RESUMEN
Dual-species biofilms formed by Candida albicans and Staphylococcus aureus have high virulence and drug resistance. In this context, biosurfactants produced by Pseudomonas aeruginosa have been widely studied, of which a new derivative (RLmix_Arg) stands out for possible application in formulations. The objective of this study was to evaluate the antibiofilm activity of RLmix_Arg, both alone and incorporated in a gel prepared with Pluronic F-127, against dual-species biofilms of fluconazole-resistant C. albicans (FRCA) and methicillin-resistant S. aureus (MRSA) in impregnated catheters. Broth microdilution tests, MTT reduction assays of mature biofilms, impregnation of RLmix_Arg and its gel in peripheral venous catheters, durability tests and scanning electron microscopy (SEM) were performed. RLmix_Arg showed antimicrobial activity against Candida spp. and S. aureus, by reducing the cell viability of mixed biofilms of FRCA and MRSA, and preventing their formation in a peripheral venous catheter. The incorporation of this biosurfactant in the Pluronic F-127 gel considerably enhanced its antibiofilm activity. Thus, RLmix_Arg has potential application in gels for impregnation in peripheral venous catheters, helping to prevent development of dual-species biofilms of FRCA and MRSA.
Asunto(s)
Antiinfecciosos , Staphylococcus aureus Resistente a Meticilina , Fluconazol/farmacología , Candida albicans , Staphylococcus aureus , Resistencia a la Meticilina , Biopelículas , Poloxámero/farmacología , Pruebas de Sensibilidad Microbiana , Antiinfecciosos/farmacología , Catéteres , Antibacterianos/farmacologíaRESUMEN
Treatment against leishmaniasis presents problems, mainly due to the toxicity of the drugs, high cost, and the emergence of resistant strains. A previous study showed that two vanillin-derived synthetic molecules, 3s [4-(2-hydroxy-3-(4-octyl-1H-1,2,3-triazol-1-yl)propoxy)-3-methoxybenzaldehyde] and 3t [4-(3-(4-decyl-1H-1,2,3-triazol-1-yl)-2-hydroxypropoxy)-3-methoxybenzaldehyde], presented antileishmanial activity against Leishmania infantum, L. amazonensis, and L. braziliensis species. In the present work, 3s and 3t were evaluated to treat L. amazonensis-infected mice. Molecules were used pure or incorporated into Poloxamer 407-based micelles. In addition, amphotericin B (AmpB) and its liposomal formulation, Ambisome®, were used as control. Animals received the treatment and, one and 30 days after, they were euthanized to evaluate immunological, parasitological, and biochemical parameters. Results showed that the micellar compositions (3s/Mic and 3t/Mic) induced significant reductions in the lesion mean diameter and parasite load in the infected tissue and distinct organs, as well as a specific and significant antileishmanial Th1-type immune response, which was based on significantly higher levels of IFN-γ, IL-12, nitrite, and IgG2a isotype antibodies. Drug controls showed also antileishmanial action; although 3s/Mic and 3t/Mic have presented better and more significant parasitological and immunological data, which were based on significantly higher IFN-γ production and lower parasite burden in treated animals. In addition, significantly lower levels of urea, creatinine, alanine transaminase, and aspartate transaminase were found in mice treated with 3s/Mic and 3t/Mic, when compared to the others. In conclusion, results suggest that 3s/Mic and 3t/Mic could be considered as therapeutic candidates to treat against L. amazonensis infection.
Asunto(s)
Antiprotozoarios , Benzaldehídos , Leishmania mexicana , Ratones Endogámicos BALB C , Micelas , Animales , Ratones , Benzaldehídos/farmacología , Benzaldehídos/química , Leishmania mexicana/efectos de los fármacos , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Antiprotozoarios/química , Leishmaniasis Cutánea/tratamiento farmacológico , Femenino , Anfotericina B/farmacología , Anfotericina B/uso terapéutico , Poloxámero/química , Poloxámero/farmacología , Masculino , Bazo/parasitologíaRESUMEN
To assess the effect of curcumin-encapsulated Pluronic® F-127 (Cur-Plu) during antimicrobial photodynamic therapy (aPDT) over duo-species biofilm of Streptococcus mutans and Candida albicans. Thermal analysis, optical absorption, and fluorescence spectroscopy were evaluated. Minimum inhibitory concentration (MIC) and minimum bactericidal/fungal concentration were obtained. The biofilms were cultured for 48 h at 37 °C and treated according to the groups: P + M + L + (photosensitizer encapsulated with Pluronic® F-127 + light); P + D + L + (photosensitizer incorporated in 1% DMSO + light); P - M + L + (no Pluronic® F-127 + light); P - D + L + (1% DMSO + light); P - L + (Milli-Q water + light); P + M + L - (photosensitizer encapsulated with Pluronic® F-127 no light); P + D + L - (photosensitizer in 1% DMSO, no light); P - M + L - (Pluronic® F-127 no light); P - D + L - (1% DMSO, no light); P - L - (Milli-Q water, no light; negative control group); CHX (0.2% chlorhexidine, positive control group); and NYS (Nystatin). Dark incubation of 5 min was used. The groups that received aPDT were irradiated by blue LED (460 nm, 15 J/cm2). Cell viability of the biofilms was performed by colony-forming units (CFU/mL) and confocal microscopy. Two-way ANOVA followed by Tukey's post hoc test was used at a significance level of 5%. P + D + L + and P + M + L + groups exhibited better log-reduction for both Candida albicans and Streptococcus mutans biofilms than P - M + L + , P - L + , and P - D + L + experimental groups. Furthermore, P + M + L + and P + D + L + showed greater reduction for Candida albicans than for Streptococcus mutans. aPDT mediated by Cur-Plu can be a potential strategy for biofilm control against duo-species biofilm of Streptococcus mutans and Candida albicans.
