Artículos (Farmacia y Tecnología Farmacéutica)

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Factores asociados a la mortalidad en pacientes hospitalizados por COVID-19 en España: datos del Registro Español de Resultados de Farmacoterapia frente a COVID-19 (RERFAR)
(Sociedad Española de Farmacia Hospitalaria, 2022) Olry de Labry Lima, Antonio; Sáez de la Fuente, Javier; Abdel-Kader Martín, Laila; Alegre del Rey, Emilio Jesús; García Cabrera, Emilio; Sierra Sánchez, Jesús F.; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Universidad de Sevilla. Departamento de Medicina Preventiva y Salud Pública
Objetivo: Determinar las características basales que se asocian a una mayor mortalidad a los 42 días en aquellos pacientes hospitalizados por COVID-19 en España. Método: Cohorte prospectiva de pacientes COVID-19 hospitalizados. La variable dependiente fue la mortalidad a los 42 días. Además, se recogieron características demográficas, clínicas, comorbilidades, tratamiento habitual, intervenciones de soporte y tratamientos en las primeras 48 horas del ingreso. Para determinar la asociación con la mortalidad, se realizó un análisis multivariante mediante regresión logística. Resultados: Se incluyeron 15.628 pacientes, de ellos falleció el 18,2% (n = 2.806). El análisis multivariante mostró que las variables asociadas significativamente (p < 0,05) con la mortalidad al ingreso fueron: proceder de un centro sociosanitario (odds ratio OR 1,9), frecuencia respiratoria (odds ratio 1,5), gravedad de neumonía (CURB-65) moderada (odds ratio 1,7) o alta (odds ratio 2,9), transaminasa aspartato aminotransferasa ≥ 100 UI/l (odds ratio 2,1), lactato-deshidrogenasa ≥ 360 UI/l (odds ratio 1,6), procalcitonina > 0,5 ng/ml (odds ratio 1,8), creatina- quinasa ≥ 294 U/l (odds ratio 1,5), dímero D > 3.000 ng/ml (odds ratio 1,5), hemoglobina < 11,6 g/dl (odds ratio 1,4) y proteína C reactiva > 120 mg/l (odds ratio 1,2), necesidad de soporte respiratorio en las primeras 48 horas (odds ratio 2,0 de oxigenoterapia; odds ratio 2,8 ventilación no invasiva y odds ratio 3,5 ventilación mecánica) y tratamiento con interferón-beta (odds ratio 1,5). Por el contrario, ser menor de 80 años se asoció a una menor mortalidad. Conclusiones: El análisis del Registro Español de Resultados de farmacoterapia frente a COVID-19 muestra que los factores asociados a peor pronóstico son: mayor edad, valoración mediante la escala CURB‑65, el nivel de requerimiento de soporte respiratorio, neumonía grave (CURB‑65), hipertransaminasemia, elevación de creatina-quinasa, lactato- deshidrogenasa, y dímero-D, anemia y elevación de la frecuencia respiratoria.
Innovations in Cancer Therapy: Endogenous Stimuli-Responsive Liposomes as Advanced Nanocarriers
(MDPI, 2025-02-13) Torres, Jazmín; Valenzuela Oses, Johanna Karina; Rabasco Álvarez, Antonio María; González Rodríguez, María Luisa; García, Mónica Cristina; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Agencia Nacional de Promoción Científica y Tecnológica. Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Argentina; Universidad de Córdoba. Argentina
Recent advancements in nanotechnology have revolutionized cancer therapy—one of the most pressing global health challenges and a leading cause of death—through the development of liposomes (L), lipid-based nanovesicles known for their biocompatibility and ability to encapsulate both hydrophilic and lipophilic drugs. More recent innovations have led to the creation of stimuli-responsive L that release their payloads in response to specific endogenous or exogenous triggers. Dual- and multi-responsive L, which react to multiple stimuli, offer even greater precision, improving therapeutic outcomes while reducing systemic toxicity. Additionally, these smart L can adjust their physicochemical properties and morphology to enable site-specific targeting and controlled drug release, enhancing treatment efficacy while minimizing adverse effects. This review explores the latest advancements in endogenous stimuli-responsive liposomal nanocarriers, as well as dual- and multi-responsive L that integrate internal and external triggers, with a focus on their design strategies, mechanisms, and applications in cancer therapy.
