RESUMEN

Multifunctional therapies have emerged as innovative strategies in cancer treatment. In this research article, we proposed a nanostructured lipid carrier (NLC) designed for the topical treatment of cutaneous melanoma, which simultaneously delivers 5-FU and Bcl-2 siRNA. The characterized nanoparticles exhibited a diameter of 259 ± 9 nm and a polydispersion index of 0.2, indicating a uniform size distribution. The NLCs were primarily localized in the epidermis, effectively minimizing the systemic release of 5-FU across skin layers. The ex vivo skin model revealed the formation of a protective lipid film, decreasing the desquamation process of the stratum corneum which can be associated to an effect of increasing permeation. In vitro assays demonstrated that A375 melanoma cells exhibited a higher sensitivity to the treatment compared to non-cancerous cells, reflecting the expected difference in their metabolic rates. The uptake of NLC by A375 cells reached approximately 90% within 4 h. The efficacy of Bcl-2 knockdown was thoroughly assessed using ELISA, Western blot, and qRT-PCR analyses, revealing a significant knockdown and synergistic action of the NLC formulation containing 5-FU and Bcl-2 siRNA (at low concentration --100 pM). Notably, the silencing of Bcl-2 mRNA also impacted other members of the Bcl-2 protein family, including Mcl-1, Bcl-xl, BAX, and BAK. The observed modulation of these proteins strongly indicated the activation of the apoptosis pathway, suggesting a successful inhibition of melanoma growth and prevention of its in vitro spread.

RESUMEN

Oral drug administration, especially when composed of mucoadhesive delivery systems, has been a research trend due to increased residence time and contact with the mucosa, potentially increasing drug bioavailability and stability. In this context, this study aimed to develop self-assembly mucoadhesive beads composed of blends of κ-carrageenan and sericin (κ-Car/Ser) loaded with the anti-inflammatory drug indomethacin (IND). We investigated the swelling, adhesion behaviour, and mechanical/physical properties of the beads, assessing their effects on cell viability, safety and permeation characteristics in both 2D and triple-culture model. The swelling ratio of the beads indicated pH-responsiveness, with maximum water absorption at pH 6.8, and strong mucoadhesion, increasing primarily with higher polymer concentrations. The beads exhibited thermal stability and no chemical interaction with IND, showing improved mechanical properties. Furthermore, the beads remained stable during accelerated and long-term storage studies. The beads were found to be biocompatible, and IND encapsulation improved cell viability (>70 % in both models, 79 % in VN) and modified IND permeation through the models (6.3 % for F5 formulation (κ-Car 0.90 % w/v | Ser 1.2 % w/v| IND 3.0 g); 10.9 % for free IND, p < 0.05). Accordingly, κ-Car/Ser/IND beads were demonstrated to be a promising IND drug carrier to improve oral administration while mitigating the side effects of non-steroidal anti-inflammatories.

Asunto(s)

Carragenina , Preparaciones de Acción Retardada , Indometacina , Sericinas , Indometacina/química , Indometacina/administración & dosificación , Indometacina/farmacocinética , Carragenina/química , Administración Oral , Humanos , Sericinas/química , Preparaciones de Acción Retardada/química , Portadores de Fármacos/química , Liberación de Fármacos , Supervivencia Celular/efectos de los fármacos , Microesferas , Animales , Células CACO-2 , Concentración de Iones de Hidrógeno

RESUMEN

We developed poly-ε-caprolactone (PCL)-based nanoparticles containing D-α-tocopherol polyethylene glycol-1000 succinate (TPGS) or Poloxamer 407 as stabilizers to efficiently encapsulate genistein (GN). Two formulations, referred to as PNTPGS and PNPol, were prepared using nanoprecipitation. They were characterized by size and PDI distribution, zeta potential, nanoparticle tracking analysis (NTA), GN association (AE%), infrared spectroscopy (FT-IR), and differential scanning calorimetry (DSC). PNTPGS-GN exhibited a particle size of 141.2 nm, a PDI of 0.189, a zeta potential of -32.9 mV, and an AE% of 77.95%. PNPol-GN had a size of 146.3 nm, a better PDI than PNTPGS-GN (0.150), a less negative zeta potential (-21.0 mV), and an AE% of 68.73%. Thermal and spectrometric analyses indicated that no new compounds were formed, and there was no incompatibility detected in the formulations. Cellular studies revealed that Poloxamer 407 conferred less toxicity to PCL nanoparticles. However, the percentage of uptake decreased compared to the use of TPGS, which exhibited almost 80% cellular uptake. This study contributes to the investigation of stabilizers capable of conferring stability to PCL nanoparticles efficiently encapsulating GN. Thus, the PCL nanoparticle proposed here is an innovative nanomedicine for melanoma therapy and represents a strong candidate for specific pre-clinical and in vivo studie

