RESUMO
Background: Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder. Levodopa (L-DOPA) remains the gold-standard drug available for treating PD. Curcumin has many pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, anti-amyloid, and antitumor properties. Copolymers composed of Poly (ethylene oxide) (PEO) and biodegradable polyesters such as Poly (ε-caprolactone) (PCL) can self-assemble into nanoparticles (NPs). This study describes the development of NH2-PEO-PCL diblock copolymer positively charged and modified by adding glutathione (GSH) on the outer surface, resulting in a synergistic delivery of L-DOPA curcumin that would be able to pass the blood-brain barrier. Methods: The NH2-PEO-PCL NPs suspensions were prepared by using a nanoprecipitation and solvent displacement method and coated with GSH. NPs were submitted to characterization assays. In order to ensure the bioavailability, Vero and PC12 cells were treated with various concentrations of the loaded and unloaded NPs to observe cytotoxicity. Results: NPs have successfully loaded L-DOPA and curcumin and were stable after freeze-drying, indicating advancing into in vitro toxicity testing. Vero and PC12 cells that were treated up to 72 h with various concentrations of L-DOPA and curcumin-loaded NP maintained high viability percentage, indicating that the NPs are biocompatible. Conclusions: NPs consisting of NH2-PEO-PCL were characterized as potential formulations for brain delivery of L-DOPA and curcumin. The results also indicate that the developed biodegradable nanomicelles that were blood compatible presented low cytotoxicity.
Assuntos
Curcumina , Nanopartículas , Doença de Parkinson , Animais , Curcumina/farmacologia , Portadores de Fármacos , Levodopa , Doença de Parkinson/tratamento farmacológico , Poliésteres/farmacologia , Polietilenoglicóis , Polímeros , RatosRESUMO
Tamoxifen citrate (TMC), a non-steroidal antiestrogen drug used for the treatment of breast cancer, was loaded in a block copolymer of maltoheptaose-b-polystyrene (MH-b-PS) nanoparticles, a potential drug delivery system to optimize oral chemotherapy. The nanoparticles were obtained from self-assembly of MH-b-PS using the standard and reverse nanoprecipitation methods. The MH-b-PS@TMC nanoparticles were characterized by their physicochemical properties, morphology, drug loading and encapsulation efficiency, and release kinetic profile in simulated intestinal fluid (pH 7.4). Finally, their cytotoxicity towards the human breast carcinoma MCF-7 cell line was assessed. The standard nanoprecipitation method proved to be more efficient than reverse nanoprecipitation to produce nanoparticles with small size and narrow particle size distribution. Moreover, tamoxifen-loaded nanoparticles displayed spherical morphology, a positive zeta potential and high drug content (238.6 ± 6.8 µg mL-1) and encapsulation efficiency (80.9 ± 0.4 %). In vitro drug release kinetics showed a burst release at early time points, followed by a sustained release profile controlled by diffusion. MH-b-PS@TMC nanoparticles showed higher cytotoxicity towards MCF-7 cells than free tamoxifen citrate, confirming their effectiveness as a delivery system for administration of lipophilic anticancer drugs.
Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Glucanos , Nanopartículas/química , Poliestirenos , Tamoxifeno/administração & dosagem , Neoplasias da Mama , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Químicos , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Glucanos/química , Humanos , Cinética , Modelos Teóricos , Estrutura Molecular , Tamanho da Partícula , Poliestirenos/química , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Tamoxifeno/químicaRESUMO
Thiosemicarbazones are an important class of compounds that have been extensively studied in recent years, mainly because of their broad profile of pharmacological activity. A new 4-nitrobenzaldehyde thiosemicarbazone compound (BZTS) that was derived from S-limonene has been demonstrated to have significant antiprotozoan activity. However, the hydrophobic characteristic of BZTS limits its administration and results in low oral bioavailability. In the present study, we proposed the synthesis of nanoparticle-based block copolymers that can encapsulate BZTS, with morphological evaluation of the nanoparticle suspensions being performed by transmission and cryo-transmission electronic microscopy. The mean particle sizes of the nanoparticle suspensions were determined by static light and dynamic light scattering (SLS/DLS), and the hydrodynamic radius (Rh) was determined using the Stokes-Einstein equation. The zeta potential (ζ) and polydispersity index (PDI) were also determined. The entrapment encapsulation efficiency of the BZTS nanoparticles was measured by ultraviolet spectrophotometry. In vitro activity of BZTS nanoparticle suspensions against intracellular amastigotes of Leishmania amazonensis and cytotoxic activity were also evaluated. The results showed the production of spherical nanoparticles with varied sizes depending on the hydrophobic portion of the amphiphilic diblock copolymers used. Significant concentration-dependent inhibitory activity against intracellular amastigotes was observed, and low cytotoxic activity was demonstrated against macrophages.