Lipid nanoparticles as an emerging platform for cannabinoid delivery: physicochemical optimization and biocompatibility
(Taylor & Francis, 2016) Durán Lobato, María Matilde; Martín Banderas, Lucía; Lopes, R.; Gonçalves, L.M.D.; Fernández Arévalo, María Mercedes; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Junta de Andalucía; Fundação para a Ciência e a Tecnologia. Portugal
This work aims at developing and optimizing a valuable oral delivery carrier for the cannabinoid derivative CB13, which presents a high therapeutic potential in chronic pain states that respond poorly to conventional analgesics, but also shows highly unfavorable physicochemical properties. CB13-loaded lipid nanoparticles (LNP) formulations were developed through solvent-emulsion evaporation and optimized in terms of physicochemical properties, long-term stability, integrity under gastric simulated conditions and in vitro interaction with NIH 3T3, HEK 293T and Caco-2 cells. An optimized formulation of LNP containing CB13 was obtained from a wide range of conditions assayed and analyzed. The selection of the lipid core, production conditions and the inclusion of lecithin proved to be key factors for the final properties of encapsulation, integrity and performance of the carriers. The LNP formulation proposed proved to be a promising carrier for the oral delivery of CB13, a cannabinoid with high therapeutic potential in chronic pain states that currently lack a valid oral treatment.
Comparative study of chitosan- and PEG-coated lipid and PLGA nanoparticles as oral delivery systems for cannabinoids
(Elsevier, 2015) Durán Lobato, María Matilde; Martín Banderas, Lucía; Gonçalves, Lídia M.D.; Fernández Arévalo, María Mercedes; Almeida, Antonio J.; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Junta de Andalucía; imed - Research Institute for Medicines. Portugal
The cannabinoid derivative 1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone (CB13) has an important therapeutic potential as analgesic in chronic pain states that respond poorly to conventional drugs. However, the incidence of its mild-to-moderate and dose-dependent adverse effects, as well as its pharmacokinetic profile, actually holds back its use in humans. Thus, the use of a suitable carrier system for oral delivery of CB13 becomes an attractive strategy to develop a valuable therapy. Polymeric poly(lactic-co-glycolic) acid (PLGA) and lipid nanoparticles (LNPs) are widely studied delivery vehicles that improve the bioavailability of lipophilic compounds and present special interest in oral delivery. Their surface can be modified to improve the adhesion of particles to the oral mucosa and increase their circulation time in blood with additives such as chitosan (CS) and polyethylene glycol (PEG), which can be feasibly incorporated onto these particles in a post-production step. In this work, CS- and PEG-modified polymeric PLGA and LNPs were successfully obtained and comparatively evaluated under the same experimental conditions as oral carriers for CB13. All the formulations presented adequate blood compatibility and absence of cytotoxicity in Caco-2 cells. Coating with CS led to a higher interaction with Caco-2 cells and a limited uptake in THP1 cells, while coating with PEG led to a limited uptake in Caco-2 cells and strongly prevented THP1 cells uptake. The performance of each formulation is discussed as a comparison of the potential of these carriers as oral delivery systems of CB13.
Engineering of Δ9-tetrahydrocannabinol delivery systems based on surface modified-PLGA nanoplatforms
(Elsevier, 2014-11-01) Martín Banderas, Lucía; Muñoz Rubio, Inmaculada; Álvarez Fuentes, Josefa; Durán Lobato, María Matilde; Arias, José L.; Holgado Villafuerte, María Ángeles; Fernández Arévalo, María Mercedes; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Junta de Andalucía; Instituto de Salud Carlos III
The objective of this work is to develop a nanoplatform that can potentiate the oral administration of Δ9-tetrahidrocannabinol, a highly lipophilic active agent with very promising antiproliferative and antiemetic activities. To that aim, colloidal carriers based on the biodegradable and biocompatible poly(d,l-lactide-co-glycolide) were investigated. Such delivery systems were prepared by nanoprecipitation, and nanoparticle engineering further involved surface modification with a poly(ethylene glycol), chitosan, or poly(ethylene glycol)-chitosan shells to assure the greatest uptake by intestinal cells and to minimize protein adsorption. Characterization of the nanoplatforms included particle geometry (size and shape), electrophoretic properties (surface charge). Δ9-tetrahydrocannabinol vehiculization capabilities (loading and release), blood compatibility, and cellular uptake and cytotoxicity. Results were satisfactorily used to define the optimum engineering conditions to formulate surface modified nanoparticles for the efficient oral administration of Δ9-tetrahydrocannabinol. To the best of our knowledge, this is the first time that biocompatible polymeric nanoparticles have been formulated for Δ9-tetrahydrocannabinoldelivery.