Asunto(s)

Genisteína/farmacología , Nanopartículas/análisis , Melanoma/tratamiento farmacológico , Tamaño de la Partícula , Análisis Espectral/clasificación , Rastreo Diferencial de Calorimetría/métodos , Cromatografía Líquida de Alta Presión/métodos

RESUMEN

Cancer is one of the major public health problems worldwide. Despite the advances in cancer therapy, it remains a challenge due to the low specificity of treatment and the development of multidrug resistance mechanisms. To overcome these drawbacks, several drug delivery nanosystems have been investigated, among them, magnetic nanoparticles (MNP), especially superparamagnetic iron oxide nanoparticles (SPION), which have been applied for treating cancer. MNPs have the ability to be guided to the tumor microenvironment through an external applied magnetic field. Furthermore, in the presence of an alternating magnetic field (AMF) this nanocarrier can transform electromagnetic energy in heat (above 42 °C) through Néel and Brown relaxation, which makes it applicable for hyperthermia treatment. However, the low chemical and physical stability of MNPs makes their coating necessary. Thus, lipid-based nanoparticles, especially liposomes, have been used to encapsulate MNPs to improve their stability and enable their use as a cancer treatment. This review addresses the main features that make MNPs applicable for treating cancer and the most recent research in the nanomedicine field using hybrid magnetic lipid-based nanoparticles for this purpose.

RESUMEN

Dental caries is the most common oral disease, with high prevalence rates in adolescents and low-income and lower-middle-income countries. This disease originates from acid production by bacteria, leading to demineralization of the dental enamel and the formation of cavities. The treatment of caries remains a global challenge and the development of effective drug delivery systems is a potential strategy. In this context, different drug delivery systems have been investigated to remove oral biofilms and remineralize dental enamel. For a successful application of these systems, it is necessary that they remain adhered to the surfaces of the teeth to allow enough time for the removal of biofilms and enamel remineralization, thus, the use of mucoadhesive systems is highly encouraged. Among the systems used for this purpose, liquid crystalline systems, polymer-based nanoparticles, lipid-based nanoparticles, and inorganic nanoparticles have demonstrated great potential for preventing and treating dental caries through their own antimicrobial and remineralization properties or through delivering drugs. Therefore, the present review addresses the main drug delivery systems investigated in the treatment and prevention of dental caries.

RESUMEN

Nanotechnology has been widely applied to develop drug delivery systems to improve therapeutic performance. The effectiveness of these systems is intrinsically related to their physicochemical properties, so their biological responses are highly susceptible to factors such as the type and quantity of each material that is employed in their synthesis and to the method that is used to produce them. In this context, quality-oriented manufacturing of nanoparticles has been an important strategy to understand and to optimize the factors involved in their production. For this purpose, Design of Experiment (DoE) tools have been applied to obtain enough knowledge about the process and hence achieve high-quality products. This review aims to set up the bases to implement DoE as a strategy to improve the manufacture of nanocarriers and to discuss the main factors involved in the production of the most common nanocarriers employed in the pharmaceutical field.

Asunto(s)

Portadores de Fármacos/química , Composición de Medicamentos/métodos , Nanopartículas/química , Proyectos de Investigación , Química Farmacéutica , Nanomedicina/métodos

RESUMEN

Glioblastoma multiforme (GBM) is a first primary Central Nervous System tumor with high incidence and lethality. Its treatment is hampered by the difficulty to overcome the blood-brain barrier (BBB) and by the non-specificity of chemotherapeutics to tumor cells. This study was based on the development characterization and in vitro efficacy of folate-modified TPGS transfersomes containing docetaxel (TF-DTX-FA) to improve GBM treatment. TF-DTX-FA and unmodified transfersomes (TF-DTX) were prepared through thin-film hydration followed by extrusion technique and characterized by physicochemical and in vitro studies. All formulations showed low particles sizes (below 200 nm), polydispersity index below 0.2, negative zeta potential (between -16.75 to -12.45 mV) and high encapsulation efficiency (78.72 ± 1.29% and 75.62 ± 0.05% for TF-DTX and TF-DTX-FA, respectively). Furthermore, cytotoxicity assay of TF-DTX-FA showed the high capacity of the nanocarriers to reduce the viability of U-87 MG in both 2D and 3D culture models, when compared with DTX commercial formulation and TF-DTX. In vitro cellular uptake assay indicated the selectivity of transfersomes to tumoral cells when compared to normal cells, and the higher ability of TF-DTX-FA to be internalized into 2D U-87 MG in comparison with TF-DTX (72.10 and 62.90%, respectively, after 24 h). Moreover, TF-DTX-FA showed higher permeability into 3D U-87 MG spheroid than TF-DTX, suggesting the potential FA modulation to target treatment of GBM.

