Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 64.269
Filtrar
1.
Molecules ; 26(3)2021 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-33525411

RESUMEN

SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, -8.7 kcal/mol), PLpro (binding energy, -7.9 kcal/mol), and Nucleocapsid (binding energy, -7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, -24.42 kcal/mol and MMPBSA, -10.80 kcal/mol), PLpro (MMGBSA, -48.69 kcal/mol and MMPBSA, -38.17 kcal/mol) and Nucleocapsid (MMGBSA, -30.05 kcal/mol and MMPBSA, -25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, -22.44 kcal/mol), PLpro (mean, -25.46 kcal/mol), and Nucleocapsid (mean, -23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.


Asunto(s)
Antivirales/química , Bases de Datos de Compuestos Químicos , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Fitoquímicos/química , Proteínas Virales/química , Antivirales/uso terapéutico , /epidemiología , Humanos , Pandemias , Fitoquímicos/uso terapéutico , Proteínas Virales/antagonistas & inhibidores
2.
BMC Genomics ; 22(1): 125, 2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602138

RESUMEN

BACKGROUND: The ongoing COVID-19 outbreak has caused devastating mortality and posed a significant threat to public health worldwide. Despite the severity of this illness and 2.3 million worldwide deaths, the disease mechanism is mostly unknown. Previous studies that characterized differential gene expression due to SARS-CoV-2 infection lacked robust validation. Although vaccines are  now available, effective treatment options are still out of reach. RESULTS: To characterize the transcriptional activity of SARS-CoV-2 infection, a gene signature consisting of 25 genes was generated using a publicly available RNA-Sequencing (RNA-Seq) dataset of cultured cells infected with SARS-CoV-2. The signature estimated infection level accurately in bronchoalveolar lavage fluid (BALF) cells and peripheral blood mononuclear cells (PBMCs) from healthy and infected patients (mean 0.001 vs. 0.958; P < 0.0001). These signature genes were investigated in their ability to distinguish the severity of SARS-CoV-2 infection in a single-cell RNA-Sequencing dataset. TNFAIP3, PPP1R15A, NFKBIA, and IFIT2 had shown bimodal gene expression in various immune cells from severely infected patients compared to healthy or moderate infection cases. Finally, this signature was assessed using the publicly available ConnectivityMap database to identify potential disease mechanisms and drug repurposing candidates. Pharmacological classes of tricyclic antidepressants, SRC-inhibitors, HDAC inhibitors, MEK inhibitors, and drugs such as atorvastatin, ibuprofen, and ketoconazole showed strong negative associations (connectivity score < - 90), highlighting the need for further evaluation of these candidates for their efficacy in treating SARS-CoV-2 infection. CONCLUSIONS: Thus, using the 25-gene SARS-CoV-2 infection signature, the SARS-CoV-2 infection status was captured in BALF cells, PBMCs and postmortem lung biopsies. In addition, candidate SARS-CoV-2 therapies with known safety profiles were identified. The signature genes could potentially also be used to characterize the COVID-19 disease severity in patients' expression profiles of BALF cells.


Asunto(s)
/genética , Sistemas de Liberación de Medicamentos , Perfilación de la Expresión Génica , /fisiología , Células A549 , Regulación de la Expresión Génica , Humanos , Modelos Biológicos , Reproducibilidad de los Resultados , Análisis de la Célula Individual
3.
PLoS One ; 16(2): e0246803, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33571320

RESUMEN

Niclosamide (NIC) has demonstrated promising in vitro antiviral efficacy against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Though NIC is already FDA-approved, administration of the currently available oral formulation results in systemic drug levels that are too low for the inhibition of SARS-CoV-2. We hypothesized that the co-formulation of NIC with an endogenous protein, human lysozyme (hLYS), could enable the direct aerosol delivery of the drug to the respiratory tract as an alternative to oral delivery, thereby effectively treating COVID-19 by targeting the primary site of SARS-CoV-2 acquisition and spread. To test this hypothesis, we engineered and optimized composite particles containing NIC and hLYS suitable for delivery to the upper and lower airways via dry powder inhaler, nebulizer, and nasal spray. The novel formulation demonstrates potent in vitro and in vivo activity against two coronavirus strains, MERS-CoV and SARS-CoV-2, and may offer protection against methicillin-resistance staphylococcus aureus pneumonia and inflammatory lung damage occurring secondary to SARS-CoV-2 infections. The suitability of the formulation for all stages of the disease and low-cost development approach will ensure rapid clinical development and wide-spread utilization.