Biocompatible gemcitabine-based nanomedicine engineered by Flow Focusing® for efficient antitumor activity
(Elsevier, 2013) Martín Banderas, Lucía; Sáez-Fernández, Eva; Holgado Villafuerte, María Ángeles; Durán Lobato, María Matilde; Prados, José C.; Melguizo, Consolación; Arias, José L.; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Instituto de Salud Carlos III
We investigated the incorporation of gemcitabine into a colloidal carrier based on the biodegradable and biocompatible poly(d,l-lactide-co-glycolide) (PLGA) to optimize its anticancer activity. Two synthesis techniques (double emulsion/solvent evaporation, and Flow Focusing®) were compared in terms of particle geometry, electrophoretic properties (surface charge), gemcitabine vehiculization capabilities (drug loading and release), blood compatibility, and in vitro antitumor activity. To the best of our knowledge, the second formulation methodology (Flow Focusing®) has never been applied to the synthesis of gemcitabine-loaded PLGA particles. With the aim of achieving the finest (nano)formulation, experimental parameters associated to these preparation procedures were analyzed. The electrokinetics of the particles suggested that the chemotherapy agent was incorporated into the polymeric matrix. Blood compatibility was demonstrated in vitro. Flow Focusing® led to a more appropriate geometry, higher gemcitabine loading and a sustained release profile. In addition, the cytotoxicity of gemcitabine-loaded particles prepared by Flow Focusing® was tested in MCF-7 human breast adenocarcinoma cells, showing significantly greater antitumor activity compared to the free drug and to the gemcitabine-loaded particles synthesized by double emulsion/solvent evaporation. Thus, it has been identified the more adequate formulation conditions in the engineering of gemcitabine-loaded PLGA nanoparticles for the effective treatment of tumours.
Functional PLGA NPs for Oral Drug Delivery: Recent Strategies and Developments
(Bentham Science, 2013) Martín Banderas, Lucía; Durán Lobato, María Matilde; Muñoz Rubio, Inmaculada; Álvarez Fuentes, Josefa; Fernández Arévalo, María Mercedes; Holgado Villafuerte, María Ángeles; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Junta de Andalucía
This article presents the potential of PLGA nanoparticles for the oral administration of drugs. Different strategies are used to improve oral absorption of these nanoparticles. These strategies are based on modification of nanoparticle surface properties. They can be achieved either by coating the nanoparticle surface with stabilizing hydrophilic bioadhesive polymers or surfactants, or by incorporating biodegradable copolymers containing a hydrophilic moiety. Some substances such as chitosan, vitamin E, methacrylates, lectins, lecithins, bile salts and RGD molecules are employed for this purpose. Of especial interest are nanoparticles production methods and, in order to improve oral bioavailability, the mechanism of each additive.
Cannabinoids as Emergent Therapy Against COVID-19
(Mary Ann Liebert, 2022-10-12) McGrail, Joseph; Martín Banderas, Lucía; Durán Lobato, María Matilde; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica
The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory distress syndrome coronavirus 2 (SARS-Cov-2), was identified for the first time in late 2019 in China, resulting in a global pandemic of massive impact. Despite a fast development and implementation of vaccination strategies, and the scouting of several pharmacological treatments, alternative effective treatments are still needed. In this regard, cannabinoids represent a promising approach because they have been proven to exhibit several immunomodulatory, anti-inflammatory, and antiviral properties in COVID-19 disease models and related pathological conditions. This mini-review aims at providing a practical brief overview of the potential applications of cannabinoids so far identified for the treatment and prevention of COVID-19, finally considering key aspects related to their technological and clinical implementation.
