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This book explores the potential of multi-functional carbon nanotubes for biomedical applications. It combines contributions from chemistry, physics, biology, engineering, and medicine. The complete overview of the state-of-the-art addresses different synthesis and biofunctionalisation routes and shows the structural and magnetic properties of nanotubes relevant to biomedical applications. Particular emphasis is put on the interaction of carbon nanotubes with biological environments, i.e. toxicity, biocompatibility, cellular uptake, intracellular distribution, interaction with the immune system and environmental impact. The insertion of NMR-active substances allows diagnostic usage as markers and sensors, e.g. for imaging and contactless local temperature sensing. The potential of nanotubes for therapeutic applications is highlighted by studies on chemotherapeutic drug filling and release, targeting and magnetic hyperthermia studies for anti-cancer treatment at the cellular level.



Fundamentals: Synthesis of multifunctional nanomaterials and their potential for medical application


Physical Properties of Carbon Nanotubes for Therapeutic Applications

Carbon nanotubes (CNTs) are molecular-scale tubes of graphitic carbon with outstanding properties. They are among the stiffest and strongest fibres known, and have remarkable electronic properties and many other unique characteristics. For these reasons they have attracted huge academic and industrial interest, with thousands of papers on nanotubes being published every year. Applications of CNTs in the field of biotechnology have emerged, raising great hopes. The discovery of carbon nanotubes has the potential of revolutionizing biomedical research as they can show superior performance over other nanoparticles. The advantage lies in a unique, unprecedented combination of electrical, magnetic, optical and chemical properties which is greatly promising for the development of a new class of CNT-based drugs and therapy. In the following discussion a brief summary of the CNT physical properties and how they can serve these purposes will be provided, followed by an overview of the current state of the art and the future perspectives.
Vittoria Raffa, Orazio Vittorio, Cristina Riggio, Gianni Ciofani, Alfred Cuschieri

Carbon Nanotubes in Regenerative Medicine

This chapter focuses on the latest developments in applications of carbonnanotubes (CNTs) for regenerative medicine. Regenerative Medicine focuses on technologies to create functional tissues to repair or replace tissues or organs lost due to trauma or disease. Carbon nonotubes (CNTs) have been under investigation in the past decade for an array of applications due to their unique and versatile properties. In the field of regenerative medicine, they have shown great promise to improve the properties of tissue engineering scaffolds. Drug delivery and imaging of engineering tissues. The chapter will review these latest advances
Bhavna S. Paratala, Balaji Sitharaman

Filling of Carbon Nanotubes with Compounds in Solution or Melted Phase

Since their discovery, carbon nanotubes (CNT) have been found to exhibit remarkable structural, mechanical and electronic properties. One such property is the ability to encapsulate foreign materials inside their cylindrical cavity, for application in different fields. The procedures to fill CNT may be classified into two main groups: (a) filling in solution, using the wet chemistry route and (b) filling with a melted phase. In both cases, the filling is induced by the capillary forces. It is also possible to fill CNT in the vapour phase, although there are only few very specific examples available in the literature to date. After filling, oxides and metallic particles can be obtained by a subsequent thermal annealing in the required atmosphere. In the wet chemistry route, the nanotubes are usually treated by an oxidizing agent in order to open their tips. The filling is then performed by placing the opened tubes in a solution of the selected compound (or a precursor). When the compound is dissolved in an oxidizing acid such as nitric acid (HNO3), it is possible to combine opening and filling in a single step. Although this method allows the introduction of heat-sensitive species inside carbon nanotubes, the yield varies strongly with the diameter of the carbon nanotubes and is generally rather low in the case of CNT with a small inner diameter. This filling route mainly leads to isolated nanoparticles or short nanowires. Filling with melted compounds is a solvent-free route. The CNT are directly immersed in the melted material and capillary forces drive the compound into the CNT. Although this route is more restrictive in terms of materials, it allows for the continuous filling of CNT with long nanocrystals (up to a few micrometers), with a higher filling yield in the available CNT (up to ca. 70%). This chapter will describe these two different methods for filling CNT and illustrate them with a few selected examples.
P. Lukanov, C.-M. Tîlmaciu, A. M. Galibert, B. Soula, E. Flahaut

Filling of Carbon Nanotubes: Containers for Magnetic Probes and Drug Delivery

Nanotechnology is a broad scientific field but one of the most explored materials in nanotechnology is carbon nanotube (CNT). A large proportion of research on CNTs is focused on their huge potential for biomedical applications. Within this context, the synthesis of carbon nanotubes filled with magnetic materials has been widely investigated, especially with iron due to its excellent ferromagnetic characteristics. Pure iron-filled carbon nanotubes (Fe-CNT) can be prepared following diverse routes. Here, an overview of the different preparation routes of Fe-CNT, using the chemical vapour deposition (CVD) synthesis method will be presented. Several working parameters were varied and investigated, the most significant being the pressure of the system, the iron and the carbon sources. The consequence of these modifications is reflected in the structure of the final material, which varies in respect of the amount of iron encapsulated in the cavity, tube diameter and the number of graphitic walls forming the CNT. The filling of hollow CNT through wet chemistry reactions (as a post-synthesis route) and CVD process (filling during the synthesis of CNTs) will also be addressed in this chapter.
E. Borowiak-Palen, C. Tripisciano, M. Rümmeli, S. Costa, X. Chen, R. J. Kalenczuk

