Showing papers by "Andre E. Nel published in 2009"

Understanding biophysicochemical interactions at the nano–bio interface

Abstract: Rapid growth in nanotechnology is increasing the likelihood of engineered nanomaterials coming into contact with humans and the environment. Nanoparticles interacting with proteins, membranes, cells, DNA and organelles establish a series of nanoparticle/biological interfaces that depend on colloidal forces as well as dynamic biophysicochemical interactions. These interactions lead to the formation of protein coronas, particle wrapping, intracellular uptake and biocatalytic processes that could have biocompatible or bioadverse outcomes. For their part, the biomolecules may induce phase transformations, free energy releases, restructuring and dissolution at the nanomaterial surface. Probing these various interfaces allows the development of predictive relationships between structure and activity that are determined by nanomaterial properties such as size, shape, surface chemistry, roughness and surface coatings. This knowledge is important from the perspective of safe use of nanomaterials.

Polyethyleneimine Coating Enhances the Cellular Uptake of Mesoporous Silica Nanoparticles and Allows Safe Delivery of siRNA and DNA Constructs

Abstract: Surface-functionalized mesoporous silica nanoparticles (MSNP) can be used as an efficient and safe carrier for bioactive molecules. In order to make the MSNP a more efficient delivery system, we modified the surface of the particles by a functional group that enhances cellular uptake and allows nucleic acid delivery in addition to traditional drug delivery. Noncovalent attachment of polyethyleneimine (PEI) polymers to the surface not only increases MSNP cellular uptake but also generates a cationic surface to which DNA and siRNA constructs could be attached. While efficient for intracellular delivery of these nucleic acids, the 25 kD PEI polymer unfortunately changes the safety profile of the MSNP that is otherwise very safe. By experimenting with several different polymer molecular weights, it was possible to retain high cellular uptake and transfection efficiency while reducing or even eliminating cationic MSNP cytotoxicity. The particles coated with the 10 kD PEI polymer were particularly efficient for transducing HEPA-1 cells with a siRNA construct that was capable of knocking down GFP expression. Similarly, transfection of a GFP plasmid induced effective expression of the fluorescent protein in >70% cells in the population. These outcomes were quantitatively assessed by confocal microscopy and flow cytometry. We also demonstrated that the enhanced cellular uptake of the nontoxic cationic MSNP enhances the delivery of the hydrophobic anticancer drug, paclitaxel, to pancreatic cancer cells. In summary, we demonstrate that, by a careful selection of PEI size, it is possible to construct cationic MSNP that are capable of nucleotide and enhanced drug delivery with minimal or no cytotoxicity. This novel use of a cationic MSNP extends its therapeutic use potential.

Potential Health Impact of Nanoparticles

Abstract: Although mankind stands to obtain great benefit from nanotechnology, it is important to consider the potential health impacts of nanomaterials (NMs). This consideration has launched the field of nanotoxicology, which is charged with assessing toxicological potential as well as promoting safe design and use of NMs. Although no human ailments have been ascribed to NMs thus far, early experimental studies indicate that NMs could initiate adverse biological responses that can lead to toxicological outcomes. One of the principal mechanisms is the generation of reactive oxygen species and oxidant injury. Because oxidant injury is also a major mechanism by which ambient ultrafine particles can induce adverse health effects, it is useful to consider the lessons learned from studying ambient particles. This review discusses the toxicological potential of NMs by comparing the possible injury mechanisms and adverse health effects of engineered and ambient ultrafine particles.

Particulate matter and atherosclerosis: role of particle size, composition and oxidative stress