Preparation and In Vivo Evaluation of Rosmarinic Acid-Loaded Transethosomes After Percutaneous Application on a Psoriasis Animal Model
(Springer Nature, 2021) Rodríguez Luna, Azahara María; Talero Barrientos, Elena Mª; Ávila Román, Francisco Javier; Fernández Romero, Ana María; Rabasco Álvarez, Antonio María; Motilva Sánchez, Virginia; González Rodríguez, María Luisa; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Junta de Andalucía; Universidad de Sevilla
The topical use of rosmarinic acid (RA) in skin inflammatory pathologies is restricted due to its poor water solubility, poor permeability, and chemical instability. In this study, RA-loaded transethosomes-in-Carbopol® formulations have been developed to evaluate its anti-inflammatory activity on imiquimod-induced psoriasis-like skin inflammation in mice. In vitro release profiles demonstrated sustained behavior due to the retentive action of gel and the entrapment of RA into the vesicles. However, the low viscosity of the combined formulation increased the drug release rate. Animal evaluation of anti-inflammatory activity demonstrated that transethosomes-in-gel containing dexamethasone (Dex-TE-Gel), as positive control, showed effect in all the pro-inflammatory parameters evaluated, evidencing that these drug-loaded nanocarriers have been effectively reached the site of action. In addition, transethosomes-in-gel containing RA (RA-TE-Gel) formulations produced a great reduction in the punch edema (P < 0.001) and in TNF-α and IL-6 (P < 0.05). However, non-significant differences were obtained for IL-1β, IL17, and MPO. Despite the protecting effect of Carbopol® and transethosomes on oxidation index and antioxidant activity of RA over the 7 days of treatment, however, a degradation process of this antioxidant to caffeic acid may be the cause of these in vivo results. We have also checked that the pH existing into the intercellular space of damaged cells (pH 6.8) may be affecting. Therefore, our results suggest that RA-TE-Gel could act as an effective RA formulation for skin delivery; further studies will help to understand the loss of activity at the cellular level.
Drug diffusion from disperse systems with a hydrophobically modified polysaccharide: Enhancer (R) vs Franz cells
(Elsevier Science Ltd, 2012-09-13) Lucero Muñoz, María Jesús; Claro Cala, Carmen María; Casas Delgado, Marta; Jiménez-Castellanos Ballesteros, María Rosa; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica
This study assesses the capacity of a new hydrophobically modified polysaccharide –hydroxypropyl cellulose–methyl methacrylate – to control drug release in semisolid formulations. The dispersed sys tems contain the new polymer, Igepal®CO520 as surfactant and theophylline as model drug at three concentrations (0.5, 1 and 1.5%, w/w). Drug release study shows that the systems containing 0.5% (w/w) of drug have faster release and higher diffusion coefficient than the other two concentrations. These results can be explained by two different structures (“relaxed” and “structured”) found from a rheologi cal point of view. Also, this paper compares two different devices for testing drug release and diffusion. It has been obtained more reliable and reproducible results with Enhancer Cell®respect to Franz diffusion cell. In both cases, Fickian diffusion was the mechanism predominant for all systems. Finally, the utility of this polymer has been demonstrated to make three-dimensional gel structure and control theophylline release from systems in topical application.
Rheological and mechanical properties of hydrophilic dispersions using a new hydrophobically modified polymer and Igepal (R) CO520
(Elsevier, 2011-08-15) Lucero Muñoz, María Jesús; Claro Cala, Carmen María; Casas Delgado, Marta; Jiménez Castellanos, María Rosa; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Biomedicina de Sevilla (IBIS); Universidad de Sevilla. CTS-1015: Desarrollo galénico de medicamentos y productos cosméticos; Universidad de Sevilla. CTS-547: Caracterización y optimización estadística de medicamentos; Universidad de Sevilla. CTS-1074: Inmunonutrición e inmunometabolismo
Hydroxypropyl cellulose-methyl methacrylate and non-ionic surfactant Igepal (R) CO520 (20-25% (w/w)) have been characterized in aqueous-based dispersions for topical application systems. The systems have similar viscosity curves independent of the surfactant's concentration, showing shear-thinning fluids. Also, the elastic and viscous moduli are constant and independent of critical stress values applied; however, the storage modulus was always higher than the loss modulus. Both parameters showed a slightly dependence on the applied frequency, indicating a gel-like behavior. The complex dynamic viscosity increases until 23% (w/w) of surfactant, keeps then constant. The hardness, compressibility and adhesiveness parameters increase when increase the Igepal (R) CO520 concentration. The adhesiveness properties are 18-47% higher than the compressibility ones, with low values for hardness (similar to 0.4 N). While fracture and Hencky's strain values increase when increase the surfactant concentration, fracture work decreased, and no relation is found to deformability modulus. Also, the dispersed system with 20% (w/w) of Igepal CO520 has less stiffness than with 25% (w/w). (C) 2011 Elsevier Ltd. All rights reserved.