Asunto(s)
Curcumina , Fotoquimioterapia , Biopelículas , Candida albicans , Curcumina/farmacología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Poloxámero/farmacología , Streptococcus mutansRESUMEN
BACKGROUND: Coronary artery bypass grafting (CABG) continues to be an effective therapy for coronary artery disease patients, but the vein graft is prone to restenosis or occlude. Adiponectin (ADP) is a plasma hormone protein with the function of regulating cell proliferation. OBJECTIVE: This study used two different doses of ADP protein in a rat vein graft model to stimulate vein graft change. The aim of our study was to investigate the effect of ADP on vein graft restenosis. METHODS: Autologous jugular veins were implanted as carotid interposition grafts through the anastomotic cuff technique in Sprague Dawley rats. Adiponectin (2.5 µg and 7.5 µg) was delivered to the vein bypass grafts in a perivascular fashion, suspended in a 30% Pluronic-F127 gel. No treatment (bypass only) and vehicle loaded Pluronic gel served as controls. Comparisons were made with one-way analysis of variance and a post-hoc test, with p < 0.05 considered significant. RESULTS: Cell proliferation (PCNA index) was significantly low in adiponectin-treated versus control and vehicle-gel-treated grafts, both in intima and adventitia, as of day 3 (p < 0.01). VCAM-1 and ICAM-1 evaluated by immunohistochemistry significantly down-regulated in the adiponectin-treated vein grafts in the fourth week (p <0.01). Treatment of vein grafts with adiponectin-loaded gels reduced intimal, media, and adventitia thickness when compared with the control and vehicle-gel-treated vein grafts at day 28 (p < 0.01). CONCLUSIONS: Our studies provide further support for the potential therapeutic role of adiponectin in modulating vascular injury and repair.
FUNDAMENTO: O enxerto de bypass na artéria coronária (CABG) continua a ser eficiente como tratamento para pacientes portadores de doença arterial coronariana; entretanto, o enxerto venoso tende a apresentar reestenose ou oclusão. A adiponectina (ADP) é uma proteína hormonal plasmática com a função de regular a proliferação celular. OBJETIVO: Foram utilizadas duas doses diferentes da proteína ADP em um modelo de enxerto venoso em ratos para estimular a alteração do enxerto venoso. O objetivo deste estudo foi investigar o efeito da ADP sobre a reestenose em enxerto venoso. MÉTODOS: Veias jugulares autólogas foram implantadas como enxertos interposicionais de carótida pela técnica de anastomose de manga em ratos Sprague Dawley. A adiponectina (2,5 µg e 7,5 µg) foi entregue ao enxerto venoso por bypass de forma perivascular, suspensa em gel Pluronic-F127 a 30%. O grupo tratado apenas com bypass e o grupo tratado com gel veículo carregado apenas com Pluronic funcionaram como controle. Foram feitas comparações com análise de via única de variância e teste post-hoc, com p <0,05 sendo considerado significativo. RESULTADOS: A proliferação celular (índice de PCNA) foi significativamente baixa no grupo tratado com adiponectina em comparação com o grupo de controle e o grupo tratado com o gel veículo na íntima e na adventícia dos enxertos a partir do dia 3 (p <0,01). VCAM-1 e ICAM-1 avaliados por imuno-histoquímica diminuíram significativamente em enxertos venosos tratados com adiponectina na quarta semana (p <0,01). O tratamento de enxertos venosos com gel carregado com adiponectina reduziu a espessura da íntima, da média e da adventícia, em comparação com os enxertos de controle e tratados com gel veículo no dia 28 (p <0,01). CONCLUSÕES: Este estudo oferece evidências adicionais do possível papel terapêutico da adiponectina na modulação de lesão vascular e seu reparo.