Abstract: Air Pollution has been associated with significant adverse health effects leading to increased morbidity and mortality. Cumulative epidemiological and experimental data have shown that exposure to air pollutants lead to increased cardiovascular ischemic events and enhanced atherosclerosis. It appears that these associations are much stronger with the air particulate matter (PM) component and that in urban areas, the smaller particles could be more pathogenic, as a result of their greater propensity to induce systemic prooxidant and proinflammatory effects. Much is still unknown about the toxicology of ambient particulates as well as the pathogenic mechanisms responsible for the induction of adverse cardiovascular health effects. It is expected that better understanding of these effects will have large implications and may lead to the formulation and implementation of new regulatory policies. Indeed, we have found that ultrafine particles (<0.18 μm) enhance early atherosclerosis, partly due to their high content in redox cycling chemicals and their ability to synergize with known proatherogenic mediators in the promotion of tissue oxidative stress. These changes take place in parallel with increased evidence of phase 2 enzymes expression, via the electrophile-sensitive transcription factor, p45-NFE2 related transcription factor 2 (Nrf2). Exposure to ultrafine particles also results in alterations of the plasma HDL anti-inflammatory function that could be indicative of systemic proatherogenic effects. This article reviews the epidemiological, clinical and experimental animal evidence that support the association of particulate matter with atherogenesis. It also discusses the possible pathogenic mechanisms involved, the physicochemical variables that may be of importance in the greater toxicity exhibited by a small particle size, interaction with genes and other proatherogenic factors as well as important elements to consider in the design of future mechanistic studies. Extensive epidemiological evidence supports the association of air pollution with adverse health effects [13]. It is increasingly being recognized that such effects lead to enhanced morbidity and mortality, mostly due to exacerbation of cardiovascular diseases and predominantly those of ischemic character [4]. Indeed, in addition to the classical risk factors such as serum lipids, smoking, hypertension, aging, gender, family history, physical inactivity and diet, recent data have implicated air pollution as an important additional risk factor for atherosclerosis. This has been the subject of extensive reviews [5,6] and a consensus statement from the American Heart Association [7]. This article reviews the supporting epidemiological and animal data, possible pathogenic mechanisms and future perspectives.

A predictive toxicological paradigm for the safety assessment of nanomaterials.

Abstract: The rate of expansion of nanomaterials calls for the consideration of appropriate toxicological paradigms in the safety assessment of nanomaterials. We advocate a predictive toxicological paradigm for the assessment of nanomaterial hazards. The predictive toxicological approach is defined as establishing and using mechanisms and pathways of injury at a cellular and molecular level to prioritize screening for adverse biological effects and health outcomes in vivo. Specifically as it relates to nanomaterials, a predictive approach has to consider the physicochemical properties of the material that leads to molecular or cellular injury and also has to be valid in terms of disease pathogenesis in whole organisms.

The Adjuvant Effect of Ambient Particulate Matter Is Closely Reflected by the Particulate Oxidant Potential

Abstract: BackgroundIt has been demonstrated that ambient particulate matter (PM) can act as an adjuvant for allergic sensitization. Redox-active organic chemicals on the particle surface play an important r...

Mesostructured Silica for Optical Functionality, Nanomachines, and Drug Delivery.

Abstract: Silica thin films and nanoparticles prepared using sol-gel chemistry are derivatized with active molecules to generate new functional materials. The mild conditions associated with sol-gel processing allow for the incorporation of a range of dopants including organic or inorganic dyes, biomolecules, surfactants, and molecular machines. Silica nanoparticles embedded with inorganic nanocrystals, and films containing living cells have also been synthesized. Silica templated with surfactants to create mesostructure contains physically and chemically different regions that can be selectively derivatized using defined techniques to create dynamic materials. Using two different techniques, donor-acceptor pairs can be doped into separated regions simultaneously and photo-induced electron transfer between the molecules can be measured. Mesoporous silica materials are also useful supports for molecular machines. Machines including snap-tops and nanoimpellers that are designed to control the release of guest molecules trapped within the pores are described. Mesoporous silica nanoparticles are promising materials for drug delivery and other biomedical applications because they are nontoxic and can be taken up by living cells. Through appropriate design and synthesis, multifunctional mesoporous silica nanoparticles for sophisticated bio-applications are created.

Oxidative Stress and Asthma: Proteome Analysis of Chitinase-like Proteins and FIZZ1 in Lung Tissue and Bronchoalveolar Lavage Fluid

Abstract: Oxidative stress plays an important role in the development of airway inflammation and hyperreactivity in asthma. The identification of oxidative stress markers in bronchoalveolar lavage fluid (BALF) and lung tissue from ovalbumin (OVA) sensitized mice could provide new insight into disease pathogenesis and possible use of antioxidants to alleviate disease severity. We used two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the impact of the thiol antioxidant, N-acetylcysteine (NAC), on protein expression in a murine OVA model. At least six proteins or protein families were found to be significantly increased in BALF from OVA-challenged mice compared to a control group: Chitinase 3-like protein 3 (Yml), Chitinase 3-like protein 4 (Ym2), acidic mammalian Chitinase (AMCase), pulmonary surfactant-associated protein D (SP-D), resistin-like molecule alpha (RELMalpha) or "found in inflammatory 1" (FIZZ1), and haptoglobin alpha-subunit. A total of nine proteins were significantly increased in lung tissue from the murine asthma model, including Yml, Ym2, FIZZ1, and other lung remodeling-related proteins. Western blotting confirmed increased Yml/Ym2, SP-D, and FIZZ1 expression measured from BAL fluid and lung tissue from OVA-challenged mice. Intraperitoneal NAC administration prior to the final OVA challenge inhibited Yml/Ym2, SP-D, and FIZZ1 expression in BALF and lung tissue. The oxidative stress proteins, Ym1/Ym2, FIZZ1, and SP-D, could play an important role in the pathogenesis of asthma and may be useful oxidative stress markers.

The University of California Center for the Environmental Implications of Nanotechnology

Abstract: Assessing nanomaterials for human health and ecotoxicological impact can be well aided by using high-throughput laboratory methods.

Comparative toxicity of C60 aggregates toward mammalian cells: role of tetrahydrofuran (THF) decomposition.

Abstract: C60 fullerene is a promising material because of its unique physiochemical properties. However, previous studies have reported that colloidal aggregates of C60 (nC60) produce toxicity in fish and human cell cultures. The preparation method of nC60 raises questions as to whether the observed effects stem from fullerenes or from the organic solvents used during the preparation of the suspensions. In this paper, we set out to elucidate the mechanism by which tetrahydrofuran (THF) treatment to enhance the preparation of nC60 leads to cytotoxicity in a mouse macrophage cell line. Our results demonstrate that THF/nC60 but not fullerol or aqueous nC60 generates cellular toxicity through a pathway that involves increased intracellular flux and mitochondrial perturbation in RAW 264.7 cells. Interestingly, the supernatant of the THF/nC60 suspension rather than the colloidal fullerene aggregates mimics the cytotoxic effects due to the presence of γ-butyrolactone and formic acid. Thus, the role of nC60 in the cellula...

The impact of air pollutants as an adjuvant for allergic sensitization and asthma.

Abstract: The current global epidemic of atopy and asthma has been related to the changes in environmental exposures brought about by the development and expansion of industrialized societies. This article reviews the evidence supporting the fundamental role of air pollutants in fostering allergic inflammation of the airways, with emphasis on the molecular and genetic pathways that link ambient particulate matter (PM) exposure to the induction of proinflammatory changes and proallergic effects in the respiratory tract. We propose that the link between PM exposure and proallergic effects involves organic PM components that generate oxygen radicals capable of perturbing the redox equilibrium mucosal immune cells.

Nano-devices having impellers for capture and release of molecules

Abstract: A nanodevice has a containment vessel defining a storage chamber therein and defining at least one port to provide transfer of molecules to or from the storage chamber, and a plurality of impellers attached to the containment vessel. The plurality of impellers are of a structure and are arranged to substantially block molecules from entering and exiting the storage chamber of the containment vessel when the impellers are static and are operable to impart motion to the molecules to cause the molecules to at least one of enter into or exit from the storage chamber of the containment vessel.

Nano-devices having valves for controlled release of molecules

Abstract: A nanodevice has a containment vessel, defining a storage chamber therein and defining at least one port to provide transfer of matter to or from the storage chamber, and a valve assembly attached to the containment vessel. The valve assembly is operable in an aqueous environment. The nanodevice comprises biocompatible materials and has a maximum dimension of less than about 1 μm and greater than about 50 nm.

Reversing the immune decline of aging by a nutraceutical antioxidant in mice

Abstract: The present invention provides a new means of restoring the immune system in aging and immunocompromised individuals using an antioxidant nutraceutical. The nutraceutical stimulates the aging immune system through the Nrf2 master gene regulatory pathway. The invention is based in part on the discovery that the Nrf2 has antioxidant and immune restorative activity. The nutraceutical improves function of both the innate and adaptive immune systems.

Methods and Compositions for Improving Immune Response by a Nutraceutical Antioxidant

Abstract: The present invention provides a new means of restoring the immune system in aging and immunocompromised individuals using an antioxidant nutraceutical. The nutraceutical stimulates the aging immune system through the Nrf2 master gene regulatory pathway. The invention is based in part on the discovery that the Nrf2 has antioxidant and immune restorative activity. The nutraceutical improves function of both the innate and adaptive immune systems.

Inversion du déclin immunitaire lié au vieillissement par un nutraceutique antioxydant chez les souris

Abstract: La presente invention concerne un nouveau moyen de restaurer le systeme immunitaire chez des individus vieillissant et immunocompromis en utilisant un nutraceutique antioxydant. Le nutraceutique stimule le systeme immunitaire vieillissant par la voie de regulation du gene maitre Nrf2. L’invention est basee en partie sur la decouverte que le Nrf2 possede une activite antioxydante et de restauration immunitaire. Le nutraceutique ameliore le fonctionnement des systemes immunitaires inne et adaptatif.