Chunying Chen

Understanding the Toxicity of Carbon Nanotubes

Because of their unique physical, chemical, electrical, and mechanical properties, carbon nanotubes (CNTs) have attracted a great deal of research interest and have many potential applications. As large-scale production and application of CNTs increases, the general population is more likely to be exposed to CNTs either directly or indirectly, which has prompted considerable attention about human health and safety issues related to CNTs. Although considerable experimental data related to CNT toxicity at the molecular, cellular, and whole animal levels have been published, the results are often conflicting. Therefore, a systematic understanding of CNT toxicity is needed but has not yet been developed. In this Account, we highlight recent investigations into the basis of CNT toxicity carried out by our team and by other laboratories. We focus on several important factors that explain the disparities in the experimental results of nanotoxicity, such as impurities, amorphous carbon, surface charge, shape, length, agglomeration, and layer numbers. The exposure routes, including inhalation, intravenous injection, or dermal or oral exposure, can also influence the in vivo behavior and fate of CNTs. The underlying mechanisms of CNT toxicity include oxidative stress, inflammatory responses, malignant transformation, DNA damage and mutation (errors in chromosome number as well as disruption of the mitotic spindle), the formation of granulomas, and interstitial fibrosis. These findings provide useful insights for de novo design and safe application of carbon nanotubes and their risk assessment to human health. To obtain reproducible and accurate results, researchers must establish standards and reliable detection methods, use standard CNT samples as a reference control, and study the impact of various factors systematically. In addition, researchers need to examine multiple types of CNTs, different cell lines and animal species, multidimensional evaluation methods, and exposure conditions. To make results comparable among different institutions and countries, researchers need to standardize choices in toxicity testing such as that of cell line, animal species, and exposure conditions. The knowledge presented here should lead to a better understanding of the key factors that can influence CNT toxicity so that their unwanted toxicity might be avoided.

Mesoporous silica-coated gold nanorods as a light-mediated multifunctional theranostic platform for cancer treatment.

Mesoporous silica-coated gold nanorods (Au@SiO(2)) are developed as a promising and versatile theranostic platform for cancer treatment. Intracellular localization of Au@SiO(2) is visualized through two-photon imaging. With doxorubicin hydrochloride loaded, Au@SiO(2)-DOX show two light-mediated therapeutic modes: low power density laser-triggered drug release for chemotherapy, and high power density laser-induced hyperthermia, which suggest the potential for in-vivo applications.

Cellular Uptake, Intracellular Trafficking, and Cytotoxicity of Nanomaterials

The interactions of nanoparticles with the soft surfaces of biological systems like cells play key roles in executing their biomedical functions and in toxicity. The discovery or design of new biomedical functions, or the prediction of the toxicological consequences of nanoparticles in vivo, first require knowledge of the interplay processes of the nanoparticles with the target cells. This article focusses on the cellular uptake, location and translocation, and any biological consequences, such as cytotoxicity, of the most widely studied and used nanoparticles, such as carbon-based nanoparticles, metallic nanoparticles, and quantum dots. The relevance of the size and shape, composition, charge, and surface chemistry of the nanoparticles in cells is considered. The intracellular uptake pathways of the nanoparticles and the cellular responses, with potential signaling pathways activated by nanoparticle interactions, are also discussed.