Reservoir-type intranasal implants for sustained release of risperidone: A potential alternative for long-term treatment of schizophrenia
(Elsevier, 2024-09) Utomo, Emilia; Li, Linlin; Gao, Jiaqi; Anjani, Qonita Kurnia; Picco, Camila J.; Moreno-Castellanos, Natalia; Donnelly, Ryan F.; Domínguez Robles, Juan; Larrañeta, Eneko; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Engineering & Physical Sciences Research Council (EPSRC); Ministerio de Ciencia e Innovación (MICIN). España
To overcome the challenges of the blood-brain barrier for drug delivery to the central nervous system (CNS), intranasal implants were developed to improve the management of CNS conditions, such as schizophrenia. In the present work, we developed and characterised a drug-containing implant consisting of two parts: a core layer made from risperidone (RIS) and water-soluble polymers, including poly(vinylpyrrolidone) (PVP) and poly(ethylene glycol) (PEG), and a coating layer made of poly(caprolactone) (PCL) membrane. The obtained implants, where the core layer contained 75 % w/w risperidone, were characterised using several techniques: scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and attenuated total reflectance-Fourier transform infrared (ATR-FTIR). Moreover, the in vitro release profile of RIS was studied, showing that the PCL membrane could extend the release of RIS from 2 days up to 100 days. The in vitro release profile of the PCL-coated implant exhibited a linear release over the first 10 days, followed by a slower release rate that reached another linear phase up to 40 days. Subsequently, the drug release rates progressively slowed down. Finally, the results of in vitro biocompatibility studies indicated that the intranasal implants were biocompatible and non-cytotoxic. These findings suggest that the implants prepared in this work have the potential to provide long-acting drug delivery for targeting the brain.
Efficacy assessment of liposome crosslinked hyaluronic acid and standard hyaluronic acid eye drops for dry eye disease management: a comparative study employing the ocular surface analyzer and subjective questionnaires
(Frontiers Media S.A., 2024-06-26) Sánchez González, José María; Hita Cantalejo, María Concepción de; González Rodríguez, María Luisa; Fernández-Trueba-Fagúndez, Ana; Ballesteros-Sánchez, Antonio; Martínez-Pérez, Clara; Caro-Díaz, Romina; Montiel Guzmán, Carla; González-Oyarce, María Fernanda; Sánchez González, María del Carmen; Universidad de Sevilla. Departamento de Física de la Materia Condensada; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica
Introduction: Dry eye disease (DED) is a prevalent condition causing ocular discomfort and visual disturbances, often managed with artificial tears. This study aimed to assess and compare the efficacy of eye drops containing Crosslinked Hyaluronic Acid (CHA) with liposomes and crocin and standard Hyaluronic Acid (HA) for DED management. Methods: A single-blind, longitudinal study was conducted on 24 participants (48 eyes), randomized to receive one of the two treatments. Ocular health measures, including the ocular surface disease index (OSDI) and the standard patient evaluation of eye dryness (SPEED) scores, were assessed at baseline and 6 weeks post-treatment using the Ocular Surface Analyzer. Results: CHA achieved a lipid layer thickness increase of 1.29 ± 1.08 Guillon pattern degree (p < 0.01), FNIBUT increase 0.64 ± 0.77 s (p < 0.01), MNIBUT increase1.28 ± 4.74 s (p = 0.19), OSDI decrease 11.72 ± 6.73 score points (p < 0.01) and SPEED decrease 1.16 ± 5.05 score points (p = 0.27). Significant reductions in the OSDI and SPEED scores post-treatment were observed with both treatments, indicating their effectiveness. Conclusion: CHA with liposomes exhibits superior efficacy compared to standard HA eye drops in the management of DED. These findings highlight the potential for personalized treatment strategies incorporating CHA, indicating a more effective approach to DED management. However, further research is required to validate these results and investigate the long-term effects, which may pave the way for a data-driven and optimized approach to managing DED.