Asunto(s)
Adiponectina , Poloxámero , Animales , Humanos , Ratas , Adiponectina/farmacología , Proliferación Celular , Venas Yugulares/trasplante , Poloxámero/farmacología , Ratas Sprague-DawleyRESUMEN
Alveolar echinococcosis is a neglected parasitic zoonosis caused by Echinococcus multilocularis. The pharmacological treatment is based on albendazole (ABZ). However, the low water solubility of the drug produces a limited dissolution rate, with the consequent failure in the treatment of the disease. Solid dispersions are a successful pharmacotechnical strategy to improve the dissolution profile of poorly water-soluble drugs. The aim of this work was to determine the in vivo efficacy of ABZ solid dispersions using poloxamer 407 as a carrier (ABZ:P407 solid dispersions (SDs)) in the murine intraperitoneal infection model for secondary alveolar echinococcosis. In the chemoprophylactic efficacy study, the ABZ suspension, the ABZ:P407 SDs and the physical mixture of ABZ and poloxamer 407 showed a tendency to decrease the development of murine cysts, causing damage to the germinal layer. In the clinical efficacy study, the ABZ:P407 SDs produced a significant decrease in the weight of murine cysts. In addition, the SDs produced extensive damage to the germinal layer. The increase in the efficacy of ABZ could be due to the improvement of water solubility and wettability of the drug due to the surfactant nature of poloxamer 407. In conclusion, this study is the basis for further research. This pharmacotechnical strategy might in the future offer novel treatment alternatives for human alveolar echinococcosis.
Asunto(s)
Albendazol/farmacología , Antiprotozoarios/farmacología , Portadores de Fármacos/farmacología , Equinococosis/prevención & control , Echinococcus multilocularis/efectos de los fármacos , Poloxámero/farmacología , Animales , Femenino , RatonesRESUMEN
BACKGROUND: Metastasis causes the most breast cancer-related deaths in women. Here, we investigated the antitumor effect of solid lipid nanoparticles (SLN-DTX) when used in the treatment of metastatic breast tumors using 4T1-bearing BALB/c mice. RESULTS: Solid lipid nanoparticles (SLNs) were produced using the high-energy method. Compritol 888 ATO was selected as the lipid matrix, and Pluronic F127 and Span 80 as the surfactants to stabilize nanoparticle dispersion. The particles had high stability for at least 120 days. The SLNs' dispersion size was 128 nm, their polydispersity index (PDI) was 0.2, and they showed a negative zeta potential. SLNs had high docetaxel (DTX) entrapment efficiency (86%), 2% of drug loading and showed a controlled drug-release profile. The half-maximal inhibitory concentration (IC50) of SLN-DTX against 4T1 cells was more than 100 times lower than that of free DTX after 24 h treatment. In the cellular uptake test, SLN-DTX was taken into the cells significantly more than free DTX. The accumulation in the G2-M phase was significantly higher in cells treated with SLN-DTX (73.7%) than in cells treated with free DTX (23.0%), which induced subsequent apoptosis. TEM analysis revealed that SLN-DTX internalization is mediated by endocytosis, and fluorescence microscopy showed DTX induced microtubule damage. In vivo studies showed that SLN-DTX compared to free docetaxel exhibited higher antitumor efficacy by reducing tumor volume (p < 0.0001) and also prevented spontaneous lung metastasis in 4T1 tumor-bearing mice. Histological studies of lungs confirmed that treatment with SLN-DTX was able to prevent tumor. IL-6 serum levels, ki-67 and BCL-2 expression were analyzed and showed a remarkably strong reduction when used in a combined treatment. CONCLUSIONS: These results indicate that DTX-loaded SLNs may be a promising carrier to treat breast cancer and in metastasis prevention.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Docetaxel/farmacología , Lípidos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Nanopartículas/química , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Portadores de Fármacos/farmacología , Ácidos Grasos/farmacología , Femenino , Hexosas/farmacología , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Tamaño de la Partícula , Poloxámero/farmacologíaRESUMEN
The ependyma of the adult spinal cord is a latent stem cell niche that is reactivated by spinal cord injury contributing new cells to the glial scar. The cellular events taking place in the early stages of the reaction of the ependyma to injury remain little understood. Ependymal cells are functionally heterogeneous with a mitotically active subpopulation lining the lateral domains of the central canal (CC) that are coupled via gap junctions. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. Thus, we hypothesized that communication via connexins in the CC is developmentally regulated and may play a part in the reactivation of this latent stem cell niche after injury. To test these possibilities, we combined patch-clamp recordings of ependymal cells with immunohistochemistry for various connexins in the neonatal and the adult (P > 90) normal and injured spinal cord of male and female mice. We find that coupling among ependymal cells is downregulated as postnatal development proceeds but increases after injury, resembling the immature CC. The increase in gap junction coupling in the adult CC was paralleled by upregulation of connexin 26, which correlated with the resumption of proliferation and a reduction of connexin hemichannel activity. Connexin blockade reduced the injury-induced proliferation of ependymal cells. Our findings suggest that connexins are involved in the early reaction of ependymal cells to injury, representing a potential target to improve the contribution of the CC stem cell niche to repair.SIGNIFICANCE STATEMENT Ependymal cells in the adult spinal cord are latent progenitors that react to injury to support some degree of endogenous repair. Understanding the mechanisms by which these progenitor-like cells are regulated in the aftermath of spinal cord injury is critical to design future manipulations aimed at improving healing and functional recovery. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. We find here that connexin signaling in the ependyma changes after injury of the adult spinal cord, functionally resembling the immature active-stem cell niche of neonatal animals. Our findings suggest that connexins in ependymal cells are potential targets to improve self-repair of the spinal cord.