Assuntos
Antiprotozoários/química , Nanopartículas/química , Tiossemicarbazonas/química , Animais , Antiprotozoários/farmacologia , Benzaldeídos/química , Linhagem Celular , Difusão Dinâmica da Luz , Leishmania/efeitos dos fármacos , Camundongos , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Espectrofotometria UltravioletaRESUMO
Trypanosoma cruzi is the causative agent of Chagas' disease, a parasitic disease that remains a serious health concern with unsatisfactory treatment. Drugs that are currently used to treat Chagas' disease are partially effective in the acute phase but ineffective in the chronic phase of the disease. The aim of the present study was to evaluate the antitrypanosomal activity and morphological, ultrastructural and biochemical alterations induced by a new molecule, 4-nitrobenzaldehyde thiosemicarbazone (BZTS), derived from S-(-)-limonene against epimastigote, trypomastigote and intracellular amastigote forms of T. cruzi. BZTS inhibited the growth of epimastigotes (IC50 = 9·2 µ m), intracellular amastigotes (IC50 = 3·23 µ m) and inhibited the viability of trypomastigotes (EC50 = 1·43 µ m). BZTS had a CC50 of 37·45 µ m in LLCMK2 cells. BZTS induced rounding and distortion of the cell body and severely damaged parasite mitochondria, reflected by extensive swelling and disorganization in the inner mitochondrial membrane and the presence of concentric membrane structures inside the organelle. Cytoplasmic vacuolization, endoplasmic reticulum that surrounded organelles, the loss of mitochondrial membrane potential, and increased mitochondrial O2 â¢- production were also observed. Our results suggest that BZTS alters the ultrastructure and physiology of mitochondria, which could be closely related to parasite death.
Assuntos
Cicloexenos/química , Estágios do Ciclo de Vida/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Terpenos/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Benzaldeídos/química , Benzaldeídos/farmacologia , Linhagem Celular , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/patologia , Retículo Endoplasmático/ultraestrutura , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/parasitologia , Estágios do Ciclo de Vida/fisiologia , Limoneno , Macaca mulatta , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Superóxidos/agonistas , Superóxidos/metabolismo , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Tripanossomicidas/química , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/metabolismo , Trypanosoma cruzi/ultraestruturaRESUMO
Here we report the preparation and physico-chemical characterization of carbohydrate-decorated micelles and their interaction with lectins. A library of biosourced amphiphiles was prepared by copper-catalyzed azide-alkyne cycloaddition (CuAAC) between alkynyl sugars (lactose, N-acetyl-D-glucosamine) and azido-functionalized poly(ethylene glycol) esters (N3-PEG900-decanoate (C10) and -dodecanoate (C12)). In water, these glycoconjugates self-assemble into micelles of homogeneous nanometric size (11 nm) as evidenced by scattering techniques (DLS for light, and SAXS for X-ray). A comparative study with previously synthesized octadecanoate counterparts pointed out that that nature of the fatty acid has no significant influence on the particle size but only affects their compactness. These findings are in favor of a possible bulk preparation from lipid mixtures such as those encountered in renewable vegetable oils. The presence of the carbohydrate epitopes on the surface of the micelles and their bioavailability for lectin targeting were also evidenced by light scattering measurements using wheat germ agglutinin (WGA) and peanut (Arachis hypogaea) (PNA) lectins, supporting possible application as targeted drug nanocarriers.
