RESUMEN
Arsenic trioxide (ATO) is a successful chemotherapeutic drug for blood cancers via selective induction of apoptosis; however its efficacy in solid tumors is limited. Here we repurpose nanodiamonds (NDs) as a safe and potent autophagic inhibitor to allosterically improve the therapeutic efficacy of ATO-based treatment in solid tumors. We find that NDs and ATO are physically separate and functionally target different cellular pathways (autophagy vs. apoptosis); whereas their metabolic coupling in human liver carcinoma cells remarkably enhances programmed cell death. Combination therapy in liver tumor mice model results in ~91% carcinoma decrease as compared with ~28% without NDs. Treated mice show 100% survival rate in 150 days with greatly reduced advanced liver carcinoma-associated symptoms, and ~80% of post-therapy mice survive for over 20 weeks. Our work presents a novel strategy to harness the power of nanoparticles to broaden the scope of ATO-based therapy and more generally to fight solid tumors.
Asunto(s)
Antineoplásicos/uso terapéutico , Trióxido de Arsénico/uso terapéutico , Carcinoma/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Nanodiamantes/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Trióxido de Arsénico/administración & dosificación , Trióxido de Arsénico/efectos adversos , Autofagia/efectos de los fármacos , Carcinoma/patología , Quimioterapia Combinada , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Ratones , Ratones Desnudos , Nanodiamantes/administración & dosificación , Nanodiamantes/efectos adversosRESUMEN
1. Today, diamond nanoparticles have several industrial applications. Nano diamond (ND) as a carbon allotrope diffuses in the air easily during producing and processing procedures. 2. In this study, we investigated sub-acute exposed to ND at the exposure chamber in mice. The animals were divided into two groups (control and exposed group to ND at the concentration of 3 µg/m3 for 3 h/day, 5 days/week for 30 days) in a whole-body inhalation chamber. 3. Our results showed that exposure to ND induced the hematological and biochemical changes. The target organs for ND were the lungs, brain and heart in the mice, respectively. Also, ND increased reactive oxygen species (ROS) generation, lipid peroxidation (LPO), the collapse of mitochondrial membrane potential (MMP), decreased a level of reduced glutathione (GSH) and finally increased a level of glutathione disulfide (GSSG) in lung, brain and heart tissues. Our results suggest that exposure to ND can induce oxidative stress in the tissue mentioned. 4. These results suggest that exposure of researchers and workers with diamond nanoparticles probably increase a risk of respiratory, cardiovascular and cerebral disorders through oxidative stress. However, good ventilation, appropriate personal protective equipment and using of anti-oxidant compounds in daily diet of worker are suggested.
Asunto(s)
Encéfalo/metabolismo , Pulmón/metabolismo , Miocardio/metabolismo , Nanodiamantes/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Administración por Inhalación , Animales , Encéfalo/patología , Disulfuro de Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Pulmón/patología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Miocardio/patología , Oxidación-Reducción/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Nanodiamonds (ND) and silica nanoparticles (SiO2-NP) have been much investigated for their toxicity at high doses, little is known about their biological activity at low concentrations. Here we report the biphasic dose response of ND and SiO2-NP in modulating normal human facial skin fibroblasts (FSF1) in culture. ND and SiO2-NP at low concentration (up to 0.5 µg/ml) had beneficial effects on FSF1 in terms of increasing their proliferation and metabolic activity. Exposure of FSF1 cells to low levels of NP enhanced their wound healing ability in vitro and slowed down aging during serial passaging as measured by maintenance of youthful morphology, reduction in the rate of loss of telomeres, and the over all proliferative characteristics. Furthermore, NP treatment induced the activation of Nrf2- and FOXO3A-mediated cellular stress responses, including an increased expression of heme oxygenease (HO-1), sirtuin (SIRT1), and DNA methyltransferase II (DNMT2). These results imply that ND and SiO2-NP at low doses are potential hormetins, which exert mild stress-induced beneficial hormetic effects through improved survival, longevity, maintenance, repair and function of human cells.
Asunto(s)
Fibroblastos/efectos de los fármacos , Hormesis , Nanopartículas del Metal/efectos adversos , Nanodiamantes/efectos adversos , Dióxido de Silicio/efectos adversos , Relación Dosis-Respuesta a Droga , Cara , Humanos , Piel/efectos de los fármacosRESUMEN
The development of nanotechnology opens up new ways for biomedical applications of unmodified and modified diamond nanoparticles which are one of the most popular nanomaterials used in biology, biotechnology, medicine, cosmetics and engineering. They have been applied as diagnostic and therapeutic agents because they can be targeted to and localized in cells causing apoptosis and necrosis. The problem of biocompatibility of nanodiamonds at higher concentrations is thus of primary importance. The first step in the modification of DNPs is usually the introduction of hydrogen groups, which can bind other functional groups. The basic method to introduce -OH groups onto nanoparticles is the Fenton reaction. The aim of this study was to compare the effect of unmodified nanodiamond particles and nanoparticles modified by introduction of -OH groups and etoposide onto their surface reaction on human non-small lung cancer cells. A549 cells were incubated with 2-100µg/ml nanopowders and at 0.6-24µg/ml etoposide in the DMEM medium. We observed a decrease of cells viability and generation of reactive oxygen/ nitrogen species in the cells after incubation, estimated by oxidation of H2DCF-DA and DAF-FM-DA. Modified detonation nanoparticles affected also the cellular content of glutathione and activities of main antioxidant enzymes (glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase and catalase). The results of TEM microscopy show changes in cell morphology. These data demonstrate that modified nanoparticles induce oxidative stress in the target cells.
Asunto(s)
Antioxidantes/metabolismo , Pulmón/metabolismo , Nanodiamantes/efectos adversos , Apoptosis/efectos de los fármacos , Materiales Biocompatibles/efectos adversos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/ultraestructura , Humanos , Pulmón/efectos de los fármacos , Pulmón/ultraestructura , Ensayo de Materiales , Microscopía Electrónica de Transmisión , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
AIM: Nanodiamonds (NDs) have been evaluated for a wide range of biomedical applications. Thus, thorough investigation of the biocompatibility of NDs has become a research priority. Platelets are highly sensitive and are one of the most abundant cell types found in blood. They have a central role in hemostasis and arterial thrombosis. In this study, we aim to investigate the direct and acute effects of carboxylated NDs on platelet function. METHODS: In this study, pro-coagulant parameters such as platelet aggregability, intracellular Ca(2+) flux, mitochondrial transmembrane potential (ΔΨm), generation of reactive oxygen species, surface exposure of phosphatidylserine, electron microscopy, cell viability assay and in vivo thromboembolism were analyzed in great detail. RESULTS: Carboxylated NDs evoked significant activation of human platelets. When administered intravenously in mice, NDs were found to induce widespread pulmonary thromboembolism, indicating the remarkable thrombogenic potential of this nanomaterial. CONCLUSION: Our findings raise concerns regarding the putative biomedical applications of NDs pertaining to diagnostics and therapeutics, and their toxicity and prothrombotic properties should be critically evaluated.
Asunto(s)
Plaquetas/efectos de los fármacos , Nanodiamantes/efectos adversos , Nanodiamantes/química , Agregación Plaquetaria/efectos de los fármacos , Tromboembolia/inducido químicamente , Animales , Plaquetas/citología , Plaquetas/metabolismo , Calcio/metabolismo , Ácidos Carboxílicos/administración & dosificación , Ácidos Carboxílicos/efectos adversos , Ácidos Carboxílicos/química , Supervivencia Celular/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Nanodiamantes/administración & dosificación , Nanodiamantes/ultraestructura , Selectina-P/análisis , Selectina-P/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Tromboembolia/sangre , Tromboembolia/metabolismoRESUMEN
Studying interactions between nano-carbons and lipid membranes is important for multiplexed drug delivery, device fabrication and for understanding toxicity. Herein, we report that nanodiamond (ND, sp(3) carbon) forms a complex with highly biocompatible zwitterionic liposomes based on hydrogen bonding, which is confirmed by pH-dependent and urea-dependent assays. Despite such weak interaction, the complex is highly stable. Comparisons were made with two sp(2) carbons: nanoscale graphene oxide (NGO) and carbon nanotubes (CNTs), where CNT adsorption is the weakest. Adsorption of the nano-carbons does not induce liposome leakage or affect lipid phase transition temperature. Therefore, the potential toxicity of nano-carbons is unlikely to be related to direct membrane damage. ND facilitates cellular uptake of liposomes and co-delivery of negatively charged calcein and positively charged doxorubicin has been demonstrated. ND has the lowest toxicity, while CNTs and NGO are slightly more toxic. The effect of introducing fusogenic lipids and cholesterol was further studied to understand the effect of lipid formulation.