Asunto(s)
Antivirales/administración & dosificación , Infecciones por Coronavirus/tratamiento farmacológico , Muramidasa/administración & dosificación , Niclosamida/administración & dosificación , Administración por Inhalación , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Línea Celular , Composición de Medicamentos , Sistemas de Liberación de Medicamentos/instrumentación , Inhaladores de Polvo Seco , Humanos , Ratones Transgénicos , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Muramidasa/farmacología , Muramidasa/uso terapéutico , Rociadores Nasales , Niclosamida/farmacología , Niclosamida/uso terapéutico , /efectos de los fármacos
4.
Adv Exp Med Biol ; 1295: 29-48, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33543454

RESUMEN

Tumor-homing peptides are widely used for improving tumor selectivity of anticancer drugs and imaging agents. The goal is to increase tumor uptake and reduce accumulation at nontarget sites. Here, we describe current approaches for tumor-homing peptide identification and validation, and provide comprehensive overview of classes of tumor-homing peptides undergoing preclinical and clinical development. We focus on unique mechanistic features and applications of a recently discovered class of tumor-homing peptides, tumor-penetrating C-end Rule (CendR) peptides, that can be used for tissue penetrative targeting of extravascular tumor tissue. Finally, we discuss unanswered questions and future directions in the field of development of peptide-guided smart drugs and imaging agents.


Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Humanos , Neoplasias/tratamiento farmacológico , Péptidos/uso terapéutico
5.
Molecules ; 26(3)2021 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-33530467

RESUMEN

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified in China as the etiologic agent of the recent COVID-19 pandemic outbreak. Due to its high transmissibility, this virus quickly spread throughout the world, causing considerable health issues. The scientific community exerted noteworthy efforts to obtain therapeutic solutions for COVID-19, and new scientific networks were constituted. No certified drugs to efficiently inhibit the virus were identified, and the development of de-novo medicines requires approximately ten years of research. Therefore, the repurposing of natural products could be an effective strategy to handle SARS-CoV-2 infection. This review aims to update on current status of the natural occurring compounds recognizing SARS-CoV-2 druggable targets. Among the clinical trials actually recruited, some natural compounds are ongoing to examine their potential role to prevent and to treat the COVID-19 infection. Many natural scaffolds, including alkaloids, terpenes, flavonoids, and benzoquinones, were investigated by in-silico, in-vitro, and in-vivo approaches. Despite the large data set obtained by a computational approach, experimental evidences in most cases are not available. To fill this gap, further efforts to validate these results are required. We believe that an accurate investigation of naturally occurring compounds may provide insights for the potential treatment of COVID-19 patients.


Asunto(s)
Antivirales , Sistemas de Liberación de Medicamentos , Antivirales/química , Antivirales/uso terapéutico , /metabolismo , Humanos , Pandemias , /metabolismo
6.
Int J Nanomedicine ; 16: 591-607, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33531803

