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1.
Pharm Biol ; 55(1): 1899-1908, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28644062

RESUMO

CONTEXT: 4-Nerolidylcatechol (4-NRC) has showed antitumor potential through apoptosis. However, its apoptotic mechanisms are still unclear, especially in leukemic cells. OBJECTIVES: To evaluate the cytotoxic potential of 4-NRC and its cell death pathways in p53-null K562 leukemic cells. MATERIALS AND METHODS: Cytotoxicity of 4-NRC (4.17-534.5 µM) over 24 h of exposure was evaluated by MTT assay. 4-NRC-induced apoptosis in K562 cells was investigated by phosphatidylserine (PS) externalization, cell cycle, sub-G1, mitochondrial evaluation, cytochrome c, cyclin D1 and intracellular reactive oxygen species (ROS) levels, and caspase activity analysis. RESULTS: IC50 values obtained were 11.40, 27.31, 15.93 and 15.70 µM for lymphocytes, K562, HL-60 and Jurkat cells, respectively. In K562 cells, 4-NRC (27 µM) promoted apoptosis as verified by cellular morphological changes, a significant increase in PS externalization and sub-G1 cells. Moreover, it significantly arrested the cells at the G0/G1 phase due to a reduction in cyclin D1 expression. These effects of 4-NRC also significantly promoted a reduction in mitochondrial activity and membrane depolarization, accumulation of cytosolic cytochrome c and ROS overproduction. Additionally, it triggered an increase in caspases -3/7, -8 and -9 activities. When the cells were pretreated with N-acetyl-l-cysteine ROS scavenger, 4-NRC-induced apoptosis was partially blocked, which suggests that it exerts cytotoxicity though not exclusively through ROS-mediated mechanisms. DISCUSSION AND CONCLUSION: 4-NRC has antileukemic properties, inducing apoptosis mediated by mitochondrial-dependent mechanisms with cyclin D1 inhibition. Given that emerging treatment concepts include novel combinations of well-known agents, 4-NRC could offer a promising alternative for chemotherapeutic combinations to maximize tumour suppression.


Assuntos
Apoptose/fisiologia , Catecóis/farmacologia , Ciclina D1/metabolismo , Fase G1/fisiologia , Mitocôndrias/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Ciclina D1/antagonistas & inibidores , Relação Dose-Resposta a Droga , Fase G1/efeitos dos fármacos , Células HL-60 , Humanos , Células Jurkat , Células K562 , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Mitocôndrias/efeitos dos fármacos
2.
Pharm Res ; 31(5): 1106-19, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24170281

RESUMO

PURPOSE: The purpose of this work was the development of a multicompartimental nanocarrier for the simultaneous encapsulation of paclitaxel (PTX) and genistein (GEN), associating antiangiogenic and cytotoxic properties in order to potentiate antitumoral activity. METHOD: Polymeric nanocapsules containing PTX were obtained by interfacial deposition of preformed polymer and coated with a phospholipid bilayer entrapping GEN. Physical-chemical and morphological characteristics were characterized, including size and size distribution, drug entrapment efficiency and drug release profile. In vivo studies were performed in EAT bearing Swiss mice. RESULTS: Entrapment efficiency for both drugs in the nanoparticles was approximately 98%. Average particle diameter was 150 nm with a monomodal distribution. In vitro assays showed distinct temporal drug release profiles for each drug. The dose of 0.2 mg/kg/day of PTX resulted in 11% tumor inhibition, however the association of 12 mg/kg/day of GEN promoted 44% tumor inhibition and a 58% decrease in VEGF levels. CONCLUSIONS: Nanoparticles containing GEN and PTX with a temporal pattern of drug release indicated that the combined effect of cytotoxic and antiangiogenic drugs present in the formulation contributed to the overall enhanced antitumor activity of the nanomedicine.


Assuntos
Antineoplásicos/uso terapêutico , Vasos Sanguíneos/metabolismo , Sistemas de Liberação de Medicamentos , Nanopartículas , Neoplasias Experimentais/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Genisteína/administração & dosagem , Genisteína/uso terapêutico , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Neoplasias Experimentais/patologia , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico
3.
J Pharm Sci ; 106(5): 1363-1370, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28159639

RESUMO

The aim of this study was to develop mucoadhesive pellets on a thiolated pectin base using the extrusion-spheronization technique. Thiolation of pectin was performed by esterification with thioglycolic acid. The molecular weight and thiol group content of the pectins were determined. Pellets containing pectin, microcrystalline cellulose, and ketoprofen were prepared and their mucoadhesive properties were evaluated through a wash-off test using porcine intestinal mucosa. The in vitro ketoprofen release was also evaluated. Thiolated pectin presented a thiol group content of 0.69 mmol/g. Thiolation caused a 13% increase in polymer molecular weight. Pellets containing thiolated pectin were still adhering to the intestinal mucosa after 480 min and showed a more gradual release of ketoprofen. Conversely, pellets prepared with nonthiolated pectin showed rapid disintegration and detached after only 15 min. It can be concluded that thiolated pectin-based pellets can be considered a potential platform for the development of mucoadhesive drug delivery systems for the oral route.


Assuntos
Adesivos/síntese química , Química Farmacêutica/métodos , Implantes de Medicamento/síntese química , Compostos de Sulfidrila/síntese química , Adesivos/metabolismo , Adesivos/farmacologia , Animais , Implantes de Medicamento/metabolismo , Implantes de Medicamento/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Pectinas , Compostos de Sulfidrila/metabolismo , Compostos de Sulfidrila/farmacologia , Suínos
4.
Toxicology ; 376: 83-93, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27129947

RESUMO

A new molecule, LQFM048, originally designed through molecular hybridization using green chemistry approach, is in development as a photoprotective agent. Eye irritation, skin toxicity and genotoxicity evaluations are mandatory for predicting health risks. In this context, the purpose of this study was to investigate the eye irritation potential of LQFM048 by combining Short Time Exposure (STE), Bovine Corneal Opacity and Permeability (BCOP) associated with corneal histomorphometry and Hen's Egg Test-Chorioallantoic Membrane (HET-CAM). Additionally, skin toxicity was evaluated by interleukin-18 production in the HaCaT keratinocyte, Local Lymph Node Assay (LLNA:BrdU-ELISA) method, 3T3 Neutral red uptake (NRU) assay and in vivo phototoxicity test. Genotoxic potential of LQFM048 was also analyzed by cytokinesis-block micronucleus assay (MNvit test-cytoB) in HepG2 cells. Our results showed that LQFM048 did not induce eye irritation and it was classified as UN GHS No Category for both STE and BCOP assays and non-irritating for HET-CAM test. LQFM048 showed non-potential skin sensitization with stimulation index (SI=0.7) in the LLNA:BrdU-ELISA method. Corroborating in vivo tests, it did not promote significant cytotoxicity in HaCaT cells and it showed similar levels of IL-18 when compared to control. Furthermore, LQFM048 induced non-phototoxic potential with photo-irritation factor (PIF) and mean photo effect (MPE) of 1 and -0.138, respectively, for 3T3 cells. Similarly, it was not phototoxic for in vivo testing with or without exposure to UVA, showing SI values of 1 and 1.2, respectively. The micronucleus test showed that LQFM048 was not genotoxic, under the conditions tested.In conclusion, LQFM048, a heterocyclic compound obtained through an environmentally acceptable simple synthetic route, seems to be safe for human use, especially for the development of a new sunscreen product, since it is neither an eye irritant, nor a contact allergen, nor mutagenic and nor phototoxic.


