Carbon nanotubes as nanomedicines: from toxicology to pharmacology

Various biomedical applications of carbon nanotubes have been proposed in the last few years leading to the emergence of a new field in diagnostics and therapeutics. Most of these applications will involve the administration or implantation of carbon nanotubes and their matrices into patients. The toxicological and pharmacological profile of such carbon nanotube systems developed as nanomedicines will have to be determined prior to any clinical studies undertaken. This review brings together all the toxicological and pharmacological in vivo studies that have been carried out using carbon nanotubes, to offer the first summary of the state-of-the-art in the pharmaceutical development of carbon nanotubes on the road to becoming viable and effective nanomedicines.     

Opportunities and challenges of carbon-based nanomaterials for cancer therapy

The possibility of incorporating carbon-based nanomaterials into living systems has opened the way for the investigation of their potential applications in the emerging field of nanomedicine. A wide variety of different nanomaterials based on allotropic forms of carbon, such as nanotubes, nanohorns and nanodiamonds, are currently being explored towards different biomedical applications. In this review, we discuss the recent advances in the development of these novel nanomaterials for cancer therapy. A comparison between the characteristics, the advantages, the drawbacks, the benefits and the risks associated with these novel biocompatible forms of carbon is presented here.     

The alluring potential of functionalized carbon nanotubes in drug discovery

Importance of the field: The possibility of carbon nanotube integration into living systems for therapeutic and diagnostic purposes has opened the way to explore their applications in drug delivery and discovery. A wide variety of chemical approaches has been developed to functionalize carbon nanotubes with therapeutic molecules towards different biomedical uses. Areas covered in this review: This review covers the recent advances in the development of functionalized carbon nanotubes to offer improvements for different diseases, in particular for cancer therapy. What the reader will gain: Functionalized carbon nanotubes are able to transport therapeutic agents. Targeted methodologies using carbon nanotube-based conjugates have been investigated to improve the efficacy of some drugs. The capacity of such nanomaterials to seamlessly translocate into cells with alternative various mechanisms and their pharmacokinetic properties is also discussed. Take home message: Although at its infancy, functionalized carbon nanotubes are very promising as a new nanomedicine platform in the field of drug discovery and delivery. They have the capacity to cross biological barriers and can be eliminated via renal and/or fecal excretion. They can transport small drug molecules while maintaining - and in some cases improving - their therapeutic efficacy.     

The emerging field of nanotube biotechnology

Nanoparticles are being developed for a host of biomedical and biotechnological applications, including drug delivery, enzyme immobilization and DNA transfection. Spherical nanoparticles are typically used for such applications, which reflects the fact that spheres are easier to make than other shapes. Micro- and nanotubes--structures that resemble tiny drinking straws--are alternatives that might offer advantages over spherical nanoparticles for some applications. This article discusses four approaches for making micro- and nanotubes, and reviews the current status of efforts to develop biomedical and biotechnological applications of these tubular structures.     

The alluring potential of functionalized carbon nanotubes in drug discovery

Importance of the field: The possibility of carbon nanotube integration into living systems for therapeutic and diagnostic purposes has opened the way to explore their applications in drug delivery and discovery. A wide variety of chemical approaches has been developed to functionalize carbon nanotubes with therapeutic molecules towards different biomedical uses.

Areas covered in this review: This review covers the recent advances in the development of functionalized carbon nanotubes to offer improvements for different diseases, in particular for cancer therapy.

What the reader will gain: Functionalized carbon nanotubes are able to transport therapeutic agents. Targeted methodologies using carbon nanotube-based conjugates have been investigated to improve the efficacy of some drugs. The capacity of such nanomaterials to seamlessly translocate into cells with alternative various mechanisms and their pharmacokinetic properties is also discussed.

Take home message: Although at its infancy, functionalized carbon nanotubes are very promising as a new nanomedicine platform in the field of drug discovery and delivery. They have the capacity to cross biological barriers and can be eliminated via renal and/or fecal excretion. They can transport small drug molecules while maintaining – and in some cases improving – their therapeutic efficacy.     

Smart nanotubes for biotechnology

Nanotechnology concerns the science of very small particles and deals with both the fundamental aspects of understanding the properties of such nanoparticles and with developing technological applications of nanoparticles. Biomedical and biotechnological applications of nanoparticles have been of special recent research and development interest, with potential applications that include use of nanoparticles as drug (or DNA) delivery vehicles, and as components in medical diagnostic kits, biosensors and membranes for bioseparations. Spherical nanoparticles are typically used for such applications, but this only reflects the fact that spheres are easier to make than nanoparticles having other shapes. Micro and nanotubes - structures that resemble tiny drinking straws - are alternatives and may offer advantages over spherical nanoparticles for some applications. This article discusses different approaches for making micro and nanotubes and reviews the current status of efforts to develop biomedical and biotechnological applications of these tubular structures.     

