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UNDERSTANDING THE CARBON NANOSTRUCTURES AND THEIR PHARMACEUTICAL APPLICATIONS


Shrimali N. 1*, Chatterjee A.2, Jaimini M.1, Chauhan B. S.1, Keshwani B
1 Department of Pharmaceutics, Jaipur College of Pharmacy, Sitapura, Jaipur
2 School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, India
3 Anjali college of pharmacy and sciences, NH-2, Agra-Firozabad Road, Etmadpur, Agra, India

 


ABSTRACT 

In 1991 the field of carbon nanotube research was launched by the initial investigational observation of carbon nanotubes by transmission electron microscopy (TEM). Carbon nanotubes (CNTs) are cylinder-shaped macromolecules with a few nanometers of radius, which can be grown up to 20 cm in length. Carbon nanotubes (CNTs) are measured as a new form of pure carbon. In nature there are two types of carbon nanotubes exist: single-walled carbon nanotube (SWNT) and multi-walled nanotube (MWNT). Nanoscale dimension (1-D) of carbon nanotubes have been well-known over the past 15 years.

Carbon nanotubes can usually be produced using arc discharge, laser ablation and chemical vapor diposition (CVD). Iijima in 1991 when he was studying the synthesis of fullerenes by using electric arc discharge technique, the molecules were first discovered. Carbon nanotubes have been introduced recently as a novel carrier system for both small and large therapeutic molecules. Carbon nanotubes have been introduced recently as a novel carrier system for both small and large therapeutic molecules. Many potential applications have been planned for carbon nanotubes, including drug delivery, cellular imaging, antibacterial, gene transfection, etc. The transporting capabilities of carbon nanotubes combined with their unique physicochemical properties and appropriate surface modifications show great assure as an ideal carrier for target drug delivery systems for cancer therapies.

Keywords: Nanotubes, Gene Transfection, Transmission Electron microscopy, Cellular Imaging.

INTRODUCTION

In the mid-1980’s unadulterated solid carbon was thought to subsist in only two physical forms, diamond and graphite. These two dissimilar physical forms of carbon atoms are called allotropes. These molecules of carbon have extraordinary properties that are used in, nanotechnology electronics.  Physical structures of Diamond and graphite are different and properties however their atoms are both arranged in covalently bonded networks.

Nanotubes have been constructed with length-to-diameter ratio of up to 132,000,000:1 significantly larger than for any other material 1. Nanotubes are members of the fullerene structural family. Their name is derived from their long, hollow structure with the walls formed by one-atom-thick sheets of carbon, called graphene. Graphene is a one atom wide sheet of carbon atoms. It is tough yet low weight and it conducts heat and electricity. In fact, graphene is the most thermally conductive material known to man. It is two- dimensional; it interacts positively with light and with other materials.  Graphene is an extremely crystalline carbon sheet. Carbon atoms are thickly packed in a regular hexagonal sp2 bonded structure. It can best be envisioned as a one-atom wide layer of graphite 2.

A Carbon Nanotube is a tube-shaped material, made of carbon, having a width measuring on the nanometer scale. A nanometer is one-billionth of a meter, or about one ten-thousandth of the thickness of a human hair. The graphite layer appears somewhat like a rolled-up chicken wire with a constant unbroken hexagonal lattice and carbon molecules at the apexes of the hexagons 3. 

Fig. 1: Length and thickness of carbon nanotubes

Carbon nanotubes can be categorized via their structures:

  • Single-wall Nanotubes (SWNT)
  • Multi-wall Nanotubes (MWNT)

Rolled-up sheets of graphite are carbon nanotubes, which are made by a chain of interlocking, hexagonal, six-carbon atom bonds. These bonds can be set in one of three configurations: zig-zag, where they alternate in a linear pattern downs the length of the cylindrical nanotube wall; armchair, where the structure is a collection of straight lines of bonds; and chiral, where the bonds float in a linear fashion to a left or right angle down the length of the tube.

Within this basic class of structures, carbon nanotubes also differ by being straight cylinders, as coiled or branched.

Fig. 2: (a) Single walled nanotubes (SWNTs), (b) Multi walled nanotubes (MWNTs) 4

Supplementary forms that have been created include the nanotube with a carbon buckyball sphere attached to it, known as a nanobud, and cup-stacked nanotubes, which are a series of concave, disc-shaped structures aligned in tube form. Torus, or donut-shaped, nanotube structures have also been made and have elevated magnetic moment properties that would make them of use as dominant sensors.

