RESUMO
The main cause of subretinal neovascularisation in wet age-related macular degeneration (AMD) is an abnormal expression in the retinal pigment epithelium (RPE) of the vascular endothelial growth factor (VEGF). Current approaches for the treatment of AMD present considerable issues that could be overcome by encapsulating anti-VEGF drugs in suitable nanocarriers, thus providing better penetration, higher retention times, and sustained release. In this work, the ability of large pore mesoporous silica nanoparticles (LP-MSNs) to transport and protect nucleic acid molecules is exploited to develop an innovative LP-MSN-based nanosystem for the topical administration of anti-VEGF siRNA molecules to RPE cells. siRNA is loaded into LP-MSN mesopores, while the external surface of the nanodevices is functionalised with polyethylenimine (PEI) chains that allow the controlled release of siRNA and promote endosomal escape to facilitate cytosolic delivery of the cargo. The successful results obtained for VEGF silencing in ARPE-19 RPE cells demonstrate that the designed nanodevice is suitable as an siRNA transporter.
Assuntos
Nanopartículas , Fator A de Crescimento do Endotélio Vascular , RNA Interferente Pequeno/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Dióxido de Silício/metabolismo , Epitélio Pigmentado da Retina/metabolismoRESUMO
Cancer-related opportunistic bacterial infections are one major barrier for successful clinical therapies, often correlated to the production of genotoxic factors and higher cancer incidence. Although dual anticancer and antimicrobial therapies are a growing therapeutic fashion, they still fall short when it comes to specific delivery and local action in in vivo systems. Nanoparticles are seen as potential therapeutic vectors, be it by means of their intrinsic antibacterial properties and effective delivery capacity, or by means of their repeatedly reported modulation and maneuverability. Herein we report on the production of a biocompatible, antimicrobial magneto-fluorescent nanosystem (NANO3) for the delivery of a dual doxorubicin-ofloxacin formulation against cancer-related bacterial infections. The drug delivery capacity, rendered by its mesoporous silica matrix, is confirmed by the high loading capacity and stimuli-driven release of both drugs, with preference for tumor-like acidic media. The pH-dependent emission of its surface fluorescent SiQDs, provides an insight into NANO3 surface behavior and pore availability, with the SiQDs working as pore gates. Hyperthermia induces heat generation to febrile temperatures, doubling drug release. NANO3-loaded systems demonstrate significant antimicrobial activity, specifically after the application of hyperthermia conditions. NANO3 structure and antimicrobial properties confirm their potential use in a future dual anticancer and antimicrobial therapeutical vector, due to their drug loading capacity and their surface availability for further modification with bioactive, targeting species.
Assuntos
Anti-Infecciosos , Neoplasias Colorretais , Hipertermia Induzida , Nanopartículas , Humanos , Portadores de Fármacos/química , Ofloxacino , Porosidade , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Doxorrubicina/química , Dióxido de Silício/química , Nanopartículas/química , Liberação Controlada de Fármacos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Sistemas de Liberação de MedicamentosRESUMO
Inâ vivo detection of cellular senescence is accomplished by using mesoporous silica nanoparticles loaded with the NIR-FDA approved Nile blue (NB) dye and capped with a galactohexasaccharide (S3). NB emission at 672â nm is highly quenched inside S3, yet a remarkable emission enhancement is observed upon cap hydrolysis in the presence of ß-galactosidase and dye release. The efficacy of the probe to detect cellular senescence is tested inâ vitro in melanoma SK-Mel-103 and breast cancer 4T1 cells and inâ vivo in palbociclib-treated BALB/cByJ mice bearing breast cancer tumor.
Assuntos
Senescência Celular/imunologia , Corantes Fluorescentes/uso terapêutico , Animais , Feminino , Humanos , Camundongos , OxazinasRESUMO
The antimicrobial activity of essential oils components (EOCs) is well-known. However, their high volatility and powerful aroma limit their application in the formulation of a wide range of food products. In this context, the antimicrobial activity of carvacrol, eugenol, thymol and vanillin grafted onto the surface of three silica supports with different morphologies, textural properties and chemical reactivities (fumed silica, amorphous silica and MCM-41) was evaluated herein. Materials characterization revealed a good immobilization yield and all the devices showed a micro-scale particle size. Sensory evaluation revealed that sensory perception of EOCs decreases after covalent immobilization. Moreover, immobilization greatly enhanced the antimicrobial activity of the essential oil components against Listeria innocua and Escherichia coli compared to free components. The incorporation of EOCs immobilized on silica particles into pasteurized milk inoculated with L. innocua demonstrated their effectiveness not only for in vitro conditions, but also in a real food system.
Assuntos
Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Testes de Sensibilidade Microbiana , Monoterpenos , Óleos Voláteis , Dióxido de Silício , TimolRESUMO
Acute inflammation is a protective response of the body to harmful stimuli, such as pathogens or damaged cells. However, dysregulated inflammation can cause secondary damage and could thus contribute to the pathophysiology of many diseases. Inflammasomes, the macromolecular complexes responsible for caspase-1 activation, have emerged as key regulators of immune and inflammatory responses. Therefore, modulation of inflammasome activity has become an important therapeutic approach. Here we describe the design of a smart nanodevice that takes advantage of the passive targeting of nanoparticles to macrophages and enhances the therapeutic effect of caspase-1 inhibitor VX-765 in vivo. The functional hybrid systems consisted of MCM-41-based nanoparticles loaded with anti-inflammatory drug VX-765 (S2-P) and capped with poly-L-lysine, which acts as a molecular gate. S2-P activity has been evaluated in cellular and in vivo models of inflammation. The results indicated the potential advantage of using nanodevices to treat inflammatory diseases.
Assuntos
Anti-Inflamatórios/administração & dosagem , Inibidores de Caspase/administração & dosagem , Dipeptídeos/administração & dosagem , Portadores de Fármacos/química , Inflamassomos/antagonistas & inibidores , Nanopartículas/química , Dióxido de Silício/química , para-Aminobenzoatos/administração & dosagem , Animais , Anti-Inflamatórios/farmacologia , Inibidores de Caspase/farmacologia , Linhagem Celular , Preparações de Ação Retardada/química , Dipeptídeos/farmacologia , Humanos , Inflamassomos/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/ultraestrutura , para-Aminobenzoatos/farmacologiaRESUMO
New capped silica mesoporous nanoparticles for intracellular controlled cargo release within cathepsinâ B expressing cells are described. Nanometric mesoporous MCM-41 supports loaded with safraninâ O (S1-P) or doxorubicin (S2-P) containing a molecular gate based on a cathepsinâ B target peptidic sequence were synthesized. Solids were designed to show "zero delivery" and to display cargo release in the presence of cathepsinâ B enzyme, which selectively hydrolyzed in vitro the capping peptide sequence. Controlled delivery in HeLa, MEFs WT, and MEFs lacking cathepsinâ B cell lines were also tested. Release of safraninâ O and doxorubicin in these cells took place when cathepsinâ B was active or present. Cells treated with S2-P showed a fall in cell viability due to nanoparticles internalization, cathepsinâ B hydrolysis of the capping peptide, and cytotoxic agent delivery, proving the possible use of these nanodevices as new therapeutic tools for cancer treatment.
Assuntos
Catepsina B/metabolismo , Nanopartículas/química , Peptídeos/química , Dióxido de Silício/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Células HeLa , Humanos , Peptídeos/síntese química , Peptídeos/metabolismo , PorosidadeRESUMO
Changes in the conformation of a peptide anchored onto the external surface of mesoporous silica nanoparticles have been used to design novel temperature-controlled delivery systems.