RESUMEN

Oral Topiramate therapy is associated with systemic adverse effects including paresthesia,abdominal pain, and fluctuations in plasma levels. The purpose of this research was to develop an intranasal in situ gel based system comprising Topiramate polymeric nanoparticles and evaluate its potential both in vitro and in vivo. Poly (lactic-co-glycolic acid) (PLGA)nanoparticles prepared by nanoprecipitation method were added into the in situ gelling system of Poloxamer 407 and HPMC K4M. Selected formulation (TG5) was evaluated for physicochemical properties, nasal permeation and in vivo pharmacokinetics in rats. PLGAnanoparticles (O1) exhibited low particle size (~ 144.4 nm), good polydispersity index (0.202), negative zeta potential (-12.7 mV), and adequate entrapment efficiency (64.7%). Developed in situ gel showed ideal pH (6.5), good gelling time (35 s), gelling temperature(37℃), suitable viscosity (1335 cP)and drug content of 96.2%. In vitro drug release conformedto Higuchi release kinetics, exhibiting a biphasic pattern of initial burst release and sustained release for 24 h. Oral administration of the drug to Sprague-Dawley rats (G3) showed higher plasma Cmax(504 ng/ml, p < 0.0001) when compared to nasal delivery of in situ gel (G4) or solution (G5). Additionally, AUC0-α of G3 (8786.82 ng/ml*h) was considerably higher than othergroups. Brain uptake data indicates a higher drug level with G4 (112.47 ng /ml) at 12 h when compared to G3. Histopathological examination of groups; G1 (intranasal saline), G2(intranasal placebo), G3, G4, and G5 did not show any lesions of pathological significance. Overall, the experimental results observed were promising and substantiated the potential of developed in situ gel for intranasal delivery.

Asunto(s)

Administración Intranasal , Encéfalo , Geles , Nanopartículas , Mucosa Nasal , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ratas Sprague-Dawley , Topiramato , Animales , Topiramato/administración & dosificación , Topiramato/farmacocinética , Nanopartículas/química , Ratas , Administración Intranasal/métodos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacos , Masculino , Tamaño de la Partícula , Fructosa/administración & dosificación , Fructosa/farmacocinética , Fructosa/química , Portadores de Fármacos/química , Liberación de Fármacos , Sistemas de Liberación de Medicamentos/métodos , Ácido Láctico/química , Ácido Láctico/administración & dosificación , Ácido Poliglicólico/química , Administración Oral

RESUMEN

The energetic metabolism of cancer cells relies on a substantial commitment of pyruvate to the catalytic action of lactate-generating dehydrogenases. This coupling mainly depends on lactate dehydrogenase A (LDH-A), which is overexpressed in different types of cancers, and therefore represents an appealing therapeutic target. Taking into account that the activity of LDHs is exclusively exerted by their tetrameric forms, it was recently shown that peptides perturbing the monomers-to-tetramer assembly inhibit human LDH-A (hLDH-A). However, to identify these peptides, tetrameric hLDH-A was transiently exposed to strongly acidic conditions inducing its dissociation into monomers, which were tested as a target for peptides at low pH. Nevertheless, the availability of native monomeric hLDH-A would allow performing similar screenings under physiological conditions. Here we report on the unprecedented isolation of recombinant monomeric hLDH-A at neutral pH, and on its use to identify peptides inhibiting the assembly of the tetrameric enzyme. Remarkably, the GQNGISDL octapeptide, mimicking the 296-303 portion of hLDH-A C-terminal region, was observed to effectively inhibit the target enzyme. Moreover, by dissecting the action of this octapeptide, the cGQND cyclic tetrapeptide was found to act as the parental compound. Furthermore, we performed assays using MCF7 and BxPC3 cultured cells, exclusively expressing hLDH-A and hLDH-B, respectively. By means of these assays we detected a selective action of linear and cyclic GQND tetrapeptides, inhibiting lactate secretion in MCF7 cells only. Overall, our observations suggest that peptides mimicking the C-terminal region of hLDH-A effectively interfere with protein-protein interactions responsible for the assembly of the tetrameric enzyme.