The structure of carbon nanotubes also determines their physical and chemical properties, where armchair nanotubes are always metallic in terms of electrical conductivity and zig-zag and chiral forms are semiconducting. The six carbon bonds that make up the basic hexagonal structure of a carbon nanotube are spaced around 0.14 nanometers from each other in strong molecular, covalent bonds. These rolled sheets of graphite are then bound to each other in multi-walled nanotubes, which are essentially cylinders within cylinders, by weak van der Waals forces, at a distance of about 0.34 nanometers between cylinder walls 4.

Other types of carbon nanotubes include great carbon nanotubes, which are simply variations on the natural design where they are very long, short, or thin. They have applications in the building of cable 20 to 100 times stronger than steel for such things as a space elevator, and for artificial muscles which can operate in a temperature range from -321° to 2,800° Fahrenheit (-196° to 1,538° Celsius). Some extreme nanotube films are also capable of capturing infrared wavelengths of light known as black body rays or heat radiation. This would make them useful in solar cells that could arrest this heat emitted by the Earth into space at night, which would allow for around-the-clock energy generation at an efficiency level of over 35%, which is two to five times better than that of conventional solar cells.

History 

1991 as the year consider by a number of people, when these tubes were revealed by Sumio Lijima. Carbon nanotubes having nanoscale dimension (1-D) have been well-known over the past 15 years 5 but there are many other examples which prove the discovery of carbon nanotube prior to 1991. A paper was published by Koyama, Oberlin, and Endo in 1976. It also showed the reality of these tubes. There is a TEM picture of this tube in this publication. This tube consisted of single wall of grapheme, later this was called as single walled nanotube by Mr. Endo. A biennial conference was held in the year of 1979, at State University of Pennsylvania. In this conference, these tubes were described as Carbon fillers. So again this proved the presence of these tubes before 1991. Many more US based and Soviet based scientist published journals proved the survival of such tubes.

In 1980 we knew of only three forms of carbon, namely diamond, graphite, and amorphous carbon. Today we know there is a whole family of other forms of carbon. The first to be discovered was the hollow, cage-like buckminsterfullerene molecule – also known as the buckyball, or the C60 fullerene. There are now thirty or more forms of fullerenes, and also an extended family of linear molecules, carbon nanotubes. C60 is the first spherical carbon molecule, with carbon atoms arranged in a soccer ball shape. In the structure there are 60 carbon atoms and a number of five-membered rings isolated by six-membered rings. The second, slightly elongated, spherical carbon molecule in the same group resembles a rugby ball, has seventy carbon atoms and is known as C70. C70’s structure has extra six-membered carbon rings.

Atoms contained within the fullerene are said to be endohedral.  Carbon Nanotubes (CNTs) are more important than  C60 fullerenes , which are connected to graphite. The molecular structure of graphite resembles stacked, one-atom-thick sheets of chicken wire – a planar system of interconnected hexagonal rings of carbon atoms. In conventional graphite, the sheets of carbon are stacked on top of one another, allowing them to easily slide over each other. That is why graphite is not hard, but it feels greasy, and can be used as a lubricant. When graphene sheets are rolled into a cylinder and their edges joined, they form Carbon Nanotubes (CNTs).

SYNTHESIS OF CARBON NANOTUBES 

Carbon nanotubes can usually be produced using three main techniques: arc discharge, laser ablation and chemical vapor deposition (CVD). Each technique can be modified to suit their specific research purpose.

  1. Arc Discharge
  2. Chemical Vapor Deposition
  3. Laser ablation

1. Arc Discharge:

Fig. 3: Arc Discharge Technique 7

Arc discharge was the initial recognized technique for producing MWNTs and SWNTs 6.  The arc discharge technique generally involves the utilize of two high-purity graphite electrodes as the anode and the cathode. The electrodes were vaporized by the passage of a DC current (~100 A) through the two high-purity graphite separated (~ 1–2 mm) in 400 mbar of Helium atmosphere. Experimental set up of arc discharge apparatus was shown in Fig. 3. After arc discharging for a period of time, a carbon rod is built up at the cathode. This method can mostly produce MWNTs but can also produce SWNT with the addition of metal catalyst such as Fe, Co, Ni, Y or Mo, on either the anode or the cathode 7.