Deepvirusclassifier: a deep learning tool for classifying SARS-CoV-2 based on viral subtypes within the coronaviridae family
(Springer Nature, 2024-07-05) Azevedo, Karolayne S.; de Souza, Luísa C.; Coutinho, Maria G. F.; Melo Barbosa, Raquel de; Fernandes, Marcelo A. C.; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Purpose: In this study, we present DeepVirusClassifier, a tool capable of accurately classifying Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral sequences among other subtypes of the coronaviridae family. This classification is achieved through a deep neural network model that relies on convolutional neural networks (CNNs). Since viruses within the same family share similar genetic and structural characteristics, the classification process becomes more challenging, necessitating more robust models. With the rapid evolution of viral genomes and the increasing need for timely classification, we aimed to provide a robust and efficient tool that could increase the accuracy of viral identification and classification processes. Contribute to advancing research in viral genomics and assist in surveilling emerging viral strains. Methods: Based on a one-dimensional deep CNN, the proposed tool is capable of training and testing on the Coronaviridae family, including SARS-CoV-2. Our model’s performance was assessed using various metrics, including F1-score and AUROC. Additionally, artificial mutation tests were conducted to evaluate the model’s generalization ability across sequence variations. We also used the BLAST algorithm and conducted comprehensive processing time analyses for comparison. Results: DeepVirusClassifier demonstrated exceptional performance across several evaluation metrics in the training and testing phases. Indicating its robust learning capacity. Notably, during testing on more than 10,000 viral sequences, the model exhibited a more than 99% sensitivity for sequences with fewer than 2000 mutations. The tool achieves superior accuracy and significantly reduced processing times compared to the Basic Local Alignment Search Tool algorithm. Furthermore, the results appear more reliable than the work discussed in the text, indicating that the tool has great potential to revolutionize viral genomic research. Conclusion: DeepVirusClassifier is a powerful tool for accurately classifying viral sequences, specifically focusing on SARS-CoV-2 and other subtypes within the Coronaviridae family. The superiority of our model becomes evident through rigorous evaluation and comparison with existing methods. Introducing artificial mutations into the sequences demonstrates the tool’s ability to identify variations and significantly contributes to viral classification and genomic research. As viral surveillance becomes increasingly critical, our model holds promise in aiding rapid and accurate identification of emerging viral strains.
Cryopreserved nanostructured fibrin-agarose hydrogels are efficient and safe hemostatic agents
(Nature Research, 2024-08-21) Casado, Carlos; Cepeda-Franco, Carmen; Pereira Arenas, Sheila; Suárez, María Dolores; Gómez Bravo, Miguel Ángel; Alaminos, Miguel; Chato-Astrain, Jesús;; Fernández Muñoz, Beatriz; Campos-Cuerva, Rafael; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Universidad de Sevilla. Departamento de Cirugía; Instituto de Salud Carlos III; Universidad de Sevilla
Uncontrolled bleeding during surgery is associated with high mortality and prolonged hospital stay, necessitating the use of hemostatic agents. Fibrin sealant patches offer an efficient solution to achieve hemostasis and improve patient outcomes in liver resection surgery. We have previously demonstrated the efficacy of a nanostructured fibrin-agarose hydrogel (NFAH). However, for the widespread distribution and commercialization of the product, it is necessary to develop an optimal preservation method that allows for prolonged stability and facilitates storage and distribution. We investigated cryopreservation as a potential method for preserving NFAH using trehalose. Structural changes in cryopreserved NFAH (Cryo-NFAH) were investigated and comparative in vitro and in vivo efficacy and safety studies were performed with freshly prepared NFAH. We also examined the long-term safety of Cryo-NFAH versus TachoSil in a rat partial hepatectomy model, including time to hemostasis, intra-abdominal adhesion, hepatic hematoma, inflammatory factors, histopathological variables, temperature and body weight, hemocompatibility and cytotoxicity. Structural analyses demonstrated that Cryo-NFAH retained most of its macro- and microscopic properties after cryopreservation. Likewise, hemostatic efficacy assays showed no significant differences with fresh NFAH. Safety evaluations indicated that Cryo-NFAH had a similar overall profile to TachoSil up to 40 days post-surgery in rats. In addition, Cryo-NFAH demonstrated superior hemostatic efficacy compared with TachoSil while also demonstrating lower levels of erythrolysis and cytotoxicity than both TachoSil and other commercially available hemostatic agents. These results indicate that Cryo-NFAH is highly effective hemostatic patch with a favorable safety and tolerability profile, supporting its potential for clinical use.