Smart nanotubes for biomedical and biotechnological applications

Nanoparticles are being developed for a host of biomedical and biotechnological applications including drug delivery, enzyme immobilization and DNA transfection. Spherical nanoparticles are typically used for such applications, but this only reflects the fact that spheres are easier to make than other shapes. Micro- and nanotubes--structures that resemble tiny drinking straws--are alternatives and may offer advantages over spherical nanoparticles for some applications. This article discusses four different approaches to making micro- and nanotubes and reviews the current status of efforts to develop biomedical and biotechnological applications of these tubular structures.     

Carbon nanotubes: Their potential and pitfalls for bone tissue regeneration and engineering

The extracellular environment which supports cell life is composed of a hierarchy of maintenance, force and regulatory systems which integrate from the nano- through to macroscale. For this reason, strategies to recreate cell supporting environments have been investigating the use of nanocomposite biomaterials. Here, we review the use of carbon nanotubes as part of a bottom-up approach for use in bone tissue engineering. We evaluate the properties of carbon nanotubes in the context of synthetic tissue substrates and contrast them with the nanoscale features of the extracellular environment. Key studies are evaluated with an emphasis on understanding the mechanisms through which carbon nanotubes interact with biological systems. This includes an examination of how the different properties of carbon nanotubes affect tissue growth, how these properties and variation to them might be leveraged in regenerative tissue therapies and how impurities or contaminates affect their toxicity and biological interaction.From the Clinical EditorIn this comprehensive review, the authors describe the status and potential applications of carbon nanotubes in bone tissue engineering.     

Carbon nanotubes as vectors for gene therapy: Past achievements,present challenges and future goals

Promising therapeutic and prophylactic effects have been achieved following advances in the gene therapy research arena, giving birth to the new generation of disease-modifying therapeutics. The greatest challenge that gene therapy vectors still face is the ability to deliver sufficient genetic payloads in order to enable efficient gene transfer into target cells. A wide variety of viral and non-viral gene therapy vectors have been developed and explored over the past 10 years, including carbon nanotubes. In this review we will address the application of carbon nanotubes as non-viral vectors in gene therapy with the aim to give a perspective on the past achievements, present challenges and future goals. A series of important topics concerning carbon nanotubes as gene therapy vectors will be addressed, including the benefits that carbon nanotubes offer over other non-viral delivery systems. Furthermore, a perspective is given on what the ideal genetic cargo to deliver using carbon nanotubes is and finally the geno-pharmacological impact of carbon nanotube-mediated gene therapy is discussed.     

Conditional somatic mutagenesis in the mouse using site-specific recombinases

In the last decade, site-specific recombinases (SSRs), such as Cre and Flp, have emerged as indispensable tools for the precise in vivo manipulation of the mouse genome. It is now feasible to control, in space and time, the onset of gene knockouts in almost any tissue of the mouse, thus greatly facilitating the creation of sophisticated animal models for human disease and drug development. This review describes the basic principles and current status of the SSR technology, with a focus on strategies for conditional somatic mutagenesis using the Cre/lox system and ligand-activated Cre recombinases. Practical hints for generating and analysing conditional mouse mutants will be given and exciting novel applications of the SSR technology will be discussed, such as cell fate mapping and the combined use of Cre, Flp and other biotechnological tools. It will be shown how genetic manipulation of the mouse by site-specific recombination can provide new solutions to old problems in the analysis of human physiology and pathophysiology and how it can be employed for drug discovery and development.     

Potential pulmonary effects of engineered carbon nanotubes: in vitro genotoxic effects

Abstract

The development of novel engineered nano-sized materials is a rapidly emerging technology with many applications in medicine and industry. In vitro and in vivo studies have suggested many deleterious effects of carbon nanotube exposure including granulomatous inflammation, release of cytosolic enzymes, pulmonary fibrosis, reactive oxygen damage, cellular atypia, DNA fragmentation, mutation and errors in chromosome number as well as mitotic spindle disruption. The physical properties of the carbon nanotubes make respiratory exposure to workers likely during the production or use of commercial products. Many of the investigations of the genotoxicity of carbon nanotubes have focused on reactive oxygen mediated DNA damage; however, the long thin tubular-shaped carbon nanotubes have a striking similarity to cellular microtubules. The similarity of carbon nanotubes to microtubules suggests a potential to interact with cellular biomolecules, such as the mitotic spindle, as well as the motor proteins that separate the chromosomes during cell division. Disruption of centrosomes and mitotic spindles would result in monopolar, tripolar, and quadrapolar divisions of chromosomes. The resulting aneuploidy is a key mechanism in the potential carcinogenicity of carbon nanotubes.     