  1. Chemical Vapor Deposition:     

Fig. 4: Chemical Vapor Deposition Technique 11

In 1993, Chemical vapor deposition (CVD) technique was first reported to construct MWNTs by Endo and his research group 8. Three years later, Dai in Smalley’s group successfully adapted CO-based CVD to create SWNTs 9. CVD technique can be achieved by taking a carbon source in the gas phase and using an energy source, such as plasma or a resistively heated coil, to transfer energy to a gaseous carbon molecule. The CVD process uses hydrocarbons as the carbon sources with methane, carbon monoxide and acetylene. The hydrocarbons flow through the quartz tube being in an oven at a high temperature (~ 720 C). Schematic diagram of the chemical vapor deposition apparatus is shown in Fig. 4. At high temperature, the hydrocarbons are broken to be the hydrogen carbon bond, producing pure carbon molecules. Then, the carbon will diffuse toward the substrate, which is heated and coated with a catalyst (usually a first row transition metal such as Ni, Fe or Co) where it will bind. The advantages of the CVD process were low power input, lower temperature range, relatively high purity and, most importantly, possibility to scale up the process. This method can produce both MWNTs and SWNTs depending on the temperature, in which production of SWNTs will occur at an elevated temperature than MWNTs.

3. Laser Ablation:

 

Fig. 5: Laser Ablation Technique 11

In 1995, Smalley and co-workers produced carbon nanotubes with laser ablation technique 10. In the laser ablation technique, a high authority laser was used to vaporize carbon from a graphite target at high temperature. Both MWNTs and SWNTs can be produced with this technique.  In order to generate SWNTs, metal particles as catalysts must be added to the graphite targets similar to the arc discharge technique. The quantity and quality of produced carbon nanotubes depend on several factors such as the amount and type of catalysts, laser power and wavelength, temperature, pressure, type of inert gas, with the fluid dynamics near the carbon target.

Schematic diagram of the laser ablation apparatus was shown in Fig. 5. The laser is focused onto a carbon targets containing 1.2 % of cobalt/nickel with 98.8 % of graphite composite that is placed in a 1200°C quartz tube furnace under the argon atmosphere (~500 Torr). These conditions were achieved for production of SWNTs in 1996 by Smalley’s group. [11] In such technique, argon gas carries the vapors from the high temperature chamber into a cooled collector positioned downstream. The diameter distribution of SWNTs from this method varies about 1.0 – 1.6 nm. Carbon nanotubes produced by laser ablation were purer (up to 90 % purity) than those produced in the arc discharge method and have an extremely tapered distribution of diameters.

USES AND APPLICATION OF CARBON NANOTUBES

Tissue Engineering:

Carbon nanotubes may be used as material of tissue engineering to improve tracking of cell, sensing of microenvironments, and scaffolding for the incorporating in the host’s body. These may be used as optical and radio tracer contrast agents for tissue formation evaluation, can be designed better engineered tissues. CNTs imparting novel properties like electrical conductivity may add in directing cell growth. So, CNTs are used in tissue engineering 12.

Drug Design & Discovery:

Carbon nanotubes (CNTs) are used as carriers for drug delivery and diagnostic applications. They enable the covalent and noncovalent introduction of several entities & allow for design of novel candidate for drug development. CNTs can be finctionalized with different functional groups to carry several moieties for targeting, imaging and therapy. Example of one of them is, one carrying a fluorescein probe together with the antifungal drug amphotericin B & antitumor agent methotrexate. The biological action of drug is retained while CNTs able to decrease the unwanted toxicity of drug administration alone 13.

As a part of increasing interest in nanobiotechnology, nanoparticle-based drug discovery and drug delivery constitute an important area in nanomedicine, and it is also driven by search for new drugs by the pharmaceutical industry 14.

Biomedical Applications:

Carbon nanotubes have potential in biological biomedical applications. A new class of bioactive CNTs which are conjugated with protein, carbohydrates or nucleic acids, it is the example of “bottom up” fabrication principle of bionanotechnology. They opens up an entire new and exciting research direction in field of chemical biology and aiming to target & to alter the behavior of cells at molecular level.  There is a biomodification of CNTs for specific delivery of genetic materials to cell, used as potential novel therapeutic approaches 15.

Targeted Drug Delivery System:

The novel properties of nanoparticles offer the ability of intermingle with complex cellular functions. This rapidly growing field requires cross-disciplinary research and provides opportunities to design and develop multifunctional strategy that can target, diagnose, and treat devastating diseases such as cancer 15.