RESUMEN

Purpose: The aim of the present study was to develop deflazacort (DFZ) ultra-elastic nanovesicles (UENVs) loaded gel for topical administration to evade gastrointestinal adverse impacts accompanying DFZ oral therapy. Methods: UENVs were elaborated according to D-optimal mixture design employing different edge activators as Span-60, Tween-85 and sodium cholate which were incorporated into the nanovesicles to improve the deformability of vesicles bilayer. DFZ-UENVs were formulated by thin-film hydration technique followed by characterization for different parameters including entrapment efficiency (%EE), particle size, in vitro release and ex vivo permeation studies. The composition of the optimized DFZ-UENV formulation was found to be DFZ (10 mg), Span-60 (30 mg), Tween-85 (30 mg), sodium cholate (3.93 mg), L-α phosphatidylcholine (60 mg) and cholesterol (30 mg). The optimum formulation was incorporated into hydrogel base then characterized in terms of physical parameters, in vitro drug release, ex vivo permeation study and pharmacodynamics evaluation. Finally, pharmacokinetic study in rabbits was performed via transdermal application of UENVs gel in comparison to oral drug. Results: The optimum UENVs formulation exhibited %EE of 74.77±1.33, vesicle diameter of 219.64±2.52 nm, 68.88±1.64% of DFZ released after 12 h and zeta potential of -55.57±1.04 mV. The current work divulged successful augmentation of the bioavailability of DFZ optimum formulation by about 1.37-fold and drug release retardation compared to oral drug tablets besides significant depression of edema, cellular inflammation and capillary congestion in carrageenan-induced rat paw edema model. Conclusion: The transdermal DFZ-UENVs can achieve boosted bioavailability and may be suggested as an auspicious non-invasive alternative platform for oral route.


Asunto(s)
Antiinflamatorios/farmacología , Sistemas de Liberación de Medicamentos , Elasticidad , Nanopartículas/química , Pregnenodionas/farmacología , Administración Cutánea , Administración Oral , Animales , Disponibilidad Biológica , Liberación de Fármacos , Edema/tratamiento farmacológico , Hidrogeles/química , Masculino , Nanopartículas/ultraestructura , Tamaño de la Partícula , Pregnenodionas/farmacocinética , Conejos , Ratas Wistar , Absorción Cutánea/efectos de los fármacos , Electricidad Estática , Comprimidos
7.
Int J Nanomedicine ; 16: 609-621, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33531804

RESUMEN

Objective: The aim of the current study was to load fenticonazole nitrate, a slightly water-soluble antifungal agent, into terpene-enriched phospholipid vesicles (terpesomes) as a potential delivery system for the management of ocular fungal infection. Methods: Thin film hydration method was used to prepare terpesomes according to a 32 full factorial design to inspect the effect of several variables on vesicles' features. The investigated factors were terpenes type (X1) and terpenes amount (X2) while the dependent responses were encapsulation efficiency percent (Y1), particle size (Y2) and polydispersity index (Y3). Design Expert® program was used to chose the best achieved formula. The selected terpesomes were further optimized via incorporation of a positive charge inducer (stearylamine) to enhance adhesion to the negatively charged mucus covering the eye surface. The in vivo performance of the optimized fenticonazole nitrate-loaded terpesomes relative to drug suspension was evaluated by measuring the antifungal activity (against Candida albicans) retained in the tear's fluid at different time intervals after ocular application in albino rabbits. Results: The optimized terpesomes showed spherical vesicles with entrapment efficiency of 79.02±2.35%, particle size of 287.25±9.55 nm, polydispersity index of 0.46±0.01 and zeta potential of 36.15±1.06 mV. The in vivo study demonstrated significantly higher ocular retention of the optimized fenticonazole nitrate-loaded terpesomes relative to the drug suspension. Moreover, the histopathological studies proved the safety and biocompatibility of the prepared terpesomes. Conclusion: The obtained results verified the potential of the terpesomes for safe and effective ocular delivery of fenticonazole nitrate.


Asunto(s)
Sistemas de Liberación de Medicamentos , Ojo/efectos de los fármacos , Imidazoles/administración & dosificación , Terpenos/farmacología , Administración Cutánea , Animales , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Portadores de Fármacos/química , Liberación de Fármacos , Concentración de Iones de Hidrógeno , Masculino , Pruebas de Sensibilidad Microbiana , Tamaño de la Partícula , Conejos , Suspensiones
8.
Int J Nanomedicine ; 16: 683-700, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33536754

