteomic studies revealed the presence of important immunogens, such as heat-labile toxin, colonization factors, adhesins and mucinases. Furthermore, these vesicles proved to be immunogenic after subcutaneous administration in BALB/c mice. Since ETEC is an enteropathogen, it is necessary to induce both systemic and mucosal immunity. For this purpose, the vesicles, free or encapsulated i...