Asunto(s)
Conexinas/fisiología , Proteínas del Tejido Nervioso/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Nicho de Células Madre/fisiología , Factores de Edad , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Membrana Celular/fisiología , Permeabilidad de la Membrana Celular , Conexinas/antagonistas & inhibidores , Epéndimo/citología , Epéndimo/crecimiento & desarrollo , Femenino , Colorantes Fluorescentes/farmacocinética , Uniones Comunicantes/fisiología , Hidrogeles , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Técnicas de Placa-Clamp , Péptidos/química , Péptidos/farmacología , Poloxámero/farmacología , Distribución AleatoriaRESUMEN
BACKGROUND: New formulations for topical treatment of ulcerative colitis with budesonide inclusion complex (BUDHP-ß-CD) and poloxamers (PL) were developed for future clinical use. AIMS: This study evaluated the efficacy of such novel formulations in a rat model of colitis. METHODS: The PL-BUDHP-ß-CD systems were prepared by direct dispersion of the complex (BUD concentration 0.5 mg mL-1) in solutions with PL407 or PL403. Male Wistar rats underwent TNBS-induced colitis and were treated for 5 days by a rectal route, as follows: BUD 1: BUDHP-ß-CD + PL407 (18%); BUD 2: BUDHP-ß-CD + PL407 (20%); BUD 3: BUDHP-ß-CD + PL407 (18%) + PL403 (2%); BUD 4: plain BUD; BUD 5: BUDHP-ß-CD; C1: HP-ß-CD + PL407 (18%); C2: HP-ß-CD + PL407 (20%); C3: HP-ß-CD + PL407 (18%) + PL403 (2%); C4: saline. A negative control group without colitis was also used. Colitis was assessed via myeloperoxidase (MPO) activity, and macroscopic and microscopic damage score in colon tissues. Protein levels of TNF-α, IL-1ß, IL-10 and endogenous glucocorticoids were obtained using ELISA. RESULTS: BUDHP-ß-CD poloxamer formulations had similar MPO activity when compared with the negative control group. All formulations presented lower MPO activity than BUDHP-ß-CD and plain BUD (p < 0.001). BUD 2 produced lower microscopic score values than plain BUD and BUDHP-ß-CD (p < 0.01). All formulations with BUDHP-ß-CD poloxamers reduced TNF-α levels (p < 0.05). CONCLUSION: Novel budesonide inclusion complex formulations improved microscopic damage and reduced colonic MPO activity and TNF-α levels.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/farmacología , Budesonida/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Hidrogeles/farmacología , Poloxámero/farmacología , Animales , Modelos Animales de Enfermedad , Combinación de Medicamentos , Masculino , Ratas , Ratas WistarRESUMEN
One of the main toxicities associated to intravenous administration of amphiphilic drugs is pronounced hemolytic activity. To overcome this limitation, we investigated the anti-hemolytic properties of polymeric micelles of Pluronics, triblock copolymers of poly(ethylene oxide) and poly(propylene oxide). We studied the encapsulation of the amphiphilic compound miltefosine (HePC) into polymeric micelles of Pluronics F108, F68, F127, L44, and L64. In vitro hemolysis indicated that, among the five copolymers studied, only F127 completely inhibited hemolytic effect of HePC at 50 µg/mL, this effect was also observed for other two amphiphilic molecules (cetyltrimethylammonium bromide and cethylpyridinium chloride). To better understand this interaction, we analyzed the HC50 (concentration causing 50% of hemolysis) for HePC free and loaded into F127 micelles. Copolymer concentration influenced the hemolytic profile of encapsulated HePC; for F127 the HC50 increased relative to free HePC (40 µg/mL) up to 184, 441, 736 and 964 µg/mL, for 1, 3, 6 and 9% F127, respectively. Interestingly, a linear relationship was found between HC50-HePC and F127 concentration. At 3% of F127, it is possible to load up to 300 µg/mL of HePC with no hemolytic effect. By achieving this level of hemolysis protection, a promising application is on the view, bringing the parenteral use of HePC and other amphiphilic drugs. Additionally, small-angle X-ray scattering (SAXS) was used to asses structural information on the interactions between HePC and F127 micelles.