Nanomedicines:

Carbon nanotubes have been now used in the diagnostics and therapeutics. Most of these applications are like administration or implantation of carbon nanotubes and their matrices into patients. The toxicological and pharmacological action of such carbon nanotube systems developed as nanomedicines. Pharmaceutical development of carbon nanotubes is taken on the road to become viable and effective nanomedicines 17 

Anticancer Drug Delivery System:

Conventional administration of chemotherapeutic agents is because of their short of selectivity which is causes a lethal effect on healthy tissues. Since therapeutic and diagnostic agents could functionalize the structure of carbon nanotubes (CNTs), the improvement of CNTs as drug containers would pave the way to their use as nanovectors into the cells. A study on cisplatin (Cis-Diamminedichloroplatinum (CDDP) – a platinum-based chemotherapy drug) embedding to single-wall CNTs (SWCNTs) is shown. After discharging of anticancer drug with surety, in vitro analysis has been performed. The inhibition of prostate cancer cells (PC3 and DU145) viability from tubes encapsulating cisplatin proved the efficiency of the produced delivery system

 

Transport and Delivery of Biological Cargos:

The internalization of SWNTs for transport and delivery into cells is mediated via endocytosis and does not appear to have any detrimental effect on either the transported cargo or the breached cell. The emergence of SWNT as a new class of cellular transporters holds many exciting promises for SWNT-based systems for drug delivery, protein delivery, and gene therapy and cancer therapy applications 19.

Electro-Sensitive Transdermal Drug Delivery System:

To control the drug release an electro-sensitive transdermal drug delivery system was prepared by the electrospinning method. A semi-interpenetrating polymer network was prepared as the matrix with polyethylene oxide and pentaerythritol triacrylate polymers. Multi-walled carbon nanotubes were used to increase the electrical sensitivity. The release experiment was carried out under different electric voltage conditions. Carbon nanotubes were observed in the middle of the electrospun fibers by SEM (Scanning Electron Microscopy) and TEM (Transmission Electron Microscopy). Amount of released drug was increased with higher applied electric voltages. These results were recognized to the excellent electrical conductivity of the carbon additive. By the use of carbon nanotubes the effects of the electro-sensitive transdermal drug delivery system were enhanced 20.

Intracellular Protein Transporters:

Various proteins adsorb instinctively on the sidewalls of single-walled carbon nanotubes. This simple nonspecific binding scheme can be used to afford noncovalent protein−nanotube conjugates. The proteins are readily transported inside mammalian cells with nanotubes working as the transporter via the endocytosis pathway. Once free from the endosomes, the internalized protein−nanotube conjugates can enter into the cytoplasm of cells and perform biological functions, evidenced by apoptosis induction by transported cytochrome c. Carbon nanotubes represent a new class of molecular transporters potentially useful for future in vitro and in vivo protein delivery applications 21.

Soft Drug Delivery Systems:

Soft drug delivery systems formed by using surfactants, polymers, and lipids. Such delivery systems are discussed and exemplified regarding both more traditional soft drug delivery systems such as micelles, liquid crystalline phases, liposomes and polymer gels, as well as more novel structures, e.g., carbon nanotubes, polyelectrolyte multilayer capsules, and liquid crystalline particles 22.

RECENT ADVANCES IN CARBON NANOTUBES:

Carbon nanotubes have been the focus of considerable research. Thse are first revealed by Iijima in 1991. Remarkable physical and chemical properties of their have reported by numerous investigators. They have higher conductivity and electronic properties than diamond. Mechanical properties of CNTs like stiffness, strength and resilience exceeds any current material, offer tremendous opportunities for the development of fundamentally new material systems in 21st century 23.

Because of their unique properties single-walled carbon nanotubes (SWNTs) have become one of the most intensely studied nanostructures. Their inherent physical properties make them ideal supports for metal nanoparticles. The use of electrodeposition to modify SWNTs in order to facilitate applications in areas related to catalysis. Preparation of raw SWNT material for electrochemical experiments involves various mild or oxidative pretreatments 24.

Carbon nanotubes have been customized with several molecules of therapeutic interest. Functionalized carbon nanotubes have been verified to deliver proteins, nucleic acids, drugs, antibodies and other therapeutics 25.

TOXICITY OF CARBON NANOTUBES:

1. Cytotoxicity of Multi-Wall Carbon Nanotubes:

Toxicity of carbon nanotubes depends upon their length. A short carbon nanotube doesn’t produce any kind of toxicity. The toxicity of carbon nanotubes has been compared to pathogenic fibres. CNTs were examined as: length, aspect ratio, iron content and crystallinity and compared to multi walled carbon nanotubes (MWCNTs).

