RESUMO
BACKGROUND: Currently, considerable efforts to standardize methods for accurate assessment of properties and safety aspects of nanomaterials are being made. However, immunomodulation effects upon skin exposure to nanomaterial have not been explored. OBJECTIVES: To investigate the immunotoxicity of single-wall carbon nanotubes, titanium dioxide, and fullerene using the current mechanistic understanding of skin sensitization by applying the concept of adverse outcome pathway (AOP). METHODS: Investigation of the ability of nanomaterials to interact with skin proteins using the micro-direct peptide reactivity assay; the expression of CD86 cell surface marker using the U937 cell activation test (OECD No. 442E/2018); and the effects of nanomaterials on modulating inflammatory response through inflammatory cytokine release by U937 cells. RESULTS: The nanomaterials easily internalized into keratinocytes cells, interacted with skin proteins, and triggered activation of U937 cells by increasing CD86 expression and modulating inflammatory cytokine production. Consequently, these nanomaterials were classified as skin sensitizers in vitro. CONCLUSIONS: Our study suggests the potential immunotoxicity of nanomaterials and highlights the importance of studying the immunotoxicity and skin sensitization potential of nanomaterials to anticipate possible human health risks using standardized mechanistic nonanimal methods with high predictive accuracy. Therefore, it contributes toward the applicability of existing OECD (Organisation for Economic Co-operation and Development) testing guidelines for accurate assessment of nanomaterial skin sensitization potential.
Assuntos
Rotas de Resultados Adversos , Dermatite Alérgica de Contato/etiologia , Dermatite Alérgica de Contato/imunologia , Fulerenos/efeitos adversos , Nanotubos de Carbono/efeitos adversos , Titânio/efeitos adversos , Antígeno B7-2/metabolismo , Biomarcadores/metabolismo , Citocinas/metabolismo , Dermatite Alérgica de Contato/metabolismo , Células HaCaT , Humanos , Imunomodulação , Queratinócitos/metabolismo , Células U937RESUMO
AIMS: This study evaluated parameters of toxicity and antiproliferative effects of (+)-N(1)-4-fluorobenzaldehyde-N(4)-{1-methyl-1-[(1R)-4-methylcyclohexene-3-il]-ethyl}-thiossemicarbazone (4-FTSC) in PC-3 adenocarcinoma prostate cells. MAIN METHODS: Cytotoxicity of 4-FTSC in PC-3 cells was evaluated using MTT assay. Morphology examination of PC-3 cells treated with 4-FTSC was also performed as well as the cell death mechanisms induced were investigated using flow cytometry. Parameters of toxicity of 4-FTSC was conducted by the investigation of its potential myelotoxicity and lymphotoxicity, hemolytic activity and acute oral toxicity profile. KEY FINDINGS: 4-FTSC showed promising cytotoxic effects against PC-3 cells (IC50â¯=â¯18.46⯵M). It also triggered apoptotic morphological changes, phosphatidylserine externalization and a significant increase of DNA fragmentation in PC-3 cells. Moreover, 4-FTSC did not show changes in the PC-3 cell cycle with levels of p21, p27, NFĸB and cyclin D1 similar to those found in both control and treated cells. 4-FTSC also promoted an increase of p53 levels associated with mitochondrial impairment through loss of ∆Ψm and ROS overproduction. 4-FTSC-induced cell death mechanism in PC-3 cells involved activation of caspase-3/-7 through apoptosis intrinsic pathway via caspase-9. Regarding toxicological profile, 4-FTSC showed in vitro lymphotoxicity, although with low cytotoxicity for bone marrow progenitors and no hemolytic potential. Moreover, it was classified as GHS category 5 (LD50â¯>â¯2000-5000â¯mg/Kg), suggesting it has low acute oral systemic toxicity. SIGNIFICANCE: 4-FTSC seems to be a promising candidate to be used as a clinical tool in prostate cancer treatment. Further studies are required to better clarify its toxicopharmacological effects found in this compound.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzaldeídos/química , Cicloexenos/farmacologia , Neoplasias da Próstata/patologia , Tiossemicarbazonas/farmacologia , Animais , Antineoplásicos/química , Células 3T3 BALB , Benzaldeídos/farmacologia , Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Cicloexenos/química , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Tiossemicarbazonas/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.