Fullerenes: Chemistry and its Applications

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Fullerenes: Chemistry and its Applications Madhura Mohan Gokhale1 and Rakesh Ravindra Somani2,* 1

Department of Pharmaceutical Chemistry, Vivekanand Education Society’s College of Pharmacy, Chembur, Mumbai, India; 2Professor & Head of Department of Pharmaceutical Chemistry, Vivekanand Education Society’s College of Pharmacy, Chembur, Mumbai, India Abstract: Fullerenes being allotropes of carbon, have been considered as new class of molecules. Unlike diamond and graphite, this is made up of hollow carbon cage structure. The idea of spheroidal cage structures of C60 arose from construction of geodesic domes made by renowned architect Buckminster Fuller. Although fullerenes have low solubility in physiological media they finds promising biological applications. The photo, electrochemical and physical properties of C60 and other fullerene Rakesh R. Somani derivatives finds applications in medical fields. The ability of fullerenes to fit inside the hydrophobic cavity of HIV proteases makes them potential inhibitor for substrates to catalytic active site of enzyme. It possesses radical scavenging and antioxidant property. At the same time, when it exposed to light it can form singlet oxygen in high quantum yields which with direct electron transfer from excited state of fullerenes and DNA bases finally results in cleavage of DNA. The fullerenes are also used as a carrier for gene and drug delivery system. The associated low toxicity of fullerenes is sufficient to attract the researchers for investigation of these interesting molecules.

Keywords: Applications, buckyball, C60, drug delivery, fullerene, toxicity. 1. INTRODUCTION Carbon, the common element and widely distributed in nature, is known to exist in several forms viz. graphite and diamond. Fullerenes are fourth allotropic form of carbon. In comparison with graphite and diamond with extended solid state structures, fullerenes are spherical molecules which have solubility in various organic solvents. This property can be used for different chemical manipulation. A fullerene is a carbon cage structure having fused ring system which consists of pentagons and hexagons. The first proposal of buckyball was given by Eiji Osawa, Japan. He recognized that corannulene, a cyclopentane ring fused with 5 benzene rings was a part of football framework and hypothesized that entire structure could exist. In 1985, the group of scientists Richard Smalley, Robert Curl, James Heath, Sean O'Brien, and Harold Kroto [1] synthesized the first fullerene molecule, buckminsterfullerene (C60) at Rice University. These scientists named newly discovered molecule in honor of architect R. Buckminster Fuller who created geodesic dome with same shape.

maps the molecule onto itself. When a carbon atom is placed at each vertex of molecule which all valences satisfied by two single bonds and one double bond, stabilized by resonance gives structure of C60 molecule, appears to be aromatic. Other forms [3] of fullerene are Fullerane which is fully saturated fullerene (example, the hydrocarbon C60H60) and Fulleroids are fullerene-like compounds as they resemble fullerenes in structure but do not confirm the definition of a fullerene (example, Heterofullerens, Norfulleres, Homofullerene, Secofullerene).

Fullerenes are composed of fused hexagons and pentagons (Fig. 1). C60 and C70 are most accessible members of this family. The high symmetry found in this molecule is an important property. C60 molecule is composed of 60 carbon atoms which are arranged as 12 pentagons and 20 hexagons [2]. All rings are fused and double bonds are highly conjugated. The reason for high symmetry of this molecule is 120 symmetrical operations found in molecule like rotation around the axis and reflection in plane which *Address correspondence to this author at the Department of Pharmaceutical Chemistry, Vivekanand Education Society’s College of Pharmacy, Chembur, Mumbai, India; Tel: +91 9833771384; E-mail: [email protected] 1570-193X/15 $58.00+.00

Fig. (1). Different fullerene derivatives. © 2015 Bentham Science Publishers

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Gokhale and Somani

2. TYPES OF FULLERENES Table 1.

Types of fullerenes.

Sr. no.

Types

Description

1.

Buckyball clusters [4] (Fig. 2)

Smallest number is C20 and most common is C60 . Because sphere of buckyball is hollow, other atoms can trapped within it.

Representation

Fig. (2). Buckyball clusters.

2.

Nanotubes