RESUMEN

Purpose: To develop an externally triggered rapid-release targeted system for treating ovarian cancer, gemcitabine (GMC) was entrapped into sonosensitive (SoS) folate (Fo)-modified liposomes (LPs). Methods: GMC-loaded LPs (GMC LPs), GMC-loaded Fo-targeted LPs (GMC-Fo LPs), and GMC-loaded Fo-targeted SoS LPs (GMC-SoS Fo LPs) were prepared utilizing a film-hydration technique and evaluated based on particle size, ζ-potential, and percentage entrapped drug. Cellular uptake of the fluorescent delivery systems in Fo-expressing ovarian cancer cells was quantified using flow cytometry. Finally, tumor-targeting ability, in vivo evaluation, and pharmacokinetic studies were performed. Results: GMC LPs, GMC-Fo LPs, and GMC-SoS Fo LPs were successfully prepared, with sizes of <120.3±2.4 nm, 39.7 mV ζ-potential, and 86.3%±1.84% entrapped drug. Cellular uptake of GMC-SoS Fo LPs improved 6.51-fold over GMC LPs (under ultrasonic irradiation - p<0.05). However, cellular uptake of GMC-Fo LPs improved just 1.24-fold over GMC LPs (p>0.05). Biodistribution study showed that of GMC concentration in tumors treated with GMC-SoS-Fo LPs (with ultrasound) improved 2.89-fold that of free GMC (p<0.05). In vivo, GMC-SoS Fo LPs showed the highest antiproliferative and antitumor action on ovarian cancer. Conclusion: These findings showed that externally triggered rapid-release SoS Fo-modified LPs are a promising system for delivering rapid-release drugs into tumors.


Asunto(s)
Desoxicitidina/análogos & derivados , Ácido Fólico/química , Ultrasonido , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Desoxicitidina/administración & dosificación , Desoxicitidina/sangre , Desoxicitidina/farmacocinética , Desoxicitidina/farmacología , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Femenino , Humanos , Liposomas , Neoplasias Ováricas/sangre , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Tamaño de la Partícula , Ratas Sprague-Dawley , Distribución Tisular/efectos de los fármacos
9.
Int J Nanomedicine ; 16: 701-714, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33536755

RESUMEN

Atherosclerosis (AS) as the leading cause of cardiovascular and cerebrovascular events has been paid much attention all the time. With the continuous development of modern medical drug treatment, surgical treatment, interventional treatment and other methods, the mortality rate of AS has shown a downward trend, while the morbidity rate is still increasing. Oral lipid-lowering or anti-inflammatory drugs are generally used for early AS, but the relatively low accumulation efficiency in lesions and the unavoidable side effects required researchers to develop more effective drug delivery approaches for the therapy of AS. Mesoporous silica nanoparticles as nanocarrier for drug delivery have received extensive attentions due to their flexible size, high specific surface area, controlled pore volume, high drug loading capacity and excellent biocompatibility. Series of good reviews about the mesoporous silica nanoparticles loaded drugs for cancer therapy have been well documented. However, their roles as nanocarrier for drug delivery to treat AS have few reports. In this review, the applications and challenges of mesoporous silica nanomaterials in the field of the diagnosis and therapy of AS have been summarized. The classification, synthesis, formation mechanism, surface modification and functionalization of mesoporous silica nanomaterials which were closely related to the theranostic effect of AS have also been included. Last but not the least, the future prospects' suggestions of mesoporous silica nanomaterial-based drug delivery system for AS are also provided.


Asunto(s)
Aterosclerosis/terapia , Nanoestructuras/uso terapéutico , Dióxido de Silicio/uso terapéutico , Aterosclerosis/diagnóstico , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Humanos , Porosidad
10.
Adv Exp Med Biol ; 1295: 3-27, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33543453

RESUMEN

Clinical responses and tolerability of conventional nanocarriers (NCs) are sometimes different from those expected in anticancer therapy. Thus, new smart drug delivery systems (DDSs) with stimuli-responsive properties and novel materials have been developed. Several clinical trials demonstrated that these DDSs have better clinical therapeutic efficacy in the treatment of many cancers than free drugs. Composition of DDSs and their surface properties increase the specific targeting of therapeutics versus cancer cells, without affecting healthy tissues, and thus limiting their toxicity versus unspecific tissues. Herein, an extensive revision of literature on NCs used as DDSs for cancer applications has been performed using the available bibliographic databases.