Asunto(s)

L-Lactato Deshidrogenasa , Ácido Láctico , Multimerización de Proteína , Humanos , L-Lactato Deshidrogenasa/metabolismo , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/antagonistas & inhibidores , L-Lactato Deshidrogenasa/química , Ácido Láctico/metabolismo , Ácido Láctico/química , Péptidos/química , Péptidos/metabolismo , Péptidos/farmacología , Concentración de Iones de Hidrógeno , Oligopéptidos/química , Oligopéptidos/metabolismo , Oligopéptidos/genética , Oligopéptidos/farmacología , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Línea Celular Tumoral

RESUMEN

To investigate the effects of lactic acid etching on the immediate and aged bond strength of the resin-dentin bonding interface, the resin-dentin bonding interface was evaluated 24 hours and 6 months later. A total of 42 isolated third molars were randomly divided into 6 experimental groups according to different lactate concentration (35%, 40%, 45%) and acid etching time (30 s, 45 s), with 37% phosphoric acid etching 15 s as a control. In each group, dentin samples were etched under different acidic conditions and bonded with Adper Single Bond 2 (3M ESPE) as directed. The immediate group was immediately stored in deionized water at 37 °C for 24 h, and the aging group was stored in artificial saliva at 37 °C for 6 months. Immediate and aged bond strengths were measured by a micro-tensile tester, and the specimen fracture surface was observed under a microscope. 14 isolated third molars were randomly divided into 7 groups, and each group was etched with acid. Collagen fibers morphology in dentin was examined after gradient dehydration with ethanol by scanning electron microscopy (SEM). Statistically, there was no difference between the resin-dentin immediate bonding strength of 35% lactic acid for 30 s and 37% phosphoric acid for 15 s, but the aged bond strength was greater than that of the phosphoric acid group. According to scanning electron microscope observations, the collagen fiber morphology in 35% and 40% lactate etching dentin 30 s groups was relatively intact compared with other groups. In conclusion, 35% lactic acid etching of dentin 30 s ensures both immediate and aged resin-dentin bond strength.

Asunto(s)

Grabado Ácido Dental , Recubrimiento Dental Adhesivo , Dentina , Ácido Láctico , Microscopía Electrónica de Rastreo , Resistencia a la Tracción , Humanos , Ácido Láctico/química , Recubrimiento Dental Adhesivo/métodos , Grabado Ácido Dental/métodos , Factores de Tiempo , Ácidos Fosfóricos/química , Recubrimientos Dentinarios/química , Tercer Molar , Ensayo de Materiales , Análisis del Estrés Dental , Propiedades de Superficie , Cementos de Resina/química , Cementos Dentales

RESUMEN

This study investigates the synthesis and optimization of nanobots (NBs) loaded with pDNA using the layer-by-layer (LBL) method and explores the impact of their collective motion on the transfection efficiency. NBs consist of biocompatible and biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles and are powered by the urease enzyme, enabling autonomous movement and collective swarming behavior. In vitro experiments were conducted to validate the delivery efficiency of fluorescently labeled NBs, using two-dimensional (2D) and three-dimensional (3D) cell models: murine urothelial carcinoma cell line (MB49) and spheroids from human urothelial bladder cancer cells (RT4). Swarms of pDNA-loaded NBs showed enhancements of 2.2- to 2.6-fold in delivery efficiency and 6.8- to 8.1-fold in material delivered compared to inhibited particles (inhibited enzyme) and the absence of fuel in a 2D cell culture. Additionally, efficient intracellular delivery of pDNA was demonstrated in both cell models by quantifying and visualizing the expression of eGFP. Swarms of NBs exhibited a >5-fold enhancement in transfection efficiency compared to the absence of fuel in a 2D culture, even surpassing the Lipofectamine 3000 commercial transfection agent (cationic lipid-mediated transfection). Swarms also demonstrated up to a 3.2-fold enhancement in the amount of material delivered in 3D spheroids compared to the absence of fuel. The successful transfection of 2D and 3D cell cultures using swarms of LBL PLGA NBs holds great potential for nucleic acid delivery in the context of bladder treatments.

Asunto(s)

ADN , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Humanos , Animales , Ratones , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Línea Celular Tumoral , Nanopartículas/química , ADN/química , ADN/metabolismo , Transfección/métodos , Ureasa/metabolismo , Ureasa/química , Ureasa/genética , Plásmidos/metabolismo , Plásmidos/genética , Plásmidos/química , Técnicas de Transferencia de Gen , Ácido Poliglicólico/química , Ácido Láctico/química , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia

RESUMEN

5-Aminolevulinic acid (5-ALA) is a prodrug of porphyrin IX (PpIX). Disadvantages of 5-ALA include poor stability, rapid elimination, poor bioavailability, and weak cell penetration, which greatly reduce the clinical effect of 5-ALA based photodynamic therapy (PDT). Presently, a novel targeting nanosystem was constructed using gold nanoparticles (AuNPs) as carriers loaded with a CSNIDARAC (CC9)-targeting peptide and 5-ALA via Au-sulphur and ionic bonds, respectively, and then wrapped in polylactic glycolic acid (PLGA) NPs via self-assembly to improve the antitumor effects and reduce the side effect. The successful preparation of ALA/CC9@ AuNPs-PLGA NPs was verified using ultraviolet-visible, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The analyses revealed good sphericity with a particle size of approximately140 nm, Zeta potential of 10.11 mV, and slow-controlled release characteristic in a weak acid environment. Confocal microscopy revealed targeting of NCL-H460 cells by NPs by actively internalising CC9 and avoiding the phagocytic action of RAW264.7 cells, and live fluorescence imaging revealed targeting of tumours in tumour-bearing mice. Compared to free 5-ALA, the nanosystem displayed amplified anticancer activity by increasing production of PpIX and reactive oxygen species to induce mitochondrial pathway apoptosis. Antitumor efficacy was consistently observed in three-dimensionally cultured cells as the loss of integrity of tumour balls. More potent anti-tumour efficacy was demonstrated in xenograft tumour models by decreased growth rate and increased tumour apoptosis. Histological analysis showed that this system was not toxic, with lowered liver toxicity of 5-ALA. Thus, ALA/CC9@AuNPs-PLGA NPs deliver 5-ALA via a carrier cascade, with excellent effects on tumour accumulation and PDT through passive enhanced permeability and retention action and active targeting. This innovative strategy for cancer therapy requires more clinical trials before being implemented.

Asunto(s)

Ácido Aminolevulínico , Oro , Neoplasias Pulmonares , Nanopartículas del Metal , Fotoquimioterapia , Ácido Aminolevulínico/química , Ácido Aminolevulínico/farmacología , Ácido Aminolevulínico/uso terapéutico , Animales , Oro/química , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Ratones , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Línea Celular Tumoral , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Portadores de Fármacos/química , Apoptosis/efectos de los fármacos , Ácido Láctico/química , Ácido Poliglicólico/química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico

RESUMEN

In disease treatment, maintaining therapeutic drug concentrations often requires multiple doses. Lipid/polymer hybrid nanoparticles (LPHNPs) offer a promising solution by facilitating sustained drug delivery within therapeutic ranges. Here, we synthesized poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with soy lecithin using nanoprecipitation and self-assembly techniques. These nanoparticles were incorporated into gelatin aerogels to ensure uniform distribution and increase the concentration. Our study focused on understanding the release kinetics of hydrophilic (gallic acid) and lipophilic (quercetin) compounds from this system. Nanoparticles exhibited hydrodynamic diameters of 100 ± 15 nm (empty), 153 ± 33 nm (gallic acid-loaded), and 149 ± 21 nm (quercetin-loaded), with encapsulation efficiencies of 90 ± 5% and 70 ± 10% respectively. Gallic acid release followed the Korsmeyer-Peppas kinetics model (n = 1.01), while quercetin showed first-order kinetics. Notably, encapsulated compounds demonstrated delayed release compared to free compounds in gelatin aerogels, illustrating LPHNPs' ability to modulate release profiles independent of the compound type. This study underscores the potential of LPHNPs in optimizing drug delivery strategies for enhanced therapeutic outcomes.

Asunto(s)

Ácido Gálico , Interacciones Hidrofóbicas e Hidrofílicas , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Quercetina , Quercetina/química , Nanopartículas/química , Ácido Gálico/química , Cinética , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Lecitinas/química , Gelatina/química , Ácido Láctico/química , Ácido Poliglicólico/química , Liberación de Fármacos , Lípidos/química , Portadores de Fármacos/química , Tamaño de la Partícula

RESUMEN

The goal of this work is to investigate if the synergistic antifungal activity between cyclosporine A, CsA, and voriconazole, VRZ, increases when both drugs are encapsulated in a nanocarrier as compared when they are free. The preparation and characterization of blank and VRZ and CsA loaded polymeric based PLGA nanoparticles (PLGA, PLGA-PEG, and PLGA+PEG) was a necessary previous step. Using the more suitable NPs, those of PLGA, the antifungal susceptibility tests performed with VRZ-loaded PLGA NPs, show no significant increase of the antifungal activity in comparison to that of free VRZ. However, the synergistic behavior found for the (VRZ+CsA)-loaded PLGA NPs was fourfold stronger than that observed for the two free drugs together. On the other hand, the investigation into the suppression of C. albicans biofilm formation showed that blank PLGA NPs inhibit the biofilm formation at high NPs concentrations. However, a minor effect or even a slight biofilm increase formation was observed at low and moderate NPs concentrations. Therefore, the enhancement of the biofilm inhibition found for the three tested treatments (CsA alone, VRZ alone, and VRZ+CsA) when comparing free and encapsulated drugs, within the therapeutic window, can be attributed to the drug encapsulation approach. Indeed, polymeric PLGA NPs loaded with CsA, VRZ, or VRZ+CsA are more effective at inhibiting the C. albicans biofilm growth than their free counterparts.