Improved antileishmanial activity and cytotoxicity of a novel nanotherapy for N-iodomethyl-N,N-dimethyl-N-(6,6-diphenylhex-5-en-1-yl)ammonium iodide
(Elsevier, 2021-02) Fernández, Maritza; Holgado Villafuerte, María Ángeles; Cayero Otero, María Dolores; Pineda, Tatiana; Yepes, Lina M; Gaspar, Diana P.; Almeida, António J.; Robledo, Sara M; Martín Banderas, Lucía; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Investigación y Desarrollo Tecnológico en Nanomedicina CTS-480 (Universidad de Sevilla)
The N-iodomethyl-N, N-Dimethyl-N-(6,6-diphenylhex-5-en-1-yl) ammonium iodide (C6I) is a new chemical entity (NCE) with demonstrated in vitro and in vivo antileishmanial activity. As many others NCE, C6I is poorly water soluble (Class II of the Biopharmaceutical Classification System), thus its oral administration is potentially compromised. To overcome the issue, nanotechnology is a real and useful tool. Moreover, nanotechnology can improve C6I internalization by macrophages, the drug targets, therefore increasing its antileishmanial activity. The present work aimed to develop a potential suitable oral nanodrug delivery system for C6I to improve its antileishmanial activity. For this purpose, polymeric and solid lipid nanoparticles were developed. Polylactic-co-glycolic acid polyester (PLGA) were prepared by nanoprecipitation while solid lipid nanoparticles made of glycerol tripalmitate (Trp) and glyceryl tristearate (Trs) were obtained by emulsion–solvent evaporation method. Physicochemical characterization of all formulations was performed, as well as stability studies. A lyophilization procedure was also established. Biological activity was evaluated by antileishmanial activity and cytotoxicity in vitro assays. Five types of commercial PLGA to encapsulate C6I were tested. The best results were obtained using PLGA 752S and d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS), the water-soluble form of vitamin E. Particles around 220 nm in diameter and encapsulation efficiency (EE) up to 60% were obtained. Solid lipid nanoparticles based on Trs and Trp lipids were also in the nanoscale showing a low polydispersity index and EE% >60%. Both types of nanoformulations, polymeric and lipidic, thd C6I cytotoxicity in human and hamster macrophages cell cultures. In vitro assays with PLGA loaded- C6I showed a noticeable improved antileishmanial activity on on intracellular amastigotes of L. (V.) panamensis, with the following EC50 values: PLGA <<< Trs-SLN<< free C6I < Trp-SLN. In conclusion, PLGA nanoformulation could be a suitable candidate for preclinical evaluation in animal model.
Enhanced Cellular Uptake and Biodistribution of a Synthetic Cannabinoid Loaded in Surface-Modified Poly(lactic-co-glycolic acid) Nanoparticles
(American Scientific Publishers, 2014) Durán Lobato, María Matilde; Muñoz Rubio, Inmaculada; Holgado Villafuerte, María Ángeles; Álvarez Fuentes, Josefa; Fernández Arévalo, María Mercedes; Martín Banderas, Lucía; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Junta de Andalucía
This article aimed to produce, characterize and evaluate different surface-modified naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (CB13) loaded poly(lactic-co-glycolic acid) nanoparticles in order to improve their oral absorption and in vivo biodistribution. Plain and surface-modified PLGA nanoparticles were successfully prepared using a nanoprecipitation method. Chitosan, Eudragit® RS, lecithin and vitamin E were used as surface modifying agents. The NPs were evaluated in terms of mean diameter and size distribution, zeta potential, morphology, drug loading, drug release profiles, mucoadhesive properties, in vitro cell viability and uptake and in vivo biodistribution. Mean particle size distributions in the range of 253–344 nm, spherical shape and controlled zeta potential values were observed depending on the additive employed. High values of entrapment efficiency were obtained for all the formulations. Lecithin and vitamin E modified particles showed higher release rates when compared to the rest of formulations. A clear improvement in ex vivo mucoadhesion properties was observed in the case of chitosan- and Eudragit® RS-modified nanoparticles. Chitosan-poly(lactic-co-glycolic acid) nanoparticles showed the highest uptake values on Caco-2 cells. Biodistribution assays proved that most of the particles were accumulated in liver and spleen. An important goal has been achieved in this investigation: CB13, a highly lipophilic drug with low water solubility, can reach the interior of cells more efficiently when it is included in these surface-modified polymeric carriers.
Statistical analysis of solid lipid nanoparticles produced by high-pressure homogenization: a practical prediction approach
(Springer Nature, 2013) Durán Lobato, María Matilde; Enguix González, Alicia; Fernández Arévalo, María Mercedes; Martín Banderas, Lucía; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Universidad de Sevilla. Departamento de Estadística e Investigación Operativa; Junta de Andalucía
Lipid nanoparticles (LNPs) are a promising carrier for all administration routes due to their safety, small size, and high loading of lipophilic compounds. Among the LNP production techniques, the easy scale-up, lack of organic solvents, and short production times of the high-pressure homogenization technique (HPH) make this method stand out. In this study, a statistical analysis was applied to the production of LNP by HPH. Spherical LNPs with mean size ranging from 65 nm to 11.623 μm, negative zeta potential under –30 mV, and smooth surface were produced. Manageable equations based on commonly used parameters in the pharmaceutical field were obtained. The lipid to emulsifier ratio (R L/S) was proved to statistically explain the influence of oil phase and surfactant concentration on final nanoparticles size. Besides, the homogenization pressure was found to ultimately determine LNP size for a given R L/S, while the number of passes applied mainly determined polydispersion. α-Tocopherol was used as a model drug to illustrate release properties of LNP as a function of particle size, which was optimized by the regression models. This study is intended as a first step to optimize production conditions prior to LNP production at both laboratory and industrial scale from an eminently practical approach, based on parameters extensively used in formulation.