Asunto(s)
Nanopartículas , Neoplasias , Portadores de Fármacos/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Neoplasias/tratamiento farmacológico
11.
Adv Exp Med Biol ; 1295: 77-95, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33543456

RESUMEN

Nanomedicine has been a hot topic in the field of tumor therapy in the past few decades. Because of the enhanced permeability and retention effect (EPR effect), nanomedicine can passively yet selectively accumulate at tumor tissues. As a result, it can improve drug concentration in tumor tissues and reduce drug distribution in normal tissues, thereby contributing to enhanced antitumor effect and reduced adverse effects. However, the therapeutic efficacy of anticancer nanomedicine is not satisfactory in clinical settings. Therefore, how to improve the clinical therapeutic effect of nanomedicine has become an urgent problem. The grand challenges of nanomedicine lie in how to overcome various pathophysiological barriers and simultaneously kill cancer cells effectively in hypoxic tumor microenvironment (TME). To this end, the development of novel stimuli-responsive nanomedicine has become a new research hotspot. While a great deal of progress has been made in this direction and preclinical results report many different kinds of promising multifunctional smart nanomedicine, the design of these intelligent nanomedicines is often too complicated, the requirements for the preparation processes are strict, the cost is high, and the clinical translation is difficult. Thus, it is more practical to find solutions to promote the therapeutic efficacy of commercialized nanomedicines, for example, Doxil®, Oncaspar®, DaunoXome®, Abraxane®, to name a few. Increasing attention has been paid to the combination of modern advanced medical technology and nanomedicine for the treatment of various malignancies. Recently, we found that hyperbaric oxygen (HBO) therapy could enhance Doxil® antitumor efficacy. Inspired by this study, we further carried out researches on the combination of HBO therapy with other nanomedicines for various cancer therapies, and revealed that HBO therapy could significantly boost antitumor efficacy of nanomedicine-mediated photodynamic therapy and photothermal therapy in different kinds of tumors, including hepatocellular carcinoma, breast cancer, and gliomas. Our results implicate that HBO therapy might be a universal strategy to boost therapeutic efficacy of nanomedicine against hypoxic solid malignancies.


Asunto(s)
Antineoplásicos , Oxigenación Hiperbárica , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Nanomedicina , Neoplasias/tratamiento farmacológico , Microambiente Tumoral
12.
Adv Exp Med Biol ; 1295: 99-120, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33543457

RESUMEN

Mesoporous silica nanoparticles (MSNs) offer many advantageous properties for applications in the field of nanobiotechnology. Loading of small molecules into MSNs is straightforward and widely applied, but with the upswing of both research and commercial interest in biological drugs in recent years, also biomacromolecules have been loaded into MSNs for delivery purposes. MSNs possess many critical properties making them a promising and versatile carrier for biomacromolecular delivery. In this chapter, we review the effects of the various structural parameters of MSNs on the effective loading of biomacromolecular therapeutics, with focus on maintaining stability and drug delivery performance. We also emphasize recent studies involving the use of MSNs in the delivery of biomacromolecular drugs, especially for cancer treatment.


Asunto(s)
Nanopartículas , Neoplasias , Portadores de Fármacos/uso terapéutico , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Porosidad , Dióxido de Silicio
13.
Adv Exp Med Biol ; 1295: 135-162, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33543459

RESUMEN

During the last 20+ years, research into the biomedical application of nanotechnology has helped in reshaping cancer treatment. The clinical use of several passively targeted nanosystems resulted in improved quality of care for patients. However, the therapeutic efficacy of these systems is not superior to the original drugs. Moreover, despite extensive investigations into actively targeted nanocarriers, numerous barriers still remain before their successful clinical translation, including sufficient bloodstream circulation time and efficient tumor targeting. The combination of synthetic nanomaterials with biological elements (e.g., cells, cell membranes, and macromolecules) is presently the cutting-edge research in cancer nanotechnology. The features provided by the biological moieties render the particles with prolonged bloodstream circulation time and homotopic targeting to the tumor site. Moreover, cancer cell membranes serve as sources of neoantigens, useful in the formulation of nanovaccines. In this chapter, we will discuss the advantages of biohybrid nanosystems in cancer chemotherapy, immunotherapy, and combined therapy, as well as highlight their preparation methods and clinical translatability.