Assuntos
Córnea/efeitos dos fármacos , Irritantes/toxicidade , Pele/efeitos dos fármacos , Protetores Solares/toxicidade , Células 3T3 , Animais , Bovinos , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Sobrevivência Celular/efeitos da radiação , Galinhas , Córnea/fisiologia , Córnea/efeitos da radiação , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Células Hep G2 , Humanos , Irritantes/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Testes de Mutagenicidade/métodos , Distribuição Aleatória , Pele/metabolismo , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos
5.
Vaccine ; 32(34): 4324-32, 2014 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-24951861

RESUMO

BACKGROUND: Tuberculosis is a disease affecting millions of people throughout the world. One of the main problems in controlling the disease is the low efficacy of the Bacillus Calmette-Guérin (BCG) vaccine in protecting young adults. The development of new vaccines that induce a long-lasting immune response or that stimulate the immunity induced by BCG may improve the control of tuberculosis. METHODS: The use of microstructured liposomes containing HspX, with or without MPL or CpG DNA adjuvants, as vaccines for tuberculosis was evaluated. The HspX-specific humoral and cellular immune responses to the different vaccine formulations were compared. RESULTS: All vaccines containing liposome microparticles and HspX were immunogenic. Vaccines formulated with CpG DNA and HspX induced the strongest humoral and cellular immune responses, mainly by inducing interferon-γ and tumor necrosis factor-α expression by both CD4(+) and CD8(+) T cells. HspX and MPL mainly induced CD8(+) T-cell activation and specific humoral responses. When evaluated the protective efficacy of the formulations against Mycobacterium tuberculosis challenge, the microstructured liposome containing L-HspX and L-HspX-CPG DNA reduced both lung inflammatory lesions and the bacterial load. CONCLUSION: We have thus demonstrated, for the first time, the use of microstructured liposomes as an adjuvant and delivery system for a vaccine formulation against tuberculosis.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Lipossomos/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Adjuvantes Imunológicos/farmacologia , Animais , Anticorpos Antibacterianos/imunologia , Carga Bacteriana , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Ilhas de CpG , Feminino , Imunidade Humoral , Imunoglobulina G/imunologia , Inflamação/imunologia , Interferon gama/imunologia , Pulmão/microbiologia , Pulmão/patologia , Ativação Linfocitária , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis , Fator de Necrose Tumoral alfa/imunologia , Vacinas de Subunidades Antigênicas/imunologia
6.
J Biomed Nanotechnol ; 9(3): 527-34, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23621010

RESUMO

The isoflavone genistein (GEN) is a natural product with potential applications for skin cancer treatment and chemoprevention; however its high lipophilicity and chemical instability limits its clinical use. Therefore, attempts towards protecting GEN against degradation and increasing its penetration in the skin might be a valid approach. In this work, GEN loaded-PLA nanocapsules (GEN-NC) were prepared by interfacial deposition of preformed polymer (nanoprecipitation); physicochemical characterization and stability studies for 90 days were conducted. GEN-NC were incorporated into semi-solid formulations and permeation experiments were carried out using porcine ear skin. GEN-NC optimized formulation presented a mean diameter of 139 +/- 7.31 nm, polydispersity index of 0.128 +/- 0.08, encapsulation efficiency of 89.63 +/- 2.27% and drug loading from 0.6 to 1.4 w/w%. Stability studies demonstrated that nanocapsules did not exhibit aggregation during the 90 days of the assay, however, a drop in encapsulation efficiency was observed in the first 10 days. Permeation experiments demonstrated that a higher amount of GEN reaches deeper layers of the skin and increased penetration was achieved when GEN-NC were incorporated in a semi-solid gel formulation, indicating that GEN-NC might be a promising nanocarrier system for skin delivery of GEN.


Assuntos
Materiais Biocompatíveis/farmacologia , Genisteína/administração & dosagem , Genisteína/farmacologia , Nanocápsulas/química , Poliésteres/química , Absorção Cutânea/efeitos dos fármacos , Administração Tópica , Animais , Biodegradação Ambiental/efeitos dos fármacos , Fenômenos Químicos , Química Farmacêutica , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Microscopia de Força Atômica , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Eletricidade Estática , Sus scrofa
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