Magnetically functionalised carbon nanotubes for medical diagnosis and therapy


Magnetic Nanoparticles for Diagnosis and Medical Therapy

Magnetic nanoparticles (MNPs) reveal promising opportunities for biomedical applications, potentially allowing minimally invasive diagnosis and therapeutic usage at several levels of human body organization (cells, tissue and organs). An increasingly broad collection of MNPs has been recently developed not only at the research level but also in some specific cases for medical applications. Superparamagnetic iron oxide (SPIO) nanoparticles are commonly used in clinical practice as contrast agents for magnetic resonance imaging (MRI) of liver and angiography. Carbon nanotubes (CNTs) are another type of nanomaterials with great potential for biomedical applications. Filled with ferromagnetic materials, an ensemble of aligned CNTs displays a highly non-linear, anisotropic and hysteretic magnetization behaviour due to their extremely high aspect ratio (length/diameter >100). The intrinsic properties of such ferromagnetic nanoparticles can potentially improve diagnosis and therapy of numerous diseases. Combining tailored biocompatible ferromagnetic nanomaterials with dedicated detection technology can provide a new approach leading to the exciting perspective of accurate medical imaging and medical therapy (magnetic hyperthermia, targeted drug delivery, etc.) at the cellular level. Elongated Fe-filled CNTs (Fe-CNTs) are foreseen as potential nanotools leading to minimally invasive, highly sensitive, and cost effective novel investigation routes for complete human body systems.
Martin Sobik, Kirsten M. Pondman, Ben Erné, Bonny Kuipers, Bennie ten Haken, Horst Rogalla

Feasibility of Magnetically Functionalised Carbon Nanotubes for Biological Applications: From Fundamental Properties of Individual Nanomagnets to Nanoscaled Heaters and Temperature Sensors

We discuss the prospects of applying the magnetic properties of magnetically functionalised carbon nanotubes to biomedical applications. The primary applications are use as a contactless local heating agent, as a standalone thermoablation treatment or in concert with remotely released anti-cancer drugs. Targeted heat treatment is an effective cancer treatment, as tumour tissue has a reduced heat tolerance. To understand the heating process in an applied alternating current (AC) magnetic field the basics of the ferro- and superparamagnetic heating mechanisms are described and brought into context with the material properties. The performance of various materials is compared with respect to heat output, and prospect of additional functionalisation. The actual heating output in AC magnetic fields is studied and discussed in this chapter. Hall magnetometry and Magnetic Force Microscopy are employed to study the magnetic properties of individual nano-ferromagnets, e.g. magnetisation reversal behaviour and domain configuration. NMR studies show that a non-invasive temperature control by virtue of a carbon-wrapped nanoscaled thermometer is feasible.
Matthias U. Lutz, Kamil Lipert, Yulia Krupskaya, Stefan Bahr, Anja Wolter, Ahmed A. El-Gendy, Silke Hampel, Albrecht Leonhardt, Arthur Taylor, Kai Krämer, Bernd Büchner, Rüdiger Klingeler

Nuclear Magnetic Resonance Spectroscopy and Imaging of Carbon Nanotubes

Nuclear magnetic resonance (NMR) spectroscopy is one of the most versatile and powerful analytical tools developed in the last century and have been proven to be a suitable means for the elucidation of structural properties as well as physico-chemical characteristics in chemistry and material sciences. In the first part of this chapter a review is given on the investigation of different types of carbon nanotube (CNT) structures and properties by solution-state NMR, solid state NMR and high-resolution magic angle spinning (HR-MAS) NMR spectroscopy. (Nuclear) Magnetic resonance imaging (MRI) is one of the most powerful noninvasive diagnostic techniques used in clinical medicine for in vivo assessment of anatomy and biological functions. CNTs are unique materials that can be used as a platform for the synthesis of hybrid construct molecules capable of enabling multiple biomedical applications in vitro and in vivo as molecular transporters for drug delivery, and potential new therapeutics. In the second part of this chapter the potential use of CNTs as contrast-enhancing agent for MRI, in vitro, ex vivo and in vivo, is reviewed.
Vijay K. Anuganti, Aldrik H. Velders

Interaction with biological systems


Exploring Carbon Nanotubes and Their Interaction with Cells Using Atomic Force Microscopy

At present, atomic force microscopy (AFM) offers a unique solution to study biological specimens on the nanometer scale under near-physiological conditions without the need for rigorous sample preparation, staining or labelling. We expect new and significant biophysical insights into the delivery process and transport mechanism of CNTs into cells employing AFM. Here we give an overview for the application of AFM to characterize and assess CNT surface bio-functionalization. Moreover, we show how topographic AFM imaging can be used to study the binding of functionalized single walled carbon nanotubes (SWCNTs), double walled carbon nanotubes (DWCNTs) and multi walled carbon nanotubes (MWCNTs) to various relevant biological membranes, including nuclear membranes and cell surfaces.
Constanze Lamprecht, Andreas Ebner, Ferry Kienberger, Peter Hinterdorfer