Exposure to carbon nanotube material: assessment of nanotube cytotoxicity using human keratinocyte cells

Carbon nanotubes are new members of carbon allotropes similar to fullerenes and graphite. Because of their unique electrical, mechanical, and thermal properties, carbon nanotubes are important for novel applications in the electronics, aerospace, and computer industries. Exposure to graphite and carbon materials has been associated with increased incidence of skin diseases, such as carbon fiber dermatitis, hyperkeratosis, and naevi. We investigated adverse effects of single-wall carbon nanotubes (SWCNT) using a cell culture of immortalized human epidermal keratinocytes (HaCaT). After 18 h of exposure of HaCaT to SWCNT, oxidative stress and cellular toxicity were indicated by formation of free radicals, accumulation of peroxidative products, antioxidant depletion, and loss of cell viability. Exposure to SWCNT also resulted in ultrastructural and morphological changes in cultured skin cells. These data indicate that dermal exposure to unrefined SWCNT may lead to dermal toxicity due to accelerated oxidative stress in the skin of exposed workers.     

Exposure to Carbon Nanotube Material: Assessment of Nanotube Cytotoxicity using Human Keratinocyte Cells

Carbon nanotubes are new members of carbon allotropes similar to fullerenes and graphite. Because of their unique electrical, mechanical, and thermal properties, carbon nanotubes are important for novel applications in the electronics, aerospace, and computer industries. Exposure to graphite and carbon materials has been associated with increased incidence of skin diseases, such as carbon fiber dermatitis, hyperkeratosis, and naevi. We investigated adverse effects of single-wall carbon nanotubes (SWCNT) using a cell culture of immortalized human epidermal keratinocytes (HaCaT). After 18 h of exposure of HaCaT to SWCNT, oxidative stress and cellular toxicity were indicated by formation of free radicals, accumulation of peroxidative products, antioxidant depletion, and loss of cell viability. Exposure to SWCNT also resulted in ultrastructural and morphological changes in cultured skin cells. These data indicate that dermal exposure to unrefined SWCNT may lead to dermal toxicity due to accelerated oxidative stress in the skin of exposed workers.     

Nanosafety studies of nanomaterials about biodistribution and immunotoxicity

A diverse array of nanomaterials such as nanosilicas and carbon nanotubes are in widespread use due to the development of nanotechnology. Nanomaterials are already being applied in universal fields such as electronics, sunscreens, cosmetics, and medicine, because they have unique physicochemical properties such as high conductivity, strength, durability, and chemical reactivity. The advent of nanomaterials has also provided extraordinary opportunities for biomedical applications. However, the increasing use of nanomaterials has raised public concern about their potential risks to human health. In particular, recent reports have indicated that carbon nanotubes induced exaggerated inflammation and mesothelioma-like lesions in mice. However, few studies have examined the immunotoxicity of nanomaterials and it is essential to progress studies on the immunotoxicity of nanomaterials to ensure their safety. In this regard, we have attempted to elucidate the pharmacodynamics and immunotoxicity of nanomaterials, in order to develop novel safe nanomaterials and to establish scientifically based regulations. In this review, we would like to introduce our data on the immunotoxicity of nanosilicas, especially the relationship between physical properties (primary grain size, configuration and surface charge), pharmacodynamics of these materials, and their immunotoxicity. We consider that our study will improve the quality of human life by safely using nanomaterials, which can benefit society in general.     

Developing Xenopus embryos recover by compacting and expelling single wall carbon nanotubes

Single wall carbon nanotubes are high aspect ratio nanomaterials being developed for use in materials, technological and biological applications due to their high mechanical stiffness, optical properties and chemical inertness. Because of their prevalence, it is inevitable that biological systems will be exposed to nanotubes, yet studies of the effects of nanotubes on developing embryos have been inconclusive and are lacking for single wall carbon nanotubes exposed to the widely studied model organism Xenopus laevis (African clawed frog). Microinjection of experimental substances into the Xenopus embryo is a standard technique for toxicology studies and cellular lineage tracing. Here we report the surprising finding that superficial (12.5 ± 7.5 µm below the membrane) microinjection of nanotubes dispersed with Pluronic F127 into one‐ to two‐cell Xenopus embryos resulted in the formation and expulsion of compacted, nanotube‐filled, punctate masses, at the blastula to mid‐gastrula developmental stages, which we call “boluses.” Such expulsion of microinjected materials by Xenopus embryos has not been reported before and is dramatically different from the typical distribution of the materials throughout the progeny of the microinjected cells. Previous studies of microinjections of nanomaterials such as nanodiamonds, quantum dots or spherical nanoparticles report that nanomaterials often induce toxicity and remain localized within the embryos. In contrast, our results demonstrate an active recovery pathway for embryos after exposure to Pluronic F127‐coated nanotubes, which we speculate is due to a combined effect of the membrane activity of the dispersing agent, Pluronic F127, and the large aspect ratio of nanotubes. Copyright © 2015 John Wiley & Sons, Ltd.     