In vivo biodistribution of venlafaxine-PLGA nanoparticles for brain delivery: plain vs. functionalized nanoparticles
(Taylor & Francis, 2019) Cayero Otero, María Dolores; Gomes, Maria João; Martins, Cláudia; Álvarez Fuentes, Josefa; Fernández Arévalo, María Mercedes; Sarmento, Bruno; Martín Banderas, Lucía; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; European Union (UE); Fundação para a Ciência e a Tecnologia. Portugal
Background: Actually, no drugs provide therapeutic benefit to approximately one-third of depressed patients. Depression is predicted to become the first global disease by 2030. So, new therapeutic interventions are imperative. Research design and methods: Venlafaxine-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were surface functionalized with two ligands against transferrin receptor to enhance access to brain. An in vitro blood–brain barrier model using hCMEC/D3 cell line was developed to evaluate permeability. In vivo biodistribution studies were performed using C57/bl6 mice. Particles were administered intranasal and main organs were analyzed. Results: Particles were obtained as a lyophilized powder easily to re-suspend. Internalization and permeability studies showed the following cell association sequence: TfRp-NPs>Tf-NPs>plain NPs. Permeability studies also showed that encapsulated VLF was not affected by P-gP pump efflux increasing its concentration in the basolateral side after 24 h. In vivo studies showed that 25% of plain NPs reach the brain after 30 min of one intranasal administration while less than 5% of functionalized NPs get the target. Conclusions: Plain NPs showed the highest ability to reach the brain vs. functionalized NPs after 30 min by intranasal administration. We suggest plain NPs probably travel via direct nose-to-brian route whereas functionalized NPs reach the brain by receptor-mediated endocytosis.
A novel nanoformulation of PLGA with high non-ionic surfactant content improves in vitro and in vivo PTX activity against lung cancer
(Elsevier, 2019-03) Jiménez López, Julia; El Hammadi, Mazen M.; Ortiz, Raul; Cayero Otero, María Dolores; Cabeza, Laura; Perazzoli, Gloria; Martín Banderas, Lucía; Baeyens, Jose M.; Prados, Jose; Melguizo, Consolación; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Junta de Andalucía; Universidad de Granada
Paclitaxel (PTX), a chemotherapy agent widely used to treat lung cancer, is characterised by high toxicity, low bioavailability and the need to use of excipients with serious side effects that limit its use. Paclitaxel encapsulation into nanoparticles (NPs) generates drug pharmacokinetic and pharmacodynamic advantages compared to free PTX. In this context, a NP carrier formed from a copolymer of lactic acid and glycolic acid (PLGA) has demonstrated high biocompatibility and low toxicity and therefore being approved by FDA to be used in humans. We synthesised a new PLGA NP and loaded it with PTX to improve drug efficacy and reduce side effects. This nanoformulation showed biocompatibility and no toxicity to human immune system. These NPs favor the intracellular uptake of PTX and enhance its antitumor effect in human and murine lung cancer cells, with up to 3.6-fold reductions in the PTX’s IC50. Although PLGA NPs did not show any inhibitory capacity against P-glycoprotein, they increased the antitumor activity of PTX in cancer stem cells. Treatment with PLGA-PTX NPs increased apoptosis and significantly reduced the volume of the tumorspheres derived from A549 and LL2 cells by up to 36% and 46.5%, respectively. Biodistribution studies with PLGA-PTX NPs revealed an increase in drug circulation time, as well as a greater accumulation in lung and brain tissues compared to free PTX. Low levels of PTX were detected in the dorsal root ganglion with PLGA-PTX NPs, which could exert a protective effect against peripheral neuropathy. In vivo treatment with PLGA-PTX NPs showed a greater decrease in tumor volume (44.6%) in immunocompetent mice compared to free PTX (24.4%) and without increasing the toxicity of the drug. These promising results suggest that developed nanosystem provide a potential strategy for improving the chemotherapeutic effect and reducing the side effects of PTX.

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