Binding of blood proteins to carbon nanotubes reduces cytotoxicity

With the potential wide uses of nanoparticles such as carbon nanotubes in biomedical applications, and the growing concerns of nanotoxicity of these engineered nanoparticles, the importance of nanoparticle–protein interactions cannot be stressed enough. In this study, we use both experimental and theoretical approaches, including atomic force microscope images, fluorescence spectroscopy, CD, SDS-PAGE, and molecular dynamics simulations, to investigate the interactions of single-wall carbon nanotubes (SWCNTs) with human serum proteins, and find a competitive binding of these proteins with different adsorption capacity and packing modes. The π-π stacking interactions between SWCNTs and aromatic residues (Trp, Phe, Tyr) are found to play a critical role in determining their adsorption capacity. Additional cellular cytotoxicity assays, with human acute monocytic leukemia cell line and human umbilical vein endothelial cells, reveal that the competitive bindings of blood proteins on the SWCNT surface can greatly alter their cellular interaction pathways and result in much reduced cytotoxicity for these protein-coated SWCNTs, according to their respective adsorption capacity. These findings have shed light toward the design of safe carbon nanotube nanomaterials by comprehensive preconsideration of their interactions with human serum proteins.

Surface chemistry and aspect ratio mediated cellular uptake of Au nanorods.

Gold nanorods (Au NRs) have been recognized as promising materials for biomedical applications, like sensing, imaging, gene and drug delivery and therapy, but their toxicological issues are still controversial, especially for the Au NRs synthesized with seed-mediated method. In this study, we investigated the influence of aspect ratio and surface coating on their toxicity and cellular uptake. The cellular uptake is highly dependent on the aspect ratio and surface coating. However, the surface chemistry has the dominant roles since PDDAC-coated Au NRs exhibit a much greater ability to be internalized by the cells. The present data demonstrated shape-independent but coating-dependent cytotoxicity. Both the CTAB molecules left in the suspended solution and on the surface of Au NRs were identified as the actual cause of cytotoxicity. CTAB can enter cells with or without Au NRs, damage mitochondria, and then induce apoptosis. The effects of surface coating upon toxicity and cellular uptake were also examined using Au NRs with different coatings. When Au NRs were added into the medium, the proteins were quickly adsorbed onto the Au NRs that made the surface negatively charged. The surface charge may not directly affect the cellular uptake. We further demonstrated that the amount of serum proteins, especially for BSA, adsorbed on the Au NRs had a positive correlation with the capacity of Au NRs to enter cells. In addition, we have successfully revealed that the cationic PDDAC-coated Au NRs with an aspect ratio of 4 possess an ideal combination of both negligible toxicity and high cellular uptake efficiency, showing a great promise as photothermal therapeutic agents.

Selective targeting of gold nanorods at the mitochondria of cancer cells: Implications for cancer therapy

We have observed that Au nanorods (NRs) have distinct effects on cell viability via killing cancer cells while posing negligible impact on normal cells and mesenchymal stem cells. Obvious differences in cellular uptake, intracellular trafficking, and susceptibility of lysosome to Au NRs by different types of cells resulted in selective accumulation of Au NRs in the mitochondria of cancer cells. Their long-term retention decreased mitochondrial membrane potential and increased reactive oxygen species level that enhances the likelihood of cell death. These findings thus provide guidance for the design of organelle-targeted nanomaterials in tumor therapy.

Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO2 nanoparticles

Nanoparticles can be administered via nasal, oral, intraocular, intratracheal (pulmonary toxicity), tail vein and other routes. Here, we focus on the time-dependent translocation and potential damage of TiO(2) nanoparticles on central nervous system (CNS) through intranasal instillation. Size and structural properties are important to assess biological effects of TiO(2) nanoparticles. In present study, female mice were intranasally instilled with two types of well-characterized TiO(2) nanoparticles (i.e. 80 nm, rutile and 155 nm, anatase; purity>99%) every other day. Pure water instilled mice were served as controls. The brain tissues were collected and evaluated for accumulation and distribution of TiO(2), histopathology, oxidative stress, and inflammatory markers at post-instillation time points of 2, 10, 20 and 30 days. The titanium contents in the sub-brain regions including olfactory bulb, cerebral cortex, hippocampus, and cerebellum were determined by inductively coupled plasma mass spectrometry (ICP-MS). Results indicated that the instilled TiO(2) directly entered the brain through olfactory bulb in the whole exposure period, especially deposited in the hippocampus region. After exposure for 30 days, the pathological changes were observed in the hippocampus and olfactory bulb using Nissl staining and transmission electron microscope. The oxidative damage expressed as lipid peroxidation increased significantly, in particular in the exposed group of anatase TiO(2) particles at 30 days postexposure. Exposure to anatase TiO(2) particles also produced higher inflammation responses, in association with the significantly increased tumor necrosis factor alpha (TNF-alpha) and interleukin (IL-1 beta) levels. We conclude that subtle differences in responses to anatase TiO(2) particles versus the rutile ones could be related to crystal structure. Thus, based on these results, rutile ultrafine-TiO(2) particles are expected to have a little lower risk potential for producing adverse effects on central nervous system. Although understanding the mechanisms requires further investigation, the present results suggest that we should pay attention to potential risk of occupational exposure for large-scaled production of TiO(2) nanoparticles.

Near-infrared light-mediated nanoplatforms for cancer thermo-chemotherapy and optical imaging.

While thermo-chemotherapy has proved to be effective in optimizing the efficacies of cancer treatments, traditional chemotherapy is subject to adverse side effects and heat delivery is often challenging in operation. Some photothermal inorganic nanoparticles responsive to near infrared light provide new opportunities for simultaneous and targeted delivery of heat and chemotherapeutics to the tumor sites in pursuit of synergistic effects for efficacy enhancement. The state of the art of nanoparticle-induced thermo-chemotherapy is summarized and the advantages and challenges of the major nanoplatforms based on gold nanoparticles, carbon nanomaterials, palladium nanosheets, and copper-based nanocrystals are highlighted. In addition, the optical-imaging potentials of the nanoplatforms that may endow them with imaging-guided therapy and therapeutic-result-monitoring capabilities are also briefly discussed.

Au@Pt nanostructures as oxidase and peroxidase mimetics for use in immunoassays

In this paper, we demonstrated that Au nanorods coated with a shell composed of Pt nanodots (Au@Pt nanostructures) exhibited intrinsic oxidase-like, peroxidase-like and catalase-like activity, catalyzing oxygen and hydrogen peroxide reduction and the dismutation decomposition of hydrogen peroxide to produce oxygen. Based on these findings, we established an Au@Pt nanostructures based enzyme linked immunosorbent assay (ELISA) for the detection of mouse interleukin 2 (IL-2). In comparison with natural enzymes, Au@Pt nanostructures have advantages of low cost, easy preparation, better stability, and tunable catalytic activity (compared with HRP), which make them a promising enzyme mimetic candidate and may find potential applications in biocatalysis, bioassays, and nano-biomedicine such as reactive oxygen species (ROS)-related fields (anti-aging and therapeutics for neurodegenerative diseases and cancers).

Near Infrared Laser-Induced Targeted Cancer Therapy Using Thermoresponsive Polymer Encapsulated Gold Nanorods

External stimuli, such as ultrasound, magnetic field, and light, can be applied to activate in vivo tumor targeting. Herein, we fabricated polymer encapsulated gold nanorods to couple the photothermal properties of gold nanorods and the thermo- and pH-responsive properties of polymers in a single nanocomposite. The activation mechamism was thus transformed from heat to near-infrared (NIR) laser, which can be more easily controlled. Doxorubicin, a clinical anticancer drug, can be loaded into the nanocomposite through electrostatic interactions with high loading content up to 24%. The nanocomposites accumulation in tumor post systematic administration can be significantly enhanced by NIR laser irradiation, providing a prerequisite for their therapeutic application which almost completely inhibited tumor growth and lung metastasis. Since laser can be manipulated very precisely and flexibly, the nanocomposite provides an ideally versatile platform to simultaneously deliver heat and anticancer drugs in a laser-activation mechanism with facile control of the area, time, and dosage. The NIR laser-induced targeted cancer thermo-chemotherapy without using targeting ligands represents a novel targeted anticancer strategy with facile control and practical efficacy.