Asunto(s)
Nanoestructuras , Neoplasias , Sistemas de Liberación de Medicamentos , Humanos , Inmunoterapia , Nanotecnología , Neoplasias/tratamiento farmacológico
14.
Int J Mol Sci ; 22(3)2021 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-33498909

RESUMEN

The prevention and control of infectious diseases is crucial to the maintenance and protection of social and public healthcare. The global impact of SARS-CoV-2 has demonstrated how outbreaks of emerging and re-emerging infections can lead to pandemics of significant public health and socio-economic burden. Vaccination is one of the most effective approaches to protect against infectious diseases, and to date, multiple vaccines have been successfully used to protect against and eradicate both viral and bacterial pathogens. The main criterion of vaccine efficacy is the induction of specific humoral and cellular immune responses, and it is well established that immunogenicity depends on the type of vaccine as well as the route of delivery. In addition, antigen delivery to immune organs and the site of injection can potentiate efficacy of the vaccine. In light of this, microvesicles have been suggested as potential vehicles for antigen delivery as they can carry various immunogenic molecules including proteins, nucleic acids and polysaccharides directly to target cells. In this review, we focus on the mechanisms of microvesicle biogenesis and the role of microvesicles in infectious diseases. Further, we discuss the application of microvesicles as a novel and effective vaccine delivery system.


Asunto(s)
/prevención & control , Vesículas Extracelulares/inmunología , Factores Inmunológicos/inmunología , Vacunas Virales/administración & dosificación , Animales , Sistemas de Liberación de Medicamentos/métodos , Humanos , Vacunación/métodos , Vacunas Virales/inmunología
15.
Nat Commun ; 12(1): 658, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33510169

RESUMEN

A microneedle array is an attractive option for a minimally invasive means to break through the skin barrier for efficient transdermal drug delivery. Here, we report the applications of solid polymer-based ion-conductive porous microneedles (PMN) containing interconnected micropores for improving iontophoresis, which is a technique of enhancing transdermal molecular transport by a direct current through the skin. The PMN modified with a charged hydrogel brings three innovative advantages in iontophoresis at once: (1) lowering the transdermal resistance by low-invasive puncture of the highly resistive stratum corneum, (2) transporting of larger molecules through the interconnected micropores, and (3) generating electroosmotic flow (EOF). In particular, the PMN-generated EOF greatly enhances the transdermal molecular penetration or extraction, similarly to the flow induced by external pressure. The enhanced efficiencies of the EOF-assisted delivery of a model drug (dextran) and of the extraction of glucose are demonstrated using a pig skin sample. Furthermore, the powering of the PMN-based transdermal EOF system by a built-in enzymatic biobattery (fructose / O2 battery) is also demonstrated as a possible totally organic iontophoresis patch.


Asunto(s)
Sistemas de Liberación de Medicamentos/instrumentación , Sistemas de Liberación de Medicamentos/métodos , Epidermis/metabolismo , Piel/metabolismo , Administración Cutánea , Animales , Dextranos/administración & dosificación , Dextranos/metabolismo , Dextranos/farmacocinética , Electroósmosis , Fluoresceína-5-Isotiocianato/administración & dosificación , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/metabolismo , Fluoresceína-5-Isotiocianato/farmacocinética , Glucosa/administración & dosificación , Glucosa/metabolismo , Glucosa/farmacocinética , Humanos , Iontoforesis/instrumentación , Iontoforesis/métodos , Masculino , Microinyecciones , Agujas , Patrón Molecular Asociado a Patógenos/administración & dosificación , Patrón Molecular Asociado a Patógenos/metabolismo , Patrón Molecular Asociado a Patógenos/farmacocinética , Porosidad , Porcinos
17.
Nat Commun ; 12(1): 102, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397994

RESUMEN

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.


Asunto(s)
Tejido Adiposo/metabolismo , Sistemas de Liberación de Medicamentos , Macrófagos/metabolismo , Mitocondrias/metabolismo , Obesidad/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Hígado Graso/genética , Hígado Graso/patología , Inflamación/genética , Inflamación/patología , Resistencia a la Insulina , Hígado/metabolismo , Hígado/patología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Obesidad/genética , Obesidad/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Pérdida de Peso/efectos de los fármacos
18.
AAPS PharmSciTech ; 22(1): 21, 2021 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-33389277

RESUMEN

In order to better explain and predict the dissolution characteristics of binary drug delivery systems (BDDSs), the dissolution behaviors of co-crystal (CC) and co-amorphous (CA) systems of sacubitril (SCB) and valsartan (VST) were evaluated in vitro and in vivo by thermodynamic and kinetic methods. The CCs of SCB and VST were prepared into a CA state through rotary evaporation. Solid-state properties were systematically evaluated. Herein, based on the results from previous studies of single-phase systems, we used thermodynamic methods to evaluate the increase in drug dissolution rate after BDDSs change from the crystalline to the amorphous state. After comparing the predicted and measured dissolution rate enhancement of the CC and CA systems, this paper attempts to explain the dissolution rate characteristics of the BDDSs. We then evaluated the bioavailability of two BDDSs in beagle dogs to confirm that there was no discrepancy in vivo with the results obtained in vitro. The results exhibited that there is strong intermolecular interaction between SCB and VST and good physical stability for the CA system. Compared with the CC, the bioavailability of SCB and VST in the CA system increased by 313.9% and 130.5%, respectively. The predicted dissolution rate ratio between CC and CA systems and their actual intrinsic dissolution rates differed by only a factor of 2.5, demonstrating the good correlation between the predicted and measured values. In the future, this method could be expanded to a variety of new samples and exciting drug prospects.


Asunto(s)
Aminobutiratos/administración & dosificación , Antagonistas de Receptores de Angiotensina/administración & dosificación , Antihipertensivos/administración & dosificación , Sistemas de Liberación de Medicamentos , Tetrazoles/administración & dosificación , Termodinámica , Valsartán/administración & dosificación , Aminobutiratos/química , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/química , Antagonistas de Receptores de Angiotensina/farmacocinética , Animales , Antihipertensivos/química , Antihipertensivos/farmacocinética , Disponibilidad Biológica , Perros , Combinación de Medicamentos , Estabilidad de Medicamentos , Cinética , Preparaciones Farmacéuticas , Difracción de Polvo , Solubilidad , Tetrazoles/química , Tetrazoles/farmacocinética , Valsartán/química , Valsartán/farmacocinética
19.
Nat Commun ; 12(1): 149, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420053

RESUMEN

Intrinsically disordered proteins have dramatically changed the structure-function paradigm of proteins in the 21st century. Resilin is a native elastic insect protein, which features intrinsically disordered structure, unusual multi-stimuli responsiveness and outstanding resilience. Advances in computational techniques, polypeptide synthesis methods and modular protein engineering routines have led to the development of novel resilin-like polypeptides (RLPs) including modular RLPs, expanding their applications in tissue engineering, drug delivery, bioimaging, biosensors, catalysis and bioelectronics. However, how the responsive behaviour of RLPs is encoded in the amino acid sequence level remains elusive. This review summarises the milestones of RLPs, and discusses the development of modular RLP-based biomaterials, their current applications, challenges and future perspectives. A perspective of future research is that sequence and responsiveness profiling of RLPs can provide a new platform for the design and development of new modular RLP-based biomaterials with programmable structure, properties and functions.


Asunto(s)
Materiales Biomiméticos/química , Proteínas de Insectos/química , Péptidos/química , Materiales inteligentes/química , Secuencia de Aminoácidos , Técnicas Biosensibles/instrumentación , Sistemas de Liberación de Medicamentos/instrumentación , Elasticidad , Proteínas de Insectos/genética , Péptidos/genética , Reología , Ingeniería de Tejidos/instrumentación
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA