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1.
ACS Appl Mater Interfaces ; 11(16): 14597-14607, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30938506

RESUMO

Along with the rapid appearance of superbacteria with multidrug resistance, it is a challenge to develop new antibacterial materials to address this big issue. Herein, we report a novel amine group-modified fullerene derivative (C70-(ethylenediamine)8 abrr. C70-(EDA)8), which reveals a high performance in killing superbacteria, and most importantly, it shows negligible toxicity to the mammalian cells. The strong antibacterial ability of this material was attributed to its unique molecular structure. On one hand, amino groups on the EDA part make it easy to affix onto the outer membrane of multidrug resistance Escherichia coli by electrostatic interactions. On the other hand, the hydrophobic surface on the C70 part makes it easy to form a strong hydrophobic interaction with the inner membrane of bacteria. Finally, C70-(EDA)8 leads to the cytoplast leakage of superbacteria. In contrast, the C70-(EDA)8 is nontoxic for mammalian cells due to different distributions of the negative charges in the cell membrane. In vivo studies indicated that C70-(EDA)8 mitigated bacterial infection and accelerated wound healing by regulating the immune response and secretion of growth factors. Our amine group-based fullerene derivatives are promising for clinical treatment of wound infection and offer a new way to fight against the superbacteria.


Assuntos
Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Infecções por Escherichia coli , Escherichia coli/crescimento & desenvolvimento , Fulerenos , Cicatrização/efeitos dos fármacos , Infecção dos Ferimentos , Animais , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Fulerenos/química , Fulerenos/farmacocinética , Fulerenos/farmacologia , Células HEK293 , Humanos , Masculino , Ratos , Ratos Wistar , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/metabolismo , Infecção dos Ferimentos/microbiologia , Infecção dos Ferimentos/patologia
2.
Xenobiotica ; 49(9): 1078-1085, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30257131

RESUMO

Fullerene C60 is used in a variety of industrial and consumer capacities. As part of a comprehensive evaluation of the toxicity of fullerene C60 by the National Toxicology Program, the disposition following intratracheal (IT) instillation and intravenous (IV) administration of 1 or 5 mg/kg b.wt. fullerene C60 was investigated in male Fischer 344 rats. Following IT instillation, fullerene C60 was detected in the lung as early as 0.5 h post-exposure with minimal clearance over the 168 h period; the concentration increased ≥20-fold with a 5-fold increase in the dose. Fullerene C60 was not detected in extrapulmonary tissues. Following IV administration, fullerene C60 was rapidly eliminated from the blood and was undetectable after 0.5 h post-administration. The highest tissue concentrations of fullerene C60 occurred in the liver, followed by the spleen, lung and kidney. Fullerene C60 was cleared slowly from the kidney and the lung with estimated half-lives of 24 and 139 h, respectively. The liver concentration of fullerene C60 did not change much with time; over 90% of the fullerene C60 remained there over the study duration up to 168 h. Fullerene C60 was also not detected in urine or feces. These data support the hypothesis that fullerene C60 accumulates in the body and therefore has the potential to induce detrimental health effects following exposure.


Assuntos
Fulerenos/administração & dosagem , Fulerenos/farmacocinética , Administração por Inalação , Administração Intravenosa , Animais , Cromatografia Líquida , Fulerenos/química , Masculino , Espectrometria de Massas , Microscopia Eletrônica de Varredura , Ratos Endogâmicos F344 , Distribuição Tecidual
3.
Eur J Drug Metab Pharmacokinet ; 43(5): 543-554, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29520718

RESUMO

BACKGROUND AND OBJECTIVES: Fullerene-based compounds are a novel class of molecules being developed for a variety of biomedical applications, with nearly 1000 publications in this area in the last 4 years alone. One such compound, the e,e,e-methanofullerene(60)-63-tris malonic acid (designated C3), is a potent catalytic superoxide dismutase mimetic which has shown neuroprotective efficacy in a number of animal models of neurologic disease, including Parkinsonian Macaca fascicularis monkeys. The aim of this study was to characterize its toxicity and pharmacokinetics in mice and monkeys. METHODS: To assess pharmacokinetics in mice, we synthesized and administered 14C-C3 to mice using various routes of delivery, including orally. To assess potential toxicity in primates, serial blood studies and electrocardiograms (ECGs) were obtained from monkeys treated with C3 (3 or 7 mg/kg/day) for 2  months. RESULTS AND CONCLUSIONS: The plasma half-life of C3 was 8.2 ± 0.2 h, and there was wide tissue distribution, including uptake into brain. The compound was cleared by both hepatic and renal excretion. C3 was quite stable, with minimal metabolism of the compound even after 7 days of treatment. The LD50 in mice was 80 mg/kg for a single intraperitoneal injection, and was > 30 mg/kg/day for sustained administration; therapeutic doses are 1-5 mg/kg/day. For primates, no evidence of renal, hepatic, electrolyte, or hematologic abnormalities were noted, and serial ECGs demonstrated no alteration in cardiac electrical activity. Thus, doses of C3 that have therapeutic efficacy appear to be well tolerated after 2 years (mice) or 2 months (non-human primates) of treatment.


Assuntos
Fulerenos/farmacocinética , Fulerenos/toxicidade , Infarto da Artéria Cerebral Média/tratamento farmacológico , Intoxicação por MPTP/tratamento farmacológico , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/toxicidade , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fulerenos/administração & dosagem , Fulerenos/sangue , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Eliminação Hepatobiliar , Infarto da Artéria Cerebral Média/sangue , Dose Letal Mediana , Intoxicação por MPTP/sangue , Intoxicação por MPTP/induzido quimicamente , Macaca fascicularis , Masculino , Taxa de Depuração Metabólica , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/sangue , Eliminação Renal , Distribuição Tecidual
4.
Part Fibre Toxicol ; 15(1): 5, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343276

RESUMO

BACKGROUND: Nanoparticles (NPs) administered orally will meet the gut microbiota, but their impacts on microbiota homeostasis and the consequent physiological relevance remain largely unknown. Here, we describe the modulatory effects and the consequent pharmacological outputs of two orally administered fullerenols NPs (Fol1 C60(OH)7(O)8 and Fol113 C60(OH)11(O)6) on gut microbiota. RESULTS: Administration of Fol1 and Fol113 NPs for 4 weeks largely shifted the overall structure of gut microbiota in mice. The bacteria belonging to putative short-chain fatty acids (SCFAs)-producing genera were markedly increased by both NPs, especially Fol1. Dynamic analysis showed that major SCFAs-producers and key butyrate-producing gene were significantly enriched after treatment for 7-28 days. The fecal contents of SCFAs were consequently increased, which was accompanied by significant decreases of triglycerides and total cholesterol levels in the blood and liver, with Fol1 superior to Fol113. Under cultivation in vitro, fullerenols NPs can be degraded by gut flora and exhibited a similar capacity of inulin to promote SCFA-producing genera. The differential effects of Fol1 and Fol113 NPs on the microbiome may be attributable to their subtly varied surface structures. CONCLUSIONS: The two fullerenol NPs remarkably modulate the gut microbiota and selectively enrich SCFA-producing bacteria, which may be an important reason for their anti-hyperlipidemic effect in mice.


Assuntos
Fulerenos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hipolipemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Nanopartículas , Animais , Ácidos Graxos Voláteis/biossíntese , Fezes/microbiologia , Fulerenos/química , Fulerenos/farmacocinética , Microbioma Gastrointestinal/genética , Homeostase/efeitos dos fármacos , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Filogenia , RNA Ribossômico 16S/genética , Propriedades de Superfície , Distribuição Tecidual
5.
Artif Cells Nanomed Biotechnol ; 46(8): 1763-1772, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29069915

RESUMO

The objective of the present study was to deliver docetaxel to cancerous cells with enhanced efficacy and safety profile, using aspartic acid linked fullerenols. This aspartic acid derivatized fullerenol conjugate linked with docetaxel was characterized by UV, FT-IR and NMR spectroscopy. Studies for particle size, PDI, zeta potential and FE-SEM were also performed. The conjugate was evaluated for release kinetics, cancer cell cytotoxicity, cellular uptake using confocal laser microscopy and also for pharmacokinetic profile. Cytotoxic studies proved that there was almost 4.3 folds decrease in IC50 with significantly enhanced cellular uptake of the nanometric conjugates. It was observed that the bioavailability was enhanced by 5.8 folds when compared to that of pure DTX. The developed nanoconstructs were erythrocyte compatible and offered decreased protein binding. The findings are encouraging and offer a novel carrier with enhanced efficacy and safety of a drug, belonging to BCS class IV.


Assuntos
Docetaxel , Portadores de Fármacos , Fulerenos , Docetaxel/química , Docetaxel/farmacocinética , Docetaxel/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Eritrócitos/metabolismo , Fulerenos/química , Fulerenos/farmacocinética , Fulerenos/farmacologia , Humanos
6.
Int J Nanomedicine ; 12: 8289-8307, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29180866

RESUMO

[60]Fullerene is a highly versatile nanoparticle (NP) platform for drug delivery to sites of pathology owing to its small size and both ease and versatility of chemical functionalization, facilitating multisite drug conjugation, drug targeting, and modulation of its physicochemical properties. The prominent and well-characterized role of the enhanced permeation and retention (EPR) effect in facilitating NP delivery to tumors motivated us to explore vascular transport kinetics of a water-soluble [60]fullerene derivatives using intravital microscopy in an immune competent murine model of breast adenocarcinoma. Herein, we present a novel local and global image analysis of vascular transport kinetics at the level of individual tumor blood vessels on the micron scale and across whole images, respectively. Similar to larger nanomaterials, [60]fullerenes displayed rapid extravasation from tumor vasculature, distinct from that in normal microvasculature. Temporal heterogeneity in fullerene delivery to tumors was observed, demonstrating the issue of nonuniform delivery beyond spatial dimensions. Trends in local region analysis of fullerene biokinetics by fluorescence quantification were in agreement with global image analysis. Further analysis of intratumoral vascular clearance rates suggested a possible enhanced penetration and retention effect of the fullerene compared to a 70 kDa vascular tracer. Overall, this study demonstrates the feasibility of tracking and quantifying the delivery kinetics and intratumoral biodistribution of fullerene-based drug delivery platforms, consistent with the EPR effect on short timescales and passive transport to tumors.


Assuntos
Adenocarcinoma/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Fulerenos/farmacocinética , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanopartículas/química , Animais , Difusão Dinâmica da Luz , Feminino , Fluorescência , Fulerenos/química , Microscopia Intravital/métodos , Cinética , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Varredura , Imagem Molecular/métodos , Solubilidade , Distribuição Tecidual , Água/química
7.
Acta Biomater ; 61: 193-203, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28801268

RESUMO

Various carbonaceous nanomaterials, including fullerene, carbon nanotube, graphene, and carbon dots, have attracted increasing attention during past decades for their potential applications in biological imaging and therapy. In this study, we have developed a fullerene-based tumor-targeted positron emission tomography (PET) imaging probe. Water-soluble functionalized C60 conjugates were radio-labeled with 64Cu and modified with cyclo (Arg-Gly-Asp) peptides (cRGD) for targeting of integrin αvß3 in glioblastoma. The specificity of fluorescein-labeled C60 conjugates against cellular integrin αvß3 was evaluated in U87MG (integrin αvß3 positive) and MCF-7 cells (integrin αvß3 negative) by confocal fluorescence microscopy and flow cytometry. Our results indicated that cRGD-conjugated C60 derivatives showed better cellular internalization compared with C60 derivatives without the cRGD attachment. Moreover, an interesting finding on intra-nuclei transportation of cRGD-conjugated C60 derivatives was observed in U87MG cells. In vivo serial PET studies showed preferential accumulation of cRGD-conjugated C60 derivatives at in U87MG tumors. In addition, the pharmacokinetic profiles of these fullerene-based nanoparticles conjugated with cRGD and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) fit well with the three compartment model. The renal clearance of C60-based nanoparticles is remarkably fast, which makes this material very promising for safer cancer theranostic applications. STATEMENT OF SIGNIFICANCE: Safety is one of the major concerns for nanomedicine and nanomaterials with fast clearance profile are highly desirable. Fullerene is a distinct type of zero-dimensional carbon nanomaterial with ultrasmall size, uniform dispersity, and versatile reactivity. Here we have developed a fullerene-based tumor-targeted positron emission tomography imaging probe using water-soluble functionalized C60 conjugates radio-labeled with 64Cu and modified with cyclo (Arg-Gly-Asp) peptides (cRGD) for glioblastoma targeting. The improved tumor targeting property along with fast renal clearance behavior of C60-based nanoparticles makes this material very promising for future safer cancer theranostic applications.


Assuntos
Fulerenos/química , Glioblastoma/diagnóstico por imagem , Rim/metabolismo , Nanopartículas/química , Tomografia por Emissão de Pósitrons , Animais , Linhagem Celular Tumoral , Simulação por Computador , Radioisótopos de Cobre/sangue , Radioisótopos de Cobre/química , Radioisótopos de Cobre/farmacocinética , Feminino , Fluoresceína/química , Fulerenos/farmacocinética , Humanos , Camundongos Nus , Espectroscopia de Infravermelho com Transformada de Fourier , Fatores de Tempo , Distribuição Tecidual
8.
J Control Release ; 260: 92-99, 2017 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-28527736

RESUMO

The aim of this study is to understand the combined and differential biokinetic effects of radiofrequency (RF) electric-field hyperthermia as an adjunctive therapy to [60]fullerene nanoparticle-based drug delivery systems in targeting the micro-vasculature and micro-environments of breast cancer tumors. Intravital microscopy (IVM) is an ideal tool to provide the spatial and temporal resolution needed for quantification in this investigation. The water-soluble and fluorescent [60]fullerene derivative (C60-serPF) was designed to be an amphiphilic nanostructure, which is able to cross several biological membranes and accumulate in tumor tissues by passing through abnormally leaky tumor blood vessels. To elucidate the coupled effects of the highly permeable, but heterogeneous tumor vasculature, with the permeabilizing effects of mild (40-42°C) hyperthermia produced by a local RF field, we controlled variables across tumor and non-tumor mammary gland microvasculature with and without application of RF hyperthermia in each condition. We notice that tumor tissue is characterized by more intense drug extravasation than in contralateral mammary fat pad tissue, which is consistent with enhanced permeability and retention (EPR) effects. The analysis of a permeability parameter (Papp), C60-serPF velocity, and the time of compound influx into the intra- and extra-vascular space suggest that mild RF hyperthermia can improve nanoparticle delivery into tumor tissue.


Assuntos
Adenocarcinoma/metabolismo , Fulerenos/administração & dosagem , Hipertermia Induzida , Neoplasias Mamárias Experimentais/metabolismo , Animais , Transporte Biológico , Linhagem Celular Tumoral , Terapia Combinada , Sistemas de Liberação de Medicamentos , Feminino , Fulerenos/farmacocinética , Camundongos Endogâmicos BALB C , Camundongos Nus , Distribuição Tecidual
9.
Acta Biomater ; 59: 158-169, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28511875

RESUMO

Cationic macromolecules are attractive for use as small interfering RNA (siRNA) carriers due to their performance in non-immunological reactions, customization during synthesis, and low costs compared to viral carriers. However, their low transfection efficiency substantially hinders their application in both clinical practices and academic research, which is mostly attributable to the low capacity of siRNA/cationic macromolecule complexes to escape lysosomes. To address this challenge, we designed an amphiphilic fullerene derivative (C60-Dex-NH2) for efficient and controllable siRNA delivery. To synthesize C60-Dex-NH2, terminally aminated dextran was conjugated to C60. The conjugate was further cationized by covalently introducing ethylenediamine to the dextran. The physicochemical characteristics of C60-Dex-NH2 was examined with elemental analyses, gel permeation chromatography, solid-state nuclear magnetic resonance (13C, HPDEC), agarose gel electrophoresis, and dynamic light scattering. The cytotoxicity, cellular uptake, intracellular distribution, and in vitro RNA interference (RNAi) of siRNA/C60-Dex-NH2 complex was evaluated in the human breast cancer cell line MDA-MB-231. The RNAi efficiencies mediated by C60-Dex-NH2in vivo was evaluated in subcutaneous tumor-bearing mice. The results showed that C60-Dex-NH2 has a specific amphiphilic skeleton and could form micelle-like aggregate structures in water, which could prevent siRNA from destroying by reactive oxygen species (ROS). When exposed to visible light, C60-Dex-NH2 could trigger controllable ROS generation which could destroy the lysosome membrane, promote the lysosomal escape, and enhance the gene silencing efficiency of siRNA in vitro and in vivo. The gene silencing efficiency could reach a maximum of 53% in the MDA-MB-231-EGFP cells and 69% in the 4T1-GFP-Luc2 tumor-bearing mice. STATEMENT OF SIGNIFICANCE: We designed a novel photosensitive amphiphilic carrier (C60-Dex-NH2) for efficient and controllable siRNA delivery, which can be used in gene therapy. We showed that C60-Dex-NH2 could destroy lysosome membrane via controllable generation of ROS when exposed to light, which can help siRNA to escape from lysosome before degradation. This can enhance the gene silencing efficiency significantly and provides a useful way to regulate RNAi efficiency by light. One advantage for C60-Dex-NH2 system is C60 has broad absorbance spectrum and can be activated by weak visible light; Furthermore, C60-Dex-NH2 has a specific amphiphilic structure, which may prevent siRNA from degrading and allows C60-Dex-NH2 to embed into the lipid membrane of lysosome to improve the ROS induced lysosomal disturbance after internalization.


Assuntos
Citosol/metabolismo , Fulerenos , Interferência de RNA/efeitos dos fármacos , RNA Interferente Pequeno , Animais , Linhagem Celular Tumoral , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Fulerenos/química , Fulerenos/farmacocinética , Fulerenos/farmacologia , Humanos , Camundongos , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacocinética , RNA Interferente Pequeno/farmacologia
10.
Mater Sci Eng C Mater Biol Appl ; 75: 1376-1388, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28415429

RESUMO

The purpose of study was to conjugate and evaluate methotrexate with C60-fullerenes and multi-walled carbon nanotubes (MWCNTs) for better drug delivery to cancer cells, and also to compare these two systems. C60-fullerenes and MWCNTs were functionalized by 1,3-dipolar cycloaddition using glycine and paraformaldehyde. Methotrexate (MTX) was esterified and conjugated to the functionalized carbon-based carriers. The conjugates were characterized for micromeritics and drug conjugation. The systems were evaluated for drug release in various pH, MTT cytotoxicity assay, protein binding, cellular uptake, haemolytic profile and pharmacokinetics. Spectroscopic studies confirmed the successful conjugation of drug to the aminated carbon-based carriers. The developed systems released more drug at the pH of cancer cells to that of the pH of plasma. The carriers were compatible with erythrocytes and offered substantial cytotoxicity. Better cellular uptake was confirmed by confocal laser scanning microscopy. C60-fullerenes/MWCNTs modulated the pharmacokinetic profile of drug in desired manner, resulting in better retention and compartment availability. However, the results from C60-fullerenes were observed to be better than that from MWCNTs. The present findings established the potential of carbon-based aminated nanocarriers for delivery of methotrexate in safer and effective manner.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Fulerenos , Metotrexato , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Fulerenos/química , Fulerenos/farmacocinética , Fulerenos/farmacologia , Humanos , Metotrexato/química , Metotrexato/farmacocinética , Metotrexato/farmacologia
11.
Nanoscale ; 9(12): 4114-4127, 2017 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-28280822