Long MWCNTs were cytotoxic to cells, and potent in pro-inflammatory and pro-fibrotic immune responses. Frustrated phagocytosis was most evident in response to long CNTs, as was respiratory burst and reduction in phagocytic ability 26.

2. Carbon Nanotube Toxicity and Environmental Health Risks:

CNTs which are very light in weight, enter the working environment as suspended particulate matter of respirable sizes, they could pose an occupational inhalation exposure hazard. Experiment on rodents in which test dust were administered intratracheally to assess the pulmonary toxicity of manufactured CNTs & a few in virtro studies  to assess biomarkers toxicity released in CNT-treated skin cell cultures. The results of the rodent studies collectively showed that regardless of the process by which CNTs were synthesized and the types and amounts of metals they contained, CNTs were capable of producing inflammation, epithelioid granulomas (microscopic nodules), fibrosis, and biochemical/toxicological changes in the lungs. Therefore, CNTs from manufactured and combustion sources in the environment could have adverse effects on human health 27.

3. T- Lymphocyte Apoptosis:

Carbon nanotubes are a man-made form of carbon. In a experiment 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 μg/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 was 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 28 

FUTURE ASPECTS OF CARBON NANOTUBES: 

  1. Biosensing and Drug Delivery at the Micro scale:

An objective of pharmaceutical research is the controlled release or delivery of drugs at the biological target site in a therapeutically and pharmacodynamically optimal amount. In relation to “intelligent” drug delivery, several basic aspects are important, i.e., release of active pharmaceutical ingredients from the formulation, transport to and penetration across biological barriers, and biotransformation depending on a controlled release process. Future development of advanced or controlled drug releasing systems, e.g. nano-pillar based drug release, or electronically mediated molecule delivery, is expected to take advantage of progress in molecular cell biology, bioelectronic properties, membrane nano-biophysics, and cell & tissue engineering 29.

  1. Carbon Nanotubes for Microelectronics:

As the semiconductor industry faces increasing technological and financial challenges, new concepts have to be assessed. The extraordinary characteristics of carbon nanotubes build them a promising candidate for applications in micro- and nanoelectronics. Catalyst mediated CVD growth is very well suited for selective, in-situ development of nanotubes compatible with the requirements of microelectronics technology. This deposition method can be exploited for carbon nanotube vias. Semiconducting single-walled tubes can be successfully operated as carbon nanotube field-effect transistors (CNTFETs) 30.

  1. Electronic Properties of Carbon Nanotubes:

While researching the unique electrical properties of single-walled carbon nanotubes (SWCNTs), researchers have verified the nanotubes’ ability to capture and store one electron per 32 carbon atoms in a SWCNT.

University of Notre Dame Scientists Anusorn Kongkanand and Prashant Kamat monitored the shift of electrons from semiconductor particles to SWCNTs as the composite system strained to attain charge equilibrium. The study, published in ACS Nano, will be useful for the design of nanotubes as a way to direct the flow charge and boost photoelectrochemical performance for applications including electronic devices and solar cells.

“Although the electron storage property of carbon nanotubes is well known, there is no convenient or simple way to make a quantitative estimate of storage capacity,” when excited by a UV laser, titanium dioxide nanoparticles undergo charge separation, where some of the semiconductor’s electrons get trapped—an estimated 3,770 electrons per 12-nm-long nanoparticle. Electrons trapped in the titanium dioxide displayed a blue coloration (a 650-nm absorption band).

But when the researchers introduced SWCNTs to the titanium dioxide particles, the blue color decreased. Because SWCNTs don’t have any detectable absorption in the visible range, this lack of color meant that some of the electrons mesmerized in the titanium dioxide were transferred to the SWCNTs.

Complete transfer consisted of 1 electron per 32 atoms of carbon atoms (building blocks of the SWCNTs), and occurred in just 10 nanoseconds. Such a high electron capacity twisted the SWCNTs into super capacitors, which can be useful in electronics applications 31.

Acknowledgement

It would not have been possible to write this article without the help and support of the kind people around me. I wish to express my gratitude to Dr. Manish Jaimini, Arindam Chatterjee, Bhupendra singh Chauhan, Bhawana Keshwani, contributing authors, for their valuable suggestions and timely help throughout the course of this article.

Conflict of Interest Statement

No conflict of interest exists, all the sources has been properly referenced.  

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