Assuntos
Glicoconjugados/química , Glicoconjugados/metabolismo , Lectinas/metabolismo , Técnicas de Química Sintética , Epitopos , Ácidos Graxos/química , Glicoconjugados/síntese química , Glicoconjugados/imunologia , Lactose/química , Micelas , Nanopartículas , Polietilenoglicóis/química , Espalhamento a Baixo Ângulo , Termodinâmica , Aglutininas do Germe de Trigo/imunologiaRESUMO
The development of novel xyloglucan-block-poly(ϵ-caprolactone) (XGO-b-PCL) nanoparticles coated with the mucoadhesive polysaccharide chitosan is described. XGO-b-PCL nanoparticles show monodisperse size distribution (Rh = 50 nm). Curcumin is successfully encapsulated within the PCL core within drug to polymer ratio of 1:5 (w/w). The coating of nanoparticles with chitosan results in an increased particle size and positive surface charge due to the polycation nature of the chitosan. Mucoadhesive properties of chitosan-coated nanoparticles are demonstrated by its exceptional ability to interact with mucin through electrostatic forces. Finally, in vitro studies show that curcumin-loaded nanoparticles exhibit higher cytotoxic effects against B16F10 melanoma cells than L929 fibroblast cells.
Assuntos
Adesivos/química , Materiais Biocompatíveis/síntese química , Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Glucanos/química , Nanopartículas/química , Poliésteres/química , Xilanos/química , Apoptose/efeitos dos fármacos , Materiais Biocompatíveis/química , Curcumina/administração & dosagem , Curcumina/química , Curcumina/farmacologia , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Modelos Moleculares , Estrutura Molecular , Ressonância de Plasmônio de SuperfícieRESUMO
In view of the fact that the oral administration of finasteride (FIN) has resulted in various undesirable systemic side effects, the topical application of polystyrene and poly(acrylic acid)-based polymersomes (underexplored system) was investigated. Undecorated PS139-b-PAA17 and PS404-b-PAA63 vesicles (C3 and C7, respectively) or vesicles decorated with chitosan samples of different molecular weight (C3/CS-oligo, C7/CS-oligo, C3/CS-37 and C7/CS-37) were prepared by the co-solvent self-assembly method and characterized by small-angle X-ray scattering,transmission electron microscopy and dynamic light scattering techniques. In vitro release experiments and ex vivo permeation using Franz diffusion cells were carried out (through comparison with hydroethanolic finasteride solution). The ideal system should provide high finasteride retention in the dermis and epidermis while allowing some control of the drug release. The particle size and in vitro release were negatively correlated with the permeation coefficient and skin retention in both the epidermis and dermis. The findings that the longest lag time was obtained for the hydroethanolic drug solution and lowest permeation for the systems able to release the drug faster support the hypothesis that nanostructured systems may be required to enhance the penetration and permeation of the drug. Chitosan-decorated polymersomes interacted more strongly with the skin components than non-decorated samples, probably due to the positive surface charge, which increased the FIN retention and reduced the lag time. C7 polymersomes decorated with chitosan were more appropriate for topical applications (high retention in the dermis and epidermis and controlled drug delivery).
Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Acrilatos/química , Quitosana/química , Portadores de Fármacos/administração & dosagem , Finasterida/administração & dosagem , Poliestirenos/química , Inibidores de 5-alfa Redutase/química , Administração Cutânea , Animais , Portadores de Fármacos/química , Finasterida/química , Técnicas In Vitro , Permeabilidade , Pele/metabolismo , SuínosRESUMO
We propose a novel plant-based amphiphilic diblock co-oligomers (BCO) surfactant containing only carbohydrate segments and examine its potential as a biosourced stabilizer. The synthesis of an amphiphilic xyloglucan-based BCO, composed of a hydrophilic xyloglucan oligosaccharide (XGO) block "clicked" to a hydrophobic peracetylated XGO is described. Dynamic light scattering experiments correlated with transmission electron microscopy observations showed that this new class of amphiphilic BCO self-assembles in water to form spherical micelles with a hydrodynamic diameter of 22 nm. Preliminary studies indicate that the XGO-based BCO sterically stabilizes gliadin and zein nanoparticle suspensions. The stabilization results were compared to those using pluronic F-68, a commercial surfactant. For gliadin nanoparticles, both surfactants result in essentially the same morphology and polydispersity. However, for the zein nanoparticles, the XGO-based BCO stabilizer gave lower polydispersity.
Assuntos
Gliadina/química , Glucanos/química , Nanopartículas/química , Xilanos/química , Zeína/química , Sequência de Carboidratos , Interações Hidrofóbicas e Hidrofílicas , Luz , Micelas , Microscopia Eletrônica de Transmissão , Dados de Sequência Molecular , Nanopartículas/ultraestrutura , Poloxâmero/química , Polimerização , Estabilidade Proteica , Espalhamento de Radiação , Suspensões , ÁguaRESUMO
We describe the mechanical defibrillation of bacterial cellulose (BC) followed by the dry-cast generation of reconstituted BC films (RBC). Xyloglucan (XGT), extracted from tamarind seeds, was incorporated into the defibrillated cellulose at various compositions, and new films were created using the same process. Microscopy and contact angle analyses of films revealed an increase in the microfibre adhesion, a reduced polydispersity in the diameters of the microfibrils and increased hydrophobic behaviour as a function of %XGT. X-ray diffraction analysis revealed changes to the crystallographic planes of the RBC and the biocomposite films with preferential orientation along the (110) plane. Compared with BC, RBC/XGT biocomposite with 10% XGT exhibited improvement in its thermal properties and in Young's modulus. These results indicated a reorganisation of the microfibres with mechanical treatment, which when combined with hydrocolloids, can create cellulose-based materials that could be applied as scaffolding for tissue engineering and drug release.
Assuntos
Celulose/química , Glucanos/química , Gluconacetobacter xylinus/química , Tamarindus/química , Xilanos/química , Materiais Biocompatíveis/química , Fenômenos Biomecânicos , Módulo de Elasticidade , Teste de Materiais/métodos , Microfibrilas/química , Estrutura Molecular , Polissacarídeos Bacterianos/química , Sementes/química , Propriedades de Superfície , Engenharia Tecidual/métodos , Difração de Raios XRESUMO
Quercetin is a natural compound that has shown several biological activities. However, it displays poor water solubility and, therefore, low bioavailability. In this study, oil-in-water nanosized emulsions were obtained by the hot solvent diffusion method, using castor oil as oily phase and poly(ethylene glycol) (660)-12-hydroxystearate (PEG 660-stearate) and lecithin as surfactants. The effect of the PEG 660-stearate concentration on the droplet size of the nanosized emulsions and on the ability of these systems to load quercetin was investigated. Dynamic light scattering (DLS), transmission electron microscopy (TEM), cryo-TEM, and small-angle X-ray scattering (SAXS) were used to characterize the systems. We have demonstrated that a critical concentration of PEG 660-stearate (2.5 wt%) was needed to obtain colloidal dispersions displaying microemulsion characteristics. This colloidal dispersion, that was not optically birefringent, was constituted by a monodisperse population of 20 nm-large droplets, and exhibited excellent stability. Besides, this system was able to solubilize five times more quercetin than nanoemulsions prepared using 0.25 wt% PEG 660-stearate. SAXS results suggest that the spherical droplets have a core-shell structure. With regard to the hot solvent diffusion method, both diffusion of the solvent towards the aqueous phase and increase of the temperature above the phase inversion temperature (PIT) of PEG 660-stearate appeared to be required for obtaining clear and isotropic colloidal dispersions.