Asunto(s)
Antifúngicos/farmacología , Portadores de Fármacos , Hemólisis/efectos de los fármacos , Fosforilcolina/análogos & derivados , Tensoactivos/farmacología , Animales , Antifúngicos/química , Cetrimonio/química , Cetrimonio/farmacología , Cetilpiridinio/química , Cetilpiridinio/farmacología , Relación Dosis-Respuesta a Droga , Composición de Medicamentos/métodos , Eritrocitos/efectos de los fármacos , Micelas , Fosforilcolina/química , Fosforilcolina/farmacología , Poloxámero/química , Poloxámero/farmacología , Ovinos , Tensoactivos/químicaRESUMEN
Poloxamer block copolymers (also known as Pluronic®) are particularly useful for drug delivery and self-assembly techniques. These nanopolymers are generally considered to be biologically inert and they were used to generate only bacteria repellent surfaces but keeps bacteria alive and as a latent threat. However, the inherent capabilities of these nanopolymers to kill bacteria have been largely overlooked. Here, we report that Pluronic shaped as superstructures (self-organized array of micelles) in fact possess a broad-spectrum bactericidal activity (capability of killing bacteria) similar to that shown for some antibiotics. This further represents the first report that shows that appropriate control of superstructured mesophase architecture is a key parameter for bactericidal efficacy. Based on this finding, we have developed a highly bactericidal coating (>99.9% kill) against all tested Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative (Salmonella typhimurium LT2, Escherichia coli K12 and Pseudomonas aeruginosa PAO1) bacteria which moreover allows the adhesion and proliferation of mammalian cells. The inexpensiveness and ease of production make these versatile nanopolymer structures a powerful tool for the development of a new generation of highly effective antimicrobial coatings.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Nanoestructuras/química , Poloxámero/química , Poloxámero/farmacología , Bacillus subtilis/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacos , Salmonella typhimurium/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacosRESUMEN
Leishmaniasis is a neglected disease and drugs approved for its treatment often lead to abandonment, failure of therapy and even death. Photodynamic therapy (PDT) has been shown to be a promising, non-invasive and selective for a target region without requiring high-cost technology. Usually, it is employed a photosensitizing agent (PS) incorporated into nanoparticles (NP). Pluronics® P-123 and F-127 micelles are very interesting aqueous NP promoting efficient and selective delivery and less adverse effects. This study aimed to detect the activity of Pluronics® P-123 and F-127 themselves since there is a scarcity of data on these NP activities without drugs incorporation. This study evaluated, in vitro, the activity of Pluronics® against promastigotes and amastigotes of Leishmania amazonensis and also their cytotoxicities. Additionally, the determination of the mitochondria membrane potential in promastigotes, internalization of these Pluronics® in the parasite membrane and macrophages and its stability in the culture medium was evaluated. Results showed that Pluronics® did not cause significant damage to human red cells and promastigotes. The P-123 and F-127 inhibited the survival rate of L. amazonensis amastigotes, and also presented loss of mitochondrial membrane potential on promastigotes. The Pluronics® showed low cytotoxic activity on J774A.1 macrophages, while only P-123 showed moderate cytotoxicity for BALB/c macrophages. The stability of P-123 and F-127 in culture medium was maintained for ten days. In conclusion, the NP studied can be used for incorporating potent leishmanicidal chemotherapy, due to their selectivity towards macrophages, being a promising system for the treatment of cutaneous leishmaniasis.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Leishmania/efectos de los fármacos , Nanopartículas/química , Fotoquimioterapia/métodos , Poloxámero/farmacología , Animales , Relación Dosis-Respuesta a Droga , Eritrocitos/efectos de los fármacos , Femenino , Macrófagos/efectos de los fármacos , Potencial de la Membrana Mitocondrial , Ratones , Ratones Endogámicos BALB CRESUMEN
The skin wounds cause serious burden to healthcare systems. The lack of sterility of the innate barrier function of the skin facilitates the development of microbial communities within the wound environment especially in biofilm form. Since biofilm is difficult to eradicate, new treatments have been established, such as silver nanoparticles (AgNPs), which antimicrobial and anti-biofilm properties have been studied, nevertheless, their toxic effects are known too. Different concentrations of AgNPs stabilized with a biocompatible and thermo-reversible vehicle as hydrogel Pluronic F-127 were synthesized, those formulations presented interesting thermo-reversibility which could be used to apply on wounds. The formulations (Gel 62.5, 125, and 250â¯ppm of AgNPs) proposed in this study showed in vitro a total inhibition of clinical strains (Staphylococcus aureus and Pseudomonas aeruginosa) in planktonic form, as well as, anti-biofilm activity was archived with the formulation of Gel 250â¯ppm, a total inhibition of biofilm formation with mixed culture was registered in the first 30â¯min of biofilm growth; even more, the viability of human fibroblasts with all gels formulations was >95%, in contrast to silver sulfadiazine cream 1% which showed the highest cytotoxic effect. PF-127 gel with AgNPs could be a prophylactic treatment for skin wounds, because its activity in critical steps on biofilm formation.
Asunto(s)
Biopelículas/efectos de los fármacos , Citotoxinas , Hidrogeles , Nanopartículas del Metal , Poloxámero , Pseudomonas aeruginosa/fisiología , Plata , Piel/lesiones , Staphylococcus aureus/fisiología , Heridas y Lesiones/tratamiento farmacológico , Biopelículas/crecimiento & desarrollo , Citotoxinas/química , Citotoxinas/farmacología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Hidrogeles/química , Hidrogeles/farmacología , Masculino , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Poloxámero/química , Poloxámero/farmacología , Plata/química , Plata/farmacología , Piel/metabolismo , Piel/patología , Heridas y Lesiones/metabolismo , Heridas y Lesiones/patologíaRESUMEN
The increasing and alarming panorama of bacterial infections and associated morbidities that occur during medical and hospital procedures makes the development of technologies that aid in controlling such bacterial infections of utmost importance. Recent studies have shown that formulations with metal nanoparticles exhibit good antibacterial properties against a broad spectrum of microorganisms. Moreover, it was demonstrated that some biologically active polymeric materials, when applied in combination with chemical antimicrobial agents, enhance the therapeutic action of the latter. The research effort entertained herein aimed at the physico-chemical characterisation of silver nanoparticles obtained by chemical reduction, stabilised by bioactive polymers polyvinyl alcohol and polyvinylpyrrolidone, and further co-stabilised by pluronic F68. Scanning electron microscopy images of the nanoparticles produced, coated with different stabilisers, have shown that the chemical nature of the stabilisation effect promoted incorporation of pluronic in the nanoparticles and was closely related to an increase in the silver concentration in the nanoparticle samples obtained via energy-dispersive X-ray spectroscopy. The study described herein also shows that the nature of the stabiliser favours the interaction of pluronic F68 with samples containing silver nanoparticles.
Asunto(s)
Nanopartículas del Metal/química , Poloxámero/química , Alcohol Polivinílico/química , Povidona/química , Plata/química , Antibacterianos/farmacología , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Poloxámero/farmacología , Alcohol Polivinílico/farmacología , Povidona/farmacología , Espectrometría por Rayos X , Espectrofotometría Ultravioleta , Staphylococcus aureus/efectos de los fármacosRESUMEN
Nanotechnology development provides new strategies to treat cancer by integration of different treatment modalities in a single multifunctional nanoparticle. In this scenario, we applied the multifunctional Pluronic P123/F127 mixed micelles for Verteporfin-mediated photodynamic therapy in PC3 and MCF-7 cancer cells. Micelles functionalization aimed the targeted delivery by the insertion of biotin moiety on micelle surface and fluorescence image-based through rhodamine-B dye conjugation in the polymer chains. Multifunctional Pluronics formed spherical nanoparticulated micelles that efficiently encapsulated the photosensitizer Verteporfin maintaining its favorable photophysical properties. Lyophilized formulations were stable at least for 6months and readily reconstituted in aqueous media. The multifunctional micelles were stable in protein-rich media due to the dual Pluronic mixed micelles characteristic: high drug loading capacity provided by its micellar core and high kinetic stability due its biocompatible shell. Biotin surface functionalized micelles showed higher internalization rates due biotin-mediated endocytosis, as demonstrated by competitive cellular uptake studies. Rhodamine B-tagged micelles allowed monitoring cellular uptake and intracellular distribution of the formulations. Confocal microscopy studies demonstrated a larger intracellular distribution of the formulation and photosensitizer, which could drive Verteporfin to act on multiple cell sites. Formulations were not toxic in the dark condition, but showed high Verteporfin-induced phototoxicity against both cancer cell lines at low drug and light doses. These results point Verteporfin-loaded multifunctional micelles as a promising tool to further developments in photodynamic therapy of cancer.
Asunto(s)
Portadores de Fármacos , Micelas , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Fotoquimioterapia , Poloxaleno , Poloxámero , Porfirinas , Nanomedicina Teranóstica/métodos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Femenino , Humanos , Células MCF-7 , Masculino , Neoplasias/metabolismo , Neoplasias/patología , Poloxaleno/química , Poloxaleno/farmacocinética , Poloxaleno/farmacología , Poloxámero/química , Poloxámero/farmacocinética , Poloxámero/farmacología , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacología , VerteporfinaRESUMEN
ABSTRACT Metronidazole (MTZ) is widely used as the standard antibiotic for the treatment of rosacea and, more recently, is being used off label in Brazilian hospitals for the treatment of wounds. Following oral administration, minimal amounts of active agent reaches the skin and side effects are strongly induced. Consequently, MTZ is currently being applied topically in order to improve the therapeutic efficacy with reduced side effects, with Rozex(r) (RZ) (an MTZ gelled formulation) being the only marketed product. This study examined whether the use of MTZ 0.75% from thermogel formulations could improve drug retention and reduce dermal exposure compared to that by Rozex(r). Following a 21 h permeation study, the highest total amount of MTZ permeated through the rat healthy and disturbed skin was seen with Rozex(r), but similar to all formulations regardless of the skin condition. On the other hand, the amount retained in the epidermis/dermis was larger for thermogel formulations; at least 4 fold that of Rozex(r), when the stratum corneum was present as a barrier. In conclusion, thermogel formulations can be favorable alternatives to Rozex(r) for the topical application of MTZ with improved efficacy and reduced side effects.
Asunto(s)
Animales , Ratas , Piel/diagnóstico por imagen , Termogénesis , Metronidazol/análisis , Anomalías Cutáneas/complicaciones , Rosácea/prevención & control , Poloxámero/farmacología , Dermatología/clasificaciónRESUMEN
In this study, we reported the development and the physico-chemical characterization of poloxamer 407 (PL407) and poloxamer 188 (PL188) binary systems as hydrogels for delivering ropivacaine (RVC), as drug model, and investigate their use in infiltrative local anesthesia for applications on the treatment of post-operative pain. We studied drug-micelle interaction and micellization process by light scattering and differential scanning calorimetry (DSC), the sol-gel transition and hydrogel supramolecular structure by small-angle-X-ray scattering (SAXS) and morphological evaluation by Scanning Electron Microscopy (SEM). In addition, we have presented the investigation of drug release mechanisms, in vitro/in vivo toxic and analgesic effects. Micellar dimensions evaluation showed the formation of PL407-PL188 mixed micelles and the drug incorporation, as well as the DSC studies showed increased enthalpy values for micelles formation after addition of PL 188 and RVC, indicating changes on self-assembly and the mixed micelles formation evoked by drug incorporation. SAXS studies revealed that the phase organization in hexagonal structure was not affected by RVC insertion into the hydrogels, maintaining their supramolecular structure. SEM analysis showed similar patterns after RVC addition. The RVC release followed the Higuchi model, modulated by the PL final concentration and the insertion of PL 188 into the system. Furthermore, the association PL407-PL188 induced lower in vitro cytotoxic effects, increased the duration of analgesia, in a single-dose model study, without evoking in vivo inflammation signs after local injection.
Asunto(s)
Anestesia Local/métodos , Sistemas de Liberación de Medicamentos/métodos , Hidrogeles , Poloxámero , Células 3T3 , Animales , Evaluación Preclínica de Medicamentos , Hidrogeles/química , Hidrogeles/farmacocinética , Hidrogeles/farmacología , Masculino , Ratones , Micelas , Poloxámero/química , Poloxámero/farmacocinética , Poloxámero/farmacología , Ratas , Ratas WistarRESUMEN
The development of specific tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia (CML). However, chemoresistance of tumor cells to TKIs has already been described, and several mechanisms account for the multidrug resistance (MDR) phenotypes, including the overexpression of P-glycoprotein (P-gp). This decreases the rate of healing and complete tumor remission. Nanotechnological tools have been studied to allow advances in this field. Poloxamers (Pluronics(®)) have been proposed as drug carriers to improve therapeutic efficacy and decrease side effects, even in cancer therapy, due to their ability to inhibit P-gp. Antipsychotic phenothiazines have been described as potent cytotoxic drugs against several types of tumor cells in vitro. Here, we show that nanostructured micellar systems containing the phenothiazine derivative chlorpromazine (CPZ) potentiated the cytotoxicity of free CPZ and increased the selectivity against CML tumor cells, demonstrating the pharmacological potential of these poloxamer-based nanostructured systems containing CPZ in cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Clorpromazina/farmacología , Portadores de Fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Nanomedicina/métodos , Nanopartículas , Poloxámero/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Clorpromazina/química , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Liberación de Fármacos , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Micelas , Poloxámero/química , Solubilidad , Factores de TiempoRESUMEN
Various animal models of hyperlipidemia are used in research. Four rodent hyperlipidemia experimental models are examined in this study: three chronic hyperlipidemia models based on dietary supplementation with lipid or sucrose for 3 months and one acute hyperlipidemia model based on administration of the nonionic surfactant poloxamer. Neither lipid supplementation nor sucrose supplementation in Wistar rats was effective for establishing hyperlipidemia. Combining both lipid and sucrose supplementation in BALB/c mice induced hypercholesterolemia, as reflected in a considerable increase in blood cholesterol concentration, but did not produce an increase in blood triglyceride concentration. Poloxamer administration in C57BL/J6 mice produced increases in blood cholesterol and triglyceride concentrations. The authors conclude that supplementation of both lipid and sucrose in BALB/c mice was the most effective method for developing chronic hypercholesterolemia.
Asunto(s)
Alimentación Animal/análisis , Dieta , Suplementos Dietéticos , Modelos Animales de Enfermedad , Hiperlipidemias/etiología , Animales , Lípidos/administración & dosificación , Lípidos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Poloxámero/administración & dosificación , Poloxámero/farmacología , Ratas , Ratas Wistar , Sacarosa/administración & dosificación , Sacarosa/farmacologíaRESUMEN
Aluminum Chloride Phthalocyanine (AlPcCl) can be used as a photosensitizer (PS) for Photodynamic Inactivation of Microorganisms (PDI). The AlPcCl showed favorable characteristics for PDI due to high quantum yield of singlet oxygen (ΦΔ ) and photostability. Physicochemical properties and photodynamic inactivation of AlPcCl incorporated in polymeric micelles of tri-block copolymer (P-123 and F-127) against microorganisms Staphylococcus aureus, Escherichia coli and Candida albicans were investigated in this work. Previously, it was observed that the AlPcCl undergoes self-aggregation in F-127, while in P-123 the PS is in a monomeric form suitable for PDI. Due to the self-aggregation of AlPcCl in F-127, this formulation did not show any effect on these microorganisms. On the other hand, AlPcCl formulated in P-123 was effective against S. aureus and C. albicans and the death of microorganisms was dependent on the PS concentration and illumination time. Additionally, it was found that the values of PS concentration and illumination time to eradicate 90% of the initial population of microorganisms (IC90 and D90 , respectively) were small for the AlPcCl in P-123, showing the effectiveness of this formulation for PDI.
Asunto(s)
Candida albicans/efectos de los fármacos , Indoles/química , Micelas , Viabilidad Microbiana/efectos de los fármacos , Compuestos Organometálicos/química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Poloxámero/análogos & derivados , Poloxámero/química , Staphylococcus aureus/efectos de los fármacos , Cloruro de Aluminio , Luz , Fármacos Fotosensibilizantes/efectos de la radiación , Poloxámero/farmacología , Staphylococcus aureus/efectos de la radiaciónRESUMEN
We investigated the structure of the binary mixture of Pluronic F-127 (PL F-127) and Pluronic L-81 (PL L-81), as hydrogels for sumatriptan delivery and investigated the mixture possible use via subcutaneous route for future applications as a long-acting antimigraine formulation. We studied the drug-micelle interaction by dynamic light scattering and differential scanning calorimetry, sol-gel process by rheology, and small-angle X-ray scattering (SAXS). We also employed pharmaceutical formulation aspects by dissolution rate, release profile, and cytotoxicity studies for apoptosis and/or necrosis in fibroblasts (3T3) and neural cells (Neuro 2a). Micellar hydrodynamic diameter studies revealed the formation of binary PL-micelles by association of PL F-127/PL L-81. The mixed micelle and binary hydrogels formation was also verified by only one phase transition temperature for all formulations, even in the presence of sumatriptan. The characterization of the hydrogel supramolecular organization by SAXS, rheology studies, and in vitro dissolution/release results showed a probable relationship between the transition of the lamellar to the hexagonal phase and the lower release constant values observed, indicating that PL L-81 participates in micelle-hydrogel formation and aggregation processes. Furthermore, the reduced cytotoxicity (annexin V-fluorescein isothiocyanate positive staining), with minor PL L-81 concentration, points to its potential use for the development of binary PL-systems containing sumatriptan capable of modulating the gelation process. This use may employ the minimum PL concentration and be interesting for pharmaceutical applications, particularly for migraine treatment.