RESUMO

The molecular level permeation mechanism of fullerenes and its derivatives through human skin could open a vast area for designing novel nanoparticles for cosmetics and drug delivery applications. In this study, we report the permeation mechanism of pristine fullerene C60 for the first time through the skin lipid layer, as determined via prolonged unconstrained and constrained coarse-grained molecular dynamics simulations. The skin layer was modelled as an equimolar ratio of ceramides, cholesterol and free fatty acids. It was observed that at lower concentrations fullerenes formed small clusters (3 or 5 molecules) in the aqueous phase, which further spontaneously permeated inside the bilayer and remained dispersed inside the bilayer interior. On the other hand, at higher concentrations fullerenes aggregated in the aqueous layer, penetrated in that form and remained aggregated in the bilayer interior. Lower concentrations of fullerenes did not induce significant structural changes in the bilayer, whereas at higher concentrations undulations were observed. The permeability of fullerene molecules was found to be concentration-dependent and was explained in terms of their free energy of permeation (thermodynamics) and diffusivity (dynamics). On the basis of the aggregation and dispersion of fullerenes, an optimum fullerene concentration was determined, which could be used for drug delivery and cosmetic applications.


Assuntos
Fulerenos/farmacocinética , Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular , Absorção Cutânea , Humanos , Termodinâmica
12.
J Biomater Sci Polym Ed ; 28(10-12): 1036-1050, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28132586

RESUMO

As novel magnetic resonance imaging (MRI) contrast agent, gadofullerene encapsulated redox nanoparticles (Gd3NPs) were prepared by encapsulation of Gd3N@C80 in the core of core-shell-type polymer micelles composed of original polyamine with a reactive oxygen species (ROS)-scavenging ability. Because Gd3NPs possess biocompatible PEG shell with a smaller size (ca. 50 nm), they had high colloidal stability in a physiological environment, and showed low cytotoxicity. Specific accumulation of Gd3NPs in a tumor was confirmed in tumor-bearing mice after systemic administration. The tumor/muscle (T/M) ratio of the Gd ion reached five at 7.5 h after the administration. T1-weighted MRI signal enhancement of the T/M ratio increased by 8% at 6 h postinjection of Gd3NPs (Gd dose:14.35 µmol/kg). Although Gd3NPs showed a tendency for extended blood circulation, they did not have severe adverse effects, probably due to the confinement of Gd in a hydrophobic fullerene in addition to the ROS-scavenging capacity of these nanoparticles. In sharp contrast, systemic administration of Gd-chelate nanoparticles (GdCNPs) to mice disrupts liver function, increases leukocyte counts, and destroys spleen and skin tissues. Leaking of Gd ions from GdCNPs may cause such adverse effects. Based on these results, we expect that Gd3NPs is high-performance MRI contrast agents for tumor diagnosis.


Assuntos
Meios de Contraste/química , Fulerenos/química , Gadolínio/química , Imagem por Ressonância Magnética/métodos , Nanopartículas , Animais , Cápsulas , Linhagem Celular Tumoral , Meios de Contraste/farmacocinética , Meios de Contraste/toxicidade , Fulerenos/farmacocinética , Fulerenos/toxicidade , Masculino , Camundongos , Oxirredução
13.
Dokl Biochem Biophys ; 468(1): 173-5, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27417712

RESUMO

The present report describes development of hexamethonium complexes based on fullerene C60. Hexamethonium has a limited penetration into CNS and therefore can antagonize central effects of nicotine only when given at high doses. In the present studies conducted in laboratory rodents, intraperitoneal administration of hexamethonium-fullerene complexes blocked effects of nicotine (convulsions and locomotor stimulation). When compared to equimolar doses of hexamethonium, complexes of hexamethonium with derivatives of fullerene C60 were 40 times more potent indicating an enhanced ability to interact with central nicotine receptors. Thus, fullerene C60 derivatives should be explored further as potential carrier systems for polar drug delivery into CNS.


Assuntos
Encéfalo/efeitos dos fármacos , Fulerenos/farmacocinética , Compostos de Hexametônio/farmacocinética , Antagonistas Nicotínicos/farmacocinética , Aminocaproatos/química , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Fulerenos/administração & dosagem , Fulerenos/química , Compostos de Hexametônio/administração & dosagem , Compostos de Hexametônio/química , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Nicotina , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/química , Ratos Wistar , Convulsões/tratamento farmacológico
14.
J Control Release ; 235: 245-258, 2016 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-27276066

RESUMO

The traditional drug delivery systems always suffer from the unexpected drug release during circulation and the sluggish release of drug in target site. To address the problem, an "off-on" type drug delivery system with precise control was developed in this study. Doxorubicin (DOX) was covalently conjugated to fullerene (C60) nanoaggregates via a reactive oxygen species (ROS)-sensitive thioketal linker (C60-DOX NPs), and then the hydrophilic shell (Distearoyl-sn-glycero-3-phosphoethanolamine-PEG-CNGRCK2HK3HK11, DSPE-PEG-NGR) was attached to the outer surface of C60-DOX, giving it (C60-DOX-NGR NP) excellent stability in physiological solutions and active tumor-targeting capacity. C60-DOX-NGR NPs were able to entrap DOX efficiently even at acidic environment (pH5.5) when they were "off" state. In sharp contrast, when the NPs were "on" state, a large number of ROS were generated by C60, leading to the breaking of ROS-sensitive linker, thereby enabling the burst release of DOX. The "off" or "on" state of C60-DOX-NGR NPs could be precisely remote-controlled by a 532nm laser (at a low power density) with a high spatial/temporal resolution. In the in vivo and in vitro studies, the C60-based drug delivery system with "off-on" state exhibited a high antitumor efficacy and a low toxicity to normal tissues due to its tumor-targeting ability, remote-controlled drug release property and combined therapeutic effect (photodynamic therapy combined with chemotherapy).


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Fulerenos/administração & dosagem , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Feminino , Fulerenos/química , Fulerenos/farmacocinética , Fulerenos/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/farmacocinética , Fosfatidiletanolaminas/uso terapêutico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacos
15.
Sci Total Environ ; 565: 299-305, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27177136

RESUMO

To understand the behavior of some emerging flame retardants (FRs) in the environment, a nonexhaustive extraction using Tenax was applied to study their behavior in aquatic ecosystems. Desorption of 8 polybrominated diphenyl ethers (PBDEs), 8 methoxylated PBDEs, 3 emerging brominated FRs and 6 halogenated norbornenes from sediments spiked in the laboratory was studied. Results showed that emerging FRs have a similar bioavailability than that of legacy FRs, already banned. In addition, some parameters such as sediment total organic carbon (TOC), aging or nanomaterial (NMs) presence in the sediment were modified in order to study their effects on the bioavailability of FRs. Bioavailability increases with a diminution of sediment TOC, while diminishes with an increase of aging. The study of effect of NM presence was performed at three different pH (acidic, neutral and basic), and for the three scenarios, FR bioavailability decreased with NM presence. The retention of pollutants in the sediment seems to be favoured by NM presence, minimizing their impact on living organisms.


Assuntos
Monitoramento Ambiental/métodos , Retardadores de Chama/análise , Retardadores de Chama/farmacologia , Fulerenos/análise , Sedimentos Geológicos/química , Éteres Difenil Halogenados/análise , Poluentes Químicos da Água/análise , Disponibilidade Biológica , Fulerenos/farmacocinética , Éteres Difenil Halogenados/farmacocinética , Poluentes Químicos da Água/farmacocinética
16.
Part Fibre Toxicol ; 13: 14, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26956156

RESUMO

BACKGROUND: Functionalization is believed to have a considerable impact on the biodistribution of fullerene in vivo. However, a direct comparison of differently functionalized fullerenes is required to prove the hypothesis. The purpose of this study was to investigate the influences of surface modification on the biodistribution of fullerene following its exposure via several routs of administration. METHODS: (13)C skeleton-labeled fullerene C60 ((13)C-C60) was functionalized with carboxyl groups ((13)C-C60-COOH) or hydroxyl groups ((13)C-C60-OH). Male ICR mice (~25 g) were exposed to a single dose of 400 µg of (13)C-C60-COOH or (13)C-C60-OH in 200 µL of aqueous 0.9% NaCl solution by three different exposure pathways, including tail vein injection, gavage and intraperitoneal exposure. Tissue samples, including blood, heart, liver, spleen, stomach, kidneys, lungs, brain, large intestine, small intestine, muscle, bone and skin were subsequently collected, dissected, homogenized, lyophilized, and analyzed by isotope ratio mass spectrometry. RESULTS: The liver, bone, muscle and skin were found to be the major target organs for C60-COOH and C60-OH after their intravenous injection, whereas unmodified C60 was mainly found in the liver, spleen and lung. The total uptakes in liver and spleen followed the order: C60 > > C60-COOH > C60-OH. The distribution rate over 24 h followed the order: C60 > C60-OH > C60-COOH. C60-COOH and C60-OH were both cleared from the body at 7 d post exposure. C60-COOH was absorbed in the gastrointestinal tract following gavage exposure and distributed into the heart, liver, spleen, stomach, lungs, intestine and bone tissues. The translocation of C60-OH was more widespread than that of C60-COOH after intraperitoneal injection. CONCLUSIONS: The surface modification of fullerene C60 led to a decreased in its accumulation level and distribution rate, as well as altering its target organs. These results therefore demonstrate that the chemical functionalization of fullerene had a significant impact on its translocation and biodistribution properties. Further surface modifications could therefore be used to reduce the toxicity of C60 and improve its biocompatibility, which would be beneficial for biomedical applications.


Assuntos
Ácidos Carboxílicos/farmacocinética , Fulerenos/farmacocinética , Administração Oral , Animais , Osso e Ossos/metabolismo , Isótopos de Carbono , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/química , Fulerenos/administração & dosagem , Fulerenos/química , Hidroxilação , Injeções Intraperitoneais , Injeções Intravenosas , Fígado/metabolismo , Masculino , Camundongos Endogâmicos ICR , Músculo Esquelético/metabolismo , Pele/metabolismo , Propriedades de Superfície , Distribuição Tecidual
17.
Acta Biomater ; 29: 282-297, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26485168

RESUMO

UNLABELLED: Taking advantages of fullerene (C60) and gold nanoparticles (AuNPs) for potentials in photodynamic therapy (PDT), drug delivery and radio frequency thermal therapy (RTT), a C60@Au hybrid nanocomposite was synthesized by chemical deposition of Au nanoparticles onto C60, and functionalized by PEG5000 via a pH cleavable hydrazone bond, making C60@Au-PEG keep the PEG on the surface of drug delivery system during circulation but dissociate PEG from the system after accumulation in tumor tissue, then doxorubicin (DOX) was loaded onto C60@Au-PEG with a very high drug loading efficiency. The release profiles of DOX from C60@Au-PEG/DOX showed strong dependences on radio frequency (RF). For the drug delivery, C60@Au-PEG/DOX afforded much higher antitumor efficacy owing to 8.6-fold higher DOX uptake of tumor than DOX. Besides, in this work, C60@Au-PEG/DOX not only served as a powerful RTT agent for RF-thermal ablation of tumor and a strong photosensitizer (PS) for PDT, but also as an X-ray contrast agent for tumor diagnosis. In the in vitro and in vivo studies, C60@Au-PEG/DOX showed excellent chemo-RF thermal-photodynamic therapeutic efficacy, RF-controlled drug releasing function, tumor targeting property, tumoral acid PEG dissociating character and X-ray imaging ability, demonstrating that there is a great potential of C60@Au-PEG/DOX for simultaneous diagnosis and therapy in cancer treatment. STATEMENT OF SIGNIFICANCE: A significant challenge in cancer therapy is to maximize the therapeutic efficacy and minimize the side effects. In the past decade, a lot of nanoparticles have been used as the carriers for efficient drug delivery. However, the design of drug delivery system (DDS) with stimuli-responsive controlled-release property, simultaneous diagnosis and therapy functions is still a challenge. Herein, we developed a new drug delivery system (C60@Au-PEG/DOX), and explored its applications in tumor therapy. The in vitro and in vivo results showed C60@Au-PEG/DOX could significantly improve the therapeutic efficacy and reduce the systemic toxicity through X-ray imaging guided locatable DOX release, photodynamic and photothermal therapies. These results are of interest as they demonstrate a multi-functional DDS for tumor theranostic applications.


Assuntos
Neoplasias da Mama/terapia , Meios de Contraste , Doxorrubicina , Fulerenos , Ouro , Hipertermia Induzida , Polietilenoglicóis , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Meios de Contraste/química , Meios de Contraste/farmacocinética , Meios de Contraste/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Feminino , Fulerenos/química , Fulerenos/farmacocinética , Fulerenos/farmacologia , Ouro/química , Ouro/farmacocinética , Ouro/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Radiografia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Mater Sci Eng C Mater Biol Appl ; 59: 398-403, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26652389

RESUMO

With an aim to elucidate the effects of C60 fullerene complexed with antibiotic doxorubicin (Dox) on model bilipid membranes (BLM), the investigation of the electrical properties of BLM under the action of Dox and C60 fullerene, and of their complex, C60+Dox,was performed. The complex as well as its components exert a clearly detectable influence on BLM, which is concentration-dependent and also depends on phospholipid composition. The mechanism of this effect originates either from intermolecular interaction of the drug with fatty-acid residues of phospholipids, or from membranotropic effects of the drug-induced lipid peroxidation, or from the sum of these two effects. By fluorescence microscopy the entering of C60 + Dox complex into HeLa cells was directly shown.


Assuntos
Doxorrubicina , Portadores de Fármacos , Fulerenos , Bicamadas Lipídicas , Peroxidação de Lipídeos/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Fulerenos/química , Fulerenos/farmacocinética , Fulerenos/farmacologia , Células HeLa , Humanos , Bicamadas Lipídicas/química , Bicamadas Lipídicas/farmacocinética , Bicamadas Lipídicas/farmacologia
19.
Nanomedicine ; 12(2): 333-51, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26707820

RESUMO

UNLABELLED: Carbon-based nanomaterials including carbon nanotubes, graphene oxide, fullerenes and nanodiamonds are potential candidates for various applications in medicine such as drug delivery and imaging. However, the successful translation of nanomaterials for biomedical applications is predicated on a detailed understanding of the biological interactions of these materials. Indeed, the potential impact of the so-called bio-corona of proteins, lipids, and other biomolecules on the fate of nanomaterials in the body should not be ignored. Enzymatic degradation of carbon-based nanomaterials by immune-competent cells serves as a special case of bio-corona interactions with important implications for the medical use of such nanomaterials. In the present review, we highlight emerging biomedical applications of carbon-based nanomaterials. We also discuss recent studies on nanomaterial 'coronation' and how this impacts on biodistribution and targeting along with studies on the enzymatic degradation of carbon-based nanomaterials, and the role of surface modification of nanomaterials for these biological interactions. FROM THE CLINICAL EDITOR: Advances in technology have produced many carbon-based nanomaterials. These are increasingly being investigated for the use in diagnostics and therapeutics. Nonetheless, there remains a knowledge gap in terms of the understanding of the biological interactions of these materials. In this paper, the authors provided a comprehensive review on the recent biomedical applications and the interactions of various carbon-based nanomaterials.


Assuntos
Materiais Biocompatíveis/metabolismo , Carbono/metabolismo , Nanoestruturas , Animais , Biocatálise , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacocinética , Materiais Biocompatíveis/toxicidade , Carbono/química , Carbono/farmacocinética , Carbono/toxicidade , Fulerenos/química , Fulerenos/metabolismo , Fulerenos/farmacocinética , Fulerenos/toxicidade , Grafite/química , Grafite/metabolismo , Grafite/farmacocinética , Grafite/toxicidade , Humanos , Metabolismo dos Lipídeos , Modelos Moleculares , Nanoestruturas/química , Nanoestruturas/toxicidade , Nanotubos de Carbono/química , Nanotubos de Carbono/toxicidade , Óxidos/química , Óxidos/metabolismo , Óxidos/farmacocinética , Óxidos/toxicidade , Coroa de Proteína/metabolismo
20.
J Appl Toxicol ; 35(12): 1438-51, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26081520

RESUMO

A comprehensive distribution study was conducted in pregnant and lactating rats exposed to a suspension of uniformly carbon-14 labeled C60 ([(14) C(U)]C60 ). Rats were administered [(14) C(U)]C60 (~0.2 mg [(14) C(U)]C60 kg(-1) body weight) or 5% polyvinylpyrrolidone (PVP)-saline vehicle via a single tail vein injection. Pregnant rats were injected on gestation day (GD) 11 (terminated with fetuses after either 24 h or 8 days), GD15 (terminated after 24 h or 4 days), or GD18 (terminated after 24 h). Lactating rats were injected on postnatal day 8 and terminated after 24 h, 3 or 11 days. The distribution of radioactivity in pregnant dams was influenced by both the state of pregnancy and time of termination after exposure. The percentage of recovered radioactivity in pregnant and lactating rats was highest in the liver and lungs. Radioactivity was quantitated in over 20 tissues. Radioactivity was found in the placenta and in fetuses of pregnant dams, and in the milk of lactating rats and in pups. Elimination of radioactivity was < 2% in urine and feces at each time point. Radioactivity remained in blood circulation up to 11 days after [(14) C(U)]C60 exposure. Biomarkers of inflammation, cardiovascular injury and oxidative stress were measured to study the biological impacts of [(14) C(U)]C60 exposure. Oxidative stress was elevated in female pups of exposed dams. Metabolomics analysis of urine showed that [(14) C(U)]C60 exposure to pregnant rats impacted the pathways of vitamin B, regulation of lipid and sugar metabolism and aminoacyl-tRNA biosynthesis. This study demonstrated that [(14) C(U)]C60 crosses the placenta at all stages of pregnancy examined, and is transferred to pups via milk.


Assuntos
Fulerenos/farmacocinética , Lactação , Exposição Materna , Troca Materno-Fetal , Leite/química , Animais , Biomarcadores/análise , Radioisótopos de Carbono , Fezes/química , Feminino , Fulerenos/administração & dosagem , Fulerenos/urina , Idade Gestacional , Injeções Intravenosas , Fígado/metabolismo , Pulmão/metabolismo , Placenta/metabolismo , Gravidez , Ratos Sprague-Dawley , Distribuição Tecidual
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