Multi-walled carbon nanotubes induce T lymphocyte apoptosis

Carbon nanotubes are a man-made form of carbon that did not exist in our environment until very recently. Due to their unique chemical, physical, optical, and magnetic properties, carbon nanotubes have found many uses in industrial products and in the field of nanotechnology, including in nanomedicine. However, very little is yet known about the toxicity of carbon nanotubes. Here, we compare the toxicity of pristine and oxidized multi-walled carbon nanotubes on human T cells and find that the latter are more toxic and induce massive loss of cell viability through programmed cell death at doses of 400 microg/ml, which corresponds to approximately 10 million carbon nanotubes per cell. Pristine, hydrophobic, carbon nanotubes were less toxic and a 10-fold lower concentration of either carbon nanotube type were not nearly as toxic. Our results suggest that carbon nanotubes indeed can be very toxic at sufficiently high concentrations and that careful toxicity studies need to be undertaken particularly in conjunction with nanomedical applications of carbon nanotubes.     

In vitro cytotoxicity of functionalized single walled carbon nanotubes for targeted gene delivery applications

Carbon nanotubes are a novel class of nanomaterials that have great potential in the field of biomedical research. This study investigates the cytotoxic effects of functionalized single walled carbon nanotubes (SWNTs) at different concentrations on a colon cancer cell line. Colorectal cancer cells were exposed to single walled carbon nanotubes functionalized with a green fluorescent protein expressing plasmid. The internalization of the nanotube-plasmid DNA complexes and their cytotoxicity were analyzed. The results indicate successful functionalization of the nanotubes and subsequent internalization of the nanotube-plasmid DNA complex by the cancer cells. The cytotoxicity was found to be significantly lower compared to a control. Cell viability was shown to have reduced with an increase in carbon nanotube concentration implying that SWNTs can be cytotoxic at higher dosages. The results show that SWNTs can be successfully used in gene delivery applications and their cytotoxic effects can be limited by optimizing the dosage levels.     

Hemotoxicity of carbon nanotubes

Carbon nanotubes may enter into the bloodstream and interact with blood components indirectly via translocation following unintended exposure or directly after an intended administration for biomedical purposes. Once introduced into systemic circulation, nanotubes will encounter various proteins, biomolecules or cells which have specific roles in the homeostasis of the circulatory system. It is therefore essential to determine whether those interactions will lead to adverse effects or not. Advances in the understanding of how carbon nanotubes interact with blood proteins, the complement system, red blood cells and the hemostatic system are reviewed in this article. While many studies on carbon nanotube health risk assessment and their biomedical applications have appeared in the last few years, reports on the hemocompatibility of these nanomaterials remain surprisingly limited. Yet, defining the hemotoxicological profile is a mandatory step toward the development of clinically-relevant medications or contrast agents based on carbon nanotubes.     

Carbon nanotubes in drug delivery: focus on infectious diseases

Carbon nanotubes have the potential to address the challenges of combating infectious agents by both minimizing toxicity by dose reduction of standard therapeutics and allowing a multiple payload capacity to achieve both targeted activity and combating infectious strains, resistant strains in particular. One of their unique characteristics is the network of carbon atoms in the nanometer scale, allowing the creation of nano-channels via cellular membranes. This review focuses on the characterization, development, integration and application of carbon nanotubes as nanocarrier-based delivery systems and their appropriate design for achieving the desired drug delivery results in the different areas of infectious diseases. While a more extensive toxicological and pharmacological profile must be obtained, this review will focus on existing research and pre-clinical data concerning the potential use of carbon nanotubes.     

Molecular diagnostic and drug delivery agents based on aptamer-nanomaterial conjugates

Recent progress in an emerging area of designing aptamer and nanomaterial conjugates as molecular diagnostic and drug delivery agents in biomedical applications is summarized. Aptamers specific for a wide range of targets are first introduced and compared to antibodies. Methods of integrating these aptamers with a variety of nanomaterials, such as gold nanoparticles, quantum dots, carbon nanotubes, and superparamagnetic iron oxide nanoparticles, each with unique optical, magnetic, and electrochemical properties, are reviewed. Applications of these systems as fluorescent, colorimetric, magnetic resonance imaging, and electrochemical sensors in medical diagnostics are given, along with new applications as smart drug delivery agents.