Uptake, Intracellular Localization and Biodistribution of Carbon Nanotubes

Carbon nanotubes (CNTs) exhibit unique size, shape and physical properties, which make them promising candidates for biomedical applications. In particular, carbon nanotubes have been intensively studied for conjugation with pre-existing therapeutic agents for more effective targeting, as a result of their ability to cross cell membranes. However, to utilise them effectively in biological systems it is extremely important to understand how they behave at the cellular level and their distribution in vivo. Additionally, in order to consider carbon nanotubes as candidate delivery systems of therapeutic agents it is important to ascertain their fate in vivo, but also take into account many factors, such as solubility, stability and clearance. Issues surrounding their short term and long term safety are currently the subject of toxicology testing. Herein, we propose to summarize the main findings on the uptake, trafficking and biodistribution of carbon nanotubes, with special focus on functionalized carbon nanotubes for delivery of therapeutic agents.
V. Neves, H. M. Coley, J. McFadden, S. R. P. Silva

Recognition of Carbon Nanotubes by the Human Innate Immune System

A major function of the human innate immune system is to recognize non-self: i.e., invading microorganisms or altered, damaged self macromolecules and cells. Various components of the human immune system recognize foreign synthetic materials, including carbon nanotubes (CNTs). The complement system proteins in blood, and the collectins, SP-A and SP-D in the lungs bind to carbon nanotubes, in competition with other plasma proteins, and may influence their subsequent adhesion to and uptake by cells and their localization in the body. Modification of the surface chemistry of carbon nanotubes alters their binding to complement proteins and collectins, and provides information on the mechanism by which binding of these proteins occurs.
Malgorzata J. Rybak-Smith, Kirsten M. Pondman, Emmanuel Flahaut, Carolina Salvador-Morales, Robert B. Sim

Toxicity and Environmental Impact of Carbon Nanotubes

As the number of applications of carbon nanotubes (CNT) in the field of nanomedicine is growing quickly (imaging, drug delivery, scaffolds for tissue engineering), questions are raised about their potential toxicity. Because their annual production is now reaching hundreds of tons per year, their application in composite materials is becoming a reality. Dissemination in the environment could also happen during different steps of their life cycle, from their production to their processing, use and finally during disposal or recycling. We will review in this paper the state of the art in the field of toxicity and ecotoxicity of carbon nanotubes and try to highlight some recommendations.
E. Flahaut

Towards targeted chemotherapy and gene delivery


Carbon Nanotubes Loaded with Anticancer Drugs: A Platform for Multimodal Cancer Treatment

Approximately every fourth person in the world currently dies of cancer. Although many efficient anticancer drugs have been developed over the last 60 years or more, most therapeutic approaches still lack specificity for their intended site of action in the body, resulting in reduced effectiveness and severe side effects. The emerging field of nanomedicine provides a whole range of materials and techniques to develop customizable drug delivery vehicles that assist the targeting of therapeutic agents to the desired site of action. Amongst these, carbon nanotubes have emerged as promising candidates, being capable of penetrating mammalian cell membranes and allowing for the attachment of high loads of drugs and targeting agents on their surface or the inner cavity. This chapter will discuss the principles of targeted, anticancer chemotherapies and introduce carbon nanotubes as novel tools for vector-based, targeted drug delivery.
Elena Heister, Vera Neves, S. Ravi P. Silva, Johnjoe McFadden, Helen M. Coley

Carbon Nanotubes Filled with Carboplatin: Towards Carbon Nanotube-Supported Delivery of Chemotherapeutic Agents

Thanks to their capillary-like structure CNTs provide a well-characterized container material for hosting miscellaneous fillings. Here we present basic studies on the use of CNTs for drug delivery. By introducing carboplatin, an anticancer drug, into the CNTs via a wet chemical approach, drug-filled nanotubes have been produced. The maintenance of the structure of carboplatin was proven using electron energy loss spectroscopy and X-ray photoelectron spectroscopy. It was shown that the drug is released into cell culture medium leading to cell death. Cell viability assays performed with bladder cancer cells EJ28 demonstrated the cytotoxicity of CNTs filled with carboplatin. For comparison a reference of unfilled, open ended CNTs did not affect the cell viability. These results point out the general capabilities of CNTs as nanocarriers for drug delivery.
D. Haase, S. Hampel, K. Kraemer, D. Kunze, A. Taylor, M. Arlt, J. Thomas, S. Oswald, M. Ritschel, R. Klingeler, A. Leonhardt, B. Büchner

Functionalized Carbon Nanotubes for Gene Biodelivery

The principles of non-covalent functionalization of carbon nanotubes will be described. The abilities of these biomolecules to solubilize carbon nanotubes and bind DNA will be also compared. Approaches for using functionalized carbon nanotubes to deliver genes to target cells and associated problems will be described. Evidence pertaining to the mechanism of entry of nucleic acid-loaded carbon nanotubes into mammalian cells will be also presented.
V. Sanz-Beltrán, Ravi Silva, Helen Coley, Johnjoe McFadden


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