Asunto(s)

Antineoplásicos , Glioblastoma , Nanopartículas , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Docetaxel/farmacología , Portadores de Fármacos , Ácido Fólico , Glioblastoma/tratamiento farmacológico , Humanos , Vitamina E

RESUMEN

INTRODUCTION: Lyotropic liquid crystals (LLCs) are organized mesophases with intermediate properties between liquids and solids. The LLC and its liquid crystalline nanoparticles (LCNPs) have attracted great interest from the scientific community in recent years as potential drug delivery systems due to the high internal ordering and symmetry with a wide interfacial area. AREAS COVERED: This article aims to gather information and to provide a description of the highly organized structures of LLCs. Updates on production methods and new insights for LCNPs optimization and physico-chemical and morphological caracterization techniques were discussed. We also discussed why these systems proved to be a platform for the design of nanocarrier drug delivery, with an emphasis on topical and transdermal applications. EXPERT OPINION: Drug delivery platforms are of particular importance to improve the biopharmaceutical aspects of therapies topically. Although several systems can be used, LLC or LCNPs appear to be favored due to their similarity to the lipid structure of the skin. The highly ordered structure and the possibility of chemical modifications make it possible to obtain better clinical responses. The results of several studies support the innovations in this field and predict that these systems can innovate the market of technologies for the treatment of cutaneous diseases and cosmetology.

Asunto(s)

Sistemas de Liberación de Medicamentos , Cristales Líquidos/química , Nanopartículas , Administración Cutánea , Animales , Humanos , Preparaciones Farmacéuticas/administración & dosificación , Piel/metabolismo , Enfermedades de la Piel/tratamiento farmacológico

RESUMEN

Triptolide (TPL) is a natural compound and active component of Tripterygium wilfordii Hook F., an Asian native woody vine widely used for over 200 years in Chinese medicine. Hot water, ethanol-ethyl acetate, and chloroform-methanol extracts are the first reported TPL preparations in the literature, and since then, several studies for application in inflammation processes and cancer are described due to the antitumor, anti-inflammatory, and immunosuppressive characteristics of the molecule. However, physicochemical properties such as poor solubility and bioavailability are the main concerns regarding the TPL safety and efficacy in clinical studies since trials have reported adverse side effects alongside the excellent TPL therapeutic effects. Here, we review the main TPL applications and issues related to the drug usage, and a comprehensive summary of diseases is provided. Special emphasis is given to drug delivery systems designed to overcome the TPL physicochemical characteristics such as poor drug solubility, and how to increase efficacy and obtain a safe drug profile. Graphical abstract.

Asunto(s)

Diterpenos , Medicamentos Herbarios Chinos , Fenantrenos , Diterpenos/farmacología , Medicamentos Herbarios Chinos/farmacología , Compuestos Epoxi , Fenantrenos/farmacología , Tripterygium

RESUMEN

In this study, we developed a water-in-oil microemulsion containing vitamin A (retinol) and vitamin E (α-tocopherol), which serves as a multifunctional nanosystem that co-delivers antioxidants and displayed additive effect against acute skin inflammation. Microemulsion (ME) was prepared by mixing a surfactant blend (Tween 80 and propylene glycol, 5:1) with isopropyl myristate and water (ratio of 50:40:10, respectively). Vitamin A (0.05% w/w concentration) and/or vitamin E (0.1% w/w concentration) were incorporated into the surfactant mixture of ME by stirring with a magnetic stirrer for 30 min. This multifunctional ME displayed physical stability, with low cytotoxicity in 3T3 cell line, as well as cellular internalization into the cytosol. In vivo treatments using ME delivering α-tocopherol reduced dermal expression of TNF-α by 1.3-fold (p < 0.01), when compared to unloaded ME treatment group. When retinol was added into the ME containing α-tocopherol, it further reduced TNF-α expression by 2-fold (p < 0.001), suggesting the additive effect of vitamin E and vitamin A in the treatment against skin inflammation. In conclusion, we successfully developed the use of water-in-oil ME to pack both vitamin E and vitamin A, and demonstrated for the first time its anti-inflammatory potential when applied topically to TPA-induced inflamed skin.

Asunto(s)

Sistemas de Liberación de Medicamentos , Inflamación/tratamiento farmacológico , Inflamación/patología , Piel/patología , Vitamina A/administración & dosificación , Vitamina E/administración & dosificación , Enfermedad Aguda , Administración Tópica , Animales , Rastreo Diferencial de Calorimetría , Supervivencia Celular/efectos de los fármacos , Emulsiones , Células HaCaT , Humanos , Ratones , Ratones Pelados , Células 3T3 NIH , Piel/efectos de los fármacos , Porcinos , Vitamina A/farmacología , Vitamina A/uso terapéutico , Vitamina E/farmacología , Vitamina E/uso terapéutico

RESUMEN

Since psoriasis is an immuno-mediated skin disease, long-term therapies are necessary for its treatment. In clinical investigations, tacrolimus (TAC), a macrolide immunosuppressive inhibitor of calcineurin, arises as an alternative for the treatment of psoriasis, acting in some cytokines involved in the pathogenesis of the disease. Here, we aim to study the psoriasis treatment with TAC and siRNA for one of most cytokines expressed in psoriasis, the TNF-α. A multifunctional nanostructure lipid carrier (NLC) was developed to co-delivery TAC and siRNA. Results showed that the particle size and zeta potential were around 230 nm and + 10 mV, respectively. The release study demonstrated a controlled release of TAC, and the permeation and retention profile in the skin tissue show to be promising for topical application. The cell viability and uptake in murine fibroblast presented low toxicity associated to uptake of NLC in 4 h, and finally, the in vivo animal model demonstrates the efficiency of the NLC multifunctional, exhibiting a reduction of the cytokine TNF-α expression about 7-fold and presenting a synergic effect between the TAC and TNF-α siRNA. The developed system was successfully to treat in vivo psoriatic animal model induced by imiquimod and the synergic combination was reported here for the first time. Graphical abstract.

Asunto(s)

Imiquimod/efectos adversos , Psoriasis/tratamiento farmacológico , ARN Interferente Pequeño/administración & dosificación , Tacrolimus/administración & dosificación , Factor de Necrosis Tumoral alfa/genética , Administración Cutánea , Animales , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Regulación hacia Abajo , Sinergismo Farmacológico , Femenino , Liposomas , Masculino , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Nanopartículas , Tamaño de la Partícula , Psoriasis/inducido químicamente , Psoriasis/genética , ARN Interferente Pequeño/farmacología , Tacrolimus/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores

RESUMEN

The physicochemical characteristics of nanostructured suspensions are important prerequisites for the success of new drug development. This work aimed to develop nanometric systems containing Cymbopogon densiflorus leaf essential oil and to evaluate their antimicrobial activity. The essential oil was isolated by hydrodistillation from leaves and analyzed by GC-MS. The main constituents were found to be trans-p-mentha-2,8-dien-1-ol, cis-p-mentha-2,8-dien-1-ol, trans-p-mentha-1(7),8-dien-2-ol, cis-piperitol, and cis-p-mentha-1(7),8-dien-2-ol. In silico prediction analysis suggested that this oil possesses antimicrobial potential and the main mechanism of action might be the peptidoglycan glycosyltransferase inhibition. Nanoemulsions were prepared by the phase inversion method, and liposomes were made by the film hydration method. Qualitative evaluation of the antimicrobial activity was performed by the diffusion disk assay with 24 microorganisms; all of them were found to be sensitive to the essential oil. Subsequently, this property was quantified by the serial microdilution technique, where the nanoformulations demonstrated improved activity in comparison with the free oil. Bactericidal action was tested by the propidium iodide method, which revealed that free essential oil and nanoemulsion increased cytoplasmic membrane permeability, while no difference was observed between negative control and liposome. These results were confirmed by images obtained using transmission electron microscopy. This study has shown an optimization in the antimicrobial activity of C. densiflorus essential oil by a nanoemulsion and a liposomal formulation of the active substances.

Asunto(s)

Antiinfecciosos/farmacología , Cymbopogon/química , Nanoestructuras , Aceites Volátiles/farmacología , Hojas de la Planta/química , Animales , Antiinfecciosos/química , Bacterias/efectos de los fármacos , Línea Celular , Permeabilidad de la Membrana Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Hongos/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Concentración de Iones de Hidrógeno , Ratones , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica de Transmisión , Aceites Volátiles/química , Tamaño de la Partícula , Relación Estructura-Actividad Cuantitativa