Asunto(s)

Antifúngicos , Biopelículas , Candida albicans , Ciclosporina , Sinergismo Farmacológico , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Voriconazol , Voriconazol/administración & dosificación , Voriconazol/farmacología , Voriconazol/química , Antifúngicos/administración & dosificación , Antifúngicos/farmacología , Antifúngicos/química , Candida albicans/efectos de los fármacos , Nanopartículas/química , Ciclosporina/administración & dosificación , Ciclosporina/farmacología , Ciclosporina/química , Biopelículas/efectos de los fármacos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Portadores de Fármacos/química , Polietilenglicoles/química , Pruebas de Sensibilidad Microbiana , Ácido Láctico/química

RESUMEN

The chemocatalystic conversion of cellulose, the main component of lignocellulosic biomass, to building-block chemicals in water under mild conditions, is an ideal but highly challenging process due to the robust crystal structure of cellulose. It is also the key to establishing a sustainable biomass-based chemical process. Here, we present a highly efficient and selective chemocatalytic hydrolysis of cellulose using ZnCl2·3H2O hydrate as the pretreatment reagent and water-compatible metal salts - ErCl3 as the catalyst, into lactic acid (LA), which is an important chemical building-block widely utilized in the food industry and in the production of chemicals and biodegradable plastic. With 94.0 % conversion of cellulose, an impressive LA yield of 84.6 % was achieved at 170 °C after 4 h under ambient air pressure in water. High yields of LA were also obtained from other carbohydrates, such as fructose (68.3 %), glucose (52.7 %), starch (54.4 %), and inulin (67 %). A series of experiments demonstrated that Er(III) combination with water catalyzed cascading steps of soluble cellulose into LA after ZnCl2·3H2O hydrate disrupted the hydrogen bonds in the cellulose, Zn(II) played an indirect role by promoting LA formation through inhibition of side reactions. A plausible mechanism was proposed for the chemocatalytic conversion of cellulose to LA.

Asunto(s)

Celulosa , Cloruros , Ácido Láctico , Compuestos de Zinc , Celulosa/química , Cloruros/química , Compuestos de Zinc/química , Ácido Láctico/química , Catálisis , Hidrólisis , Agua/química , Sales (Química)/química

RESUMEN

Mitochondrial pyruvate carrier (MPC) inhibitors promote the development of hair follicle stem cells without affecting normal cells, which is promising for the treatment of hair loss. Herein, a series of cyano-cinnamate derivatives of UK-5099 were designed and synthesized. All these new compounds have been tested for their ability to promote cellular lactate production in vitro. Compound 4i (LA content:0.322 µmol/106cell) showed better cellular lactate production activity than UK-5099 (LA content:0.185 µmol/106cell). Further compound 4i was also tested on shaved mice by topical treatment and promoted obvious hair growth on mice.

Asunto(s)

Cinamatos , Diseño de Fármacos , Animales , Ratones , Cinamatos/farmacología , Cinamatos/química , Cinamatos/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Humanos , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Transportadores de Ácidos Monocarboxílicos/metabolismo , Relación Dosis-Respuesta a Droga , Ácido Láctico/química , Ácido Láctico/síntesis química , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo

RESUMEN

The goal of the current study was to formulate and examine the potential of poly (lactic-co-glycolic acid) (PLGA) as carriers to facilitate the targeted administration of edoxaban tosylate monohydrate (ETM). ETM-PLGA-NPs were effectively formulated using the nanoprecipitation technique. Particle size, drug entrapment percentage, zeta potential, assessment of intestinal absorption, FT-IR, SEM, drug dissolution behavior, and histopathology investigations were used to describe ETM-PLGA-NPs. The produced NPs had a roughly spherical shape with a particle size of 99.85 d.nm, a PDI of 0.478, and a zeta potential of 38.5 mV with a maximum drug entrapment of 82.1 %. FTIR measurements showed that the drug's chemical stability remained intact after preapred into nanoparticles. In vitro drug release behavior followed the Higuchi model and revealed an early burst release of 30 % and persistent drug release of 78 % from optimized NPs for up to 120 hrs. According to in vitro data, a 1:10 ratio of ETM to PLGA provided longer-lasting ETM release and improved encapsulation efficiency. Images captured with an inverted fluorescent microscope exhibited that NPs may both greatly increase the amount of ETM accumulated in the intestinal tract and make it easier for ETM to enter the membrane beneath the cells of the intestines. The study found that using PLGA nanoparticles to encapsulate the ETM resulted in longer circulation duration (aPTT, PT, TT). In vivo investigations found that nanoparticles encapsulated had no negative impact on hematological parameters, lung, liver, or kidney tissues. All things considered, the NPs are a potential delivery method to increase the oral absorption and antithrombotic activity of ETM.

Asunto(s)

Portadores de Fármacos , Liberación de Fármacos , Nanopartículas , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Piridinas , Tiazoles , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanopartículas/química , Animales , Portadores de Fármacos/química , Tiazoles/farmacocinética , Tiazoles/administración & dosificación , Tiazoles/química , Piridinas/administración & dosificación , Piridinas/farmacocinética , Piridinas/química , Ratas , Masculino , Ácido Láctico/química , Absorción Intestinal/efectos de los fármacos , Ácido Poliglicólico/química , Sistemas de Liberación de Medicamentos/métodos , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/farmacocinética , Ratas Wistar , Distribución Tisular

RESUMEN

Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT.

Asunto(s)

Acidosis , Compuestos Ferrosos , Glutatión , Sulfuro de Hidrógeno , Nanomedicina , Animales , Humanos , Acidosis/tratamiento farmacológico , Nanomedicina/métodos , Línea Celular Tumoral , Glutatión/metabolismo , Compuestos Ferrosos/química , Compuestos Ferrosos/administración & dosificación , Metalocenos/química , Neoplasias/tratamiento farmacológico , Inhibidores de Anhidrasa Carbónica/administración & dosificación , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Ratones Endogámicos BALB C , Peróxido de Hidrógeno , Ratones , Micelas , Femenino , Nanopartículas/química , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacología , Ratones Desnudos , Polímeros/química , Ácido Láctico/química , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasa Carbónica IX/metabolismo , Catalasa/metabolismo

RESUMEN

Hot melt extrusion (HME) processed Poly (lactic-co-glycolic acid) (PLGA) implant is one of the commercialized drug delivery products, which has solid, well-designed shape and rigid structures that afford efficient locoregional drug delivery on the spot of interest for months. In general, there are a variety of material, processing, and physiological factors that impact the degradation rates of PLGA-based implants and concurrent drug release kinetics. The objective of this study was to investigate the impacts of PLGA's material characteristics on PLGA degradation and subsequent drug release behavior from the implants. Three model drugs (Dexamethasone, Carbamazepine, and Metformin hydrochloride) with different water solubility and property were formulated with different grades of PLGAs possessing distinct co-polymer ratios, molecular weights, end groups, and levels of residual monomer (high/ViatelTM and low/ ViatelTM Ultrapure). Physicochemical characterizations revealed that the plasticity of PLGA was inversely proportional to its molecular weight; moreover, the residual monomer could impose a plasticizing effect on PLGA, which increased its thermal plasticity and enhanced its thermal processability. Although the morphology and microstructure of the implants were affected by many factors, such as processing parameters, polymer and drug particle size and distribution, polymer properties and polymer-drug interactions, implants prepared with ViatelTM PLGA showed a smoother surface and a stronger PLGA-drug intimacy than the implants with ViatelTM Ultrapure PLGA, due to the higher plasticity of the ViatelTM PLGA. Subsequently, the implants with ViatelTM PLGA exhibited less burst release than implants with ViatelTM Ultrapure PLGA, however, their onset and progress of the lag and substantial release phases were shorter and faster than the ViatelTM Ultrapure PLGA-based implants, owing to the residual monomer accelerated the water diffusion and autocatalyzed PLGA hydrolysis. Even though the drug release profiles were also influenced by other factors, such as composition, drug properties and polymer-drug interaction, all three cases revealed that the residual monomer accelerated the swelling and degradation of PLGA and impaired the implant's integrity, which could negatively affect the subsequent drug release behavior and performance of the implants. These results provided insights to formulators on rational PLGA implant design and polymer selection.

Asunto(s)

Carbamazepina , Preparaciones de Acción Retardada , Dexametasona , Liberación de Fármacos , Tecnología de Extrusión de Fusión en Caliente , Metformina , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Solubilidad , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Dexametasona/química , Dexametasona/administración & dosificación , Metformina/química , Metformina/administración & dosificación , Preparaciones de Acción Retardada/química , Carbamazepina/química , Carbamazepina/administración & dosificación , Tecnología de Extrusión de Fusión en Caliente/métodos , Implantes de Medicamentos/química , Ácido Poliglicólico/química , Portadores de Fármacos/química , Calor , Ácido Láctico/química

RESUMEN

BACKGROUND: Colorectal cancer is a common disease worldwide with non-specific symptoms such as blood in the stool, bowel movements, weight loss and fatigue. Chemotherapy drugs can cause side effects such as nausea, vomiting and a weakened immune system. The use of antioxidants such as hesperidin could reduce the side effects, but its low bioavailability is a major problem. In this research, we aimed to explore the drug delivery and efficiency of this antioxidant on the HCT116 colorectal cancer cell line by loading hesperidin into PLGA nanoparticles. MATERIALS AND METHODS: Hesperidin loaded PLGA nanoparticles were produced by single emulsion evaporation method. The physicochemical properties of the synthesized hesperidin-loaded nanoparticles were determined using SEM, AFM, FT-IR, DLS and UV-Vis. Subsequently, the effect of the PLGA loaded hesperidin nanoparticles on the HCT116 cell line after 48 h was investigated by MTT assay at three different concentrations of the nanoparticles. RESULT: The study showed that 90% of hesperidin were loaded in PLGA nanoparticles by UV-Vis spectrophotometry and FT-IR spectrum. The nanoparticles were found to be spherical and uniform with a hydrodynamic diameter of 76.2 nm in water. The release rate of the drug was about 93% after 144 h. The lowest percentage of cell viability of cancer cells was observed at a concentration of 10 µg/ml of PLGA nanoparticles loaded with hesperidin. CONCLUSION: The results indicate that PLGA nanoparticles loaded with hesperidin effectively reduce the survival rate of HCT116 colorectal cancer cells. However, further studies are needed to determine the appropriate therapeutic dosage and to conduct animal and clinical studies.

Asunto(s)

Neoplasias Colorrectales , Hesperidina , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Humanos , Hesperidina/química , Hesperidina/farmacología , Hesperidina/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Neoplasias Colorrectales/tratamiento farmacológico , Células HCT116 , Nanopartículas/química , Supervivencia Celular/efectos de los fármacos , Ácido Láctico/química , Ácido Poliglicólico/química , Sistemas de Liberación de Medicamentos , Tamaño de la Partícula , Portadores de Fármacos/química , Espectroscopía Infrarroja por Transformada de Fourier , Antineoplásicos/farmacología , Antineoplásicos/química , Sistema de Administración de Fármacos con Nanopartículas/química

RESUMEN

Antioxidant therapies are of interest in the prevention and management of ocular disorders such as cataracts. Although an active area of interest, topical therapy with antioxidants for the treatment of cataracts is complicated by multiple ocular anatomical barriers, product stability, and solubility. Entrapment and delivery of antioxidants with poly(lactic-co-glycolic acid) nanoparticles is a possible solution to these challenges, however, little is known regarding their effects in vitro or in vivo. Our first aim was to investigate the impact of blank and lutein loaded PLGA nanoparticles on viability and development of reactive oxygen species in lens epithelial cells in vitro. Photo-oxidative stress was induced by ultraviolet light exposure with cell viability and reactive oxygen species monitored. Next, an in vivo, selenite model was utilized to induce cataract formation in rodents. Eyes were treated topically with both free lutein and lutein loaded nanoparticles (LNP) at varying concentrations. Eyes were monitored for the development of anterior segment changes and cataract formation. The ability of nanodelivered lutein to reach the anterior segment of the eye was evaluated by liquid chromatography coupled to mass spectrometry of aqueous humor samples and liquid chromatography coupled to tandem mass spectrometry (targeted LC-MS/MS) of lenses. LNP had a minimal impact on the viability of lens epithelial cells during the short exposure timeframe (24 h) and at concentrations < 0.2 µg LNP/µl. A significant reduction in the development of reactive oxygen species was also noted. Animals treated with LNPs at an equivalent lutein concentration of 1,278 µg /mL showed the greatest reduction in cataract scores. Lutein delivery to the anterior segment was confirmed through evaluation of aqueous humor and lens sample evaluation. Topical treatment was not associated with the development of secondary keratitis or anterior uveitis when applied once daily for one week. LNPs may be an effective in the treatment of cataracts.

Asunto(s)

Administración Tópica , Catarata , Luteína , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Animales , Luteína/farmacología , Luteína/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanopartículas/química , Catarata/tratamiento farmacológico , Ratas , Cristalino/efectos de los fármacos , Cristalino/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/administración & dosificación , Humanos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humor Acuoso/efectos de los fármacos , Humor Acuoso/metabolismo , Masculino , Línea Celular , Ácido Láctico/química , Ácido Poliglicólico/química

RESUMEN

In recent studies we have reported on the near-UV light-induced degradation of iron complexes of various pharmaceutical excipients, such as Fe(III)-citrate and Fe(III)-amino acid complexes. Mechanistic studies revealed a common photo-degradation pattern, i.e. the formation of carbon dioxide radical anion, a potent reducing agent, via an alkoxyl/amino radical intermediate generated by light-induced ligand-to-metal charge transfer (LMCT) involving α-hydroxycarboxylates or amino acids. Herein, we confirm the proposed general photo-degradation pathways through the study of the iron complexes of other α-hydroxycarboxylates that may be present in protein formulations, such as lactate and glycolate. The results indicate that lactate generates even higher yields of •CO2- as compared to citrate, suggesting a significant potential of lactate for the promotion of photo-degradation in pharmaceutical formulations.

Asunto(s)

Dióxido de Carbono , Compuestos Férricos , Ácido Láctico , Rayos Ultravioleta , Dióxido de Carbono/química , Ácido Láctico/química , Compuestos Férricos/química , Aniones/química , Fotólisis , Glicolatos/química

RESUMEN

We investigated the single particle kinetics of the molecular release processes from two types of microcapsules used as drug delivery systems (DDS): biodegradable poly(lactic-co-glycolic) acid (PLGA) and a light-triggered-degradable liposome encapsulating gold nanospheres (liposome-GNP). To optimize the design of DDS capsules, it is highly desirable to develop a method for real-time monitoring of the release process. Using a combination of optical tweezers and confocal fluorescence microspectroscopy we successfully analyzed a single optically trapped PLGA particle and liposome-GNPs in solution. From temporal decay profiles of the fluorescence intensity, we determined the time constant τ of the release processes. We demonstrated that the release rate of spontaneously degradable microcapsules (PLGA) decreased with increasing size, while conversely, the release rate of external stimuli-degradable microcapsules (liposome-GNPs) increased in proportion to their size. This result is explained by the differences in the disruption mechanisms of the capsules, with PLGA undergoing hydrolysis and the GNPs in the liposome-GNP undergoing a photoacoustic effect under nanosecond pulsed laser irradiation. The present approach offers a way forward to an alternative microanalysis system for single drug delivery nanocarriers.

Asunto(s)

Oro , Ácido Láctico , Liposomas , Nanosferas , Pinzas Ópticas , Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Oro/química , Liposomas/química , Ácido Láctico/química , Nanosferas/química , Ácido Poliglicólico/química , Tamaño de la Partícula , Sistemas de Liberación de Medicamentos

RESUMEN

Imatinib is a chemotherapeutic agent known to cause severe side effects when administrated systemically. Encapsulating imatinib in co-polymer poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) offers a targeted drug delivery. In this work, PLGA 50:50 and PLGA 75:25 NPs encapsulated imatinib using the electrohydrodynamic atomisation technique. All particles generated were spherical with a smooth surface with a size distribution of 455±115 nm (PLGA 50:50) and 363±147 nm (PLGA 75:25). Encapsulation of imatinib was shown to be higher than 75 % and was shown to increase the zeta potential of the loaded NPs. The release of imatinib showed an initial burst in the first 12 h, followed by different sustained releases with up to 70 %. Both types of imatinib-loaded NPs' effect on cell viability and their cellular uptake were also studied on A549 cells, and the antiproliferative effect was comparable to that of cells treated with free drugs. Finally, Rhodamine-B-loaded NP-treated cells demonstrated the cellular uptake of NPs.

Asunto(s)

Antineoplásicos , Supervivencia Celular , Portadores de Fármacos , Mesilato de Imatinib , Nanopartículas , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/farmacocinética , Humanos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanopartículas/química , Células A549 , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Ácido Láctico/química , Liberación de Fármacos , Ácido Poliglicólico/química , Polímeros/química , Línea Celular Tumoral

RESUMEN

Aim: This study focused on developing a topical gel incorporating lornoxicam-loaded poly(lactic-co-glycolic acid) and polyethylene glycol (PLGA-PEG) blend nanoparticles to mitigate gastrointestinal (GIT) side effects and enhance therapeutic efficacy. Materials & methods: Synthesized nanoparticles were subjected to in vitro characterization, ex vivo permeation studies, and acute oral toxicity analysis post-incorporation into the gel using a S/O/W double emulsion solvent. Results & conclusion: The nanoparticles displayed a smooth, spherical morphology (170-321 nm) with increased entrapment efficiency (96.2%). LOX exhibited a permeation rate of 70-94% from the nanoparticle-infused gel, demonstrating favorable biocompatibility at the cellular level. The formulated gel, enriched with nanoparticles, holds promising prospects for drug-delivery systems and promising improved therapeutic outcomes for LOX.

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Asunto(s)

Administración Cutánea , Nanopartículas , Piroxicam , Polietilenglicoles , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Piroxicam/análogos & derivados , Piroxicam/administración & dosificación , Piroxicam/química , Polietilenglicoles/química , Animales , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanopartículas/química , Humanos , Portadores de Fármacos/química , Tamaño de la Partícula , Inflamación/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Ratones , Ácido Láctico/química , Masculino , Ratas , Ácido Poliglicólico/química , Piel/metabolismo , Piel/efectos de los fármacos

RESUMEN

In recent decades, microfluidics has presented new opportunities for the production of nanoparticles (NPs). However, to achieve rapid clinical translation, the production of PLGA NPs in a single microfluidic channel for both the pharmaceutical research and industry without the need for scaling is still limited. The aim of this study was to accomplish the production of reproducible and stable 5-FU loaded Poly(lactic-co-glycolic acid) (PLGA) NPs, using an innovative toroidal microfluidic system, for cancer therapy. The toroidal microfluidic system enabled the production of spherical NPs ranging from 100 to 150 nm by adjusting both the TFR within the range of 5-15 mL/min and FRR between 1:3 and 1:7. A systematic assessment of critical process variables (total flow rate; TFR, flow rate ratio; FRR) for the production of PLGA NPs was conducted using Design of Experiment (DoE). The NPs, which exhibit a uniform size distribution, remained stable even after centrifugation and storage for 3 months at 4 °C. The encapsulation efficiency of drug and the concentration of NPs were not affected by changing process parameters. The effective 5-FU encapsulation into NPs resulted in a controlled in vitro drug release. Due to the controlled release profile of the 5-FU loaded PLGA NPs, the formulation was a promising candidate for mitigating the toxic side effects of free 5-FU and improving cancer treatment. In conclusion, toroidal microfluidic system enables high-volume production of stable PLGA NPs, both with and without 5-FU.

Asunto(s)

Fluorouracilo , Microfluídica , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Fluorouracilo/administración & dosificación , Fluorouracilo/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanopartículas/química , Microfluídica/métodos , Liberación de Fármacos , Tamaño de la Partícula , Portadores de Fármacos/química , Ácido Láctico/química , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/química , Estabilidad de Medicamentos , Ácido Poliglicólico/química

RESUMEN

Background: Development of an inhalable nanoformulation of dacomitinib (DMB) encapsulated in poly-(lactic-co-glycolic acid) nanoparticles (NPs) to improve solubility, facilitate direct lung delivery and overcome the systemic adverse effects.Methods: DMB-loaded poly-(lactic-co-glycolic acid) NPs were prepared using solvent evaporation and characterized for particle size, polydispersity index and zeta-potential. The NPs were evaluated for in vitro drug release, aerosolization performance and in vitro efficacy studies.Results: The NPs showed excellent particle characteristics and displayed a cumulative release of ∼40% in 5 days. The NPs demonstrated a mass median aerodynamic diameter of ∼3 µm and fine particle fraction of ∼80%. Further, in vitro cell culture studies showed improved cytotoxic potential of DMB-loaded NPs compared with free drug.Conclusion: The study underscores the potential of DMB-loaded NPs as a viable approach for non-small cell lung cancer treatment.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Portadores de Fármacos , Liberación de Fármacos , Neoplasias Pulmonares , Nanopartículas , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Quinazolinonas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Administración por Inhalación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanopartículas/química , Portadores de Fármacos/química , Quinazolinonas/química , Quinazolinonas/administración & dosificación , Quinazolinonas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Administración Oral , Línea Celular Tumoral , Ácido Poliglicólico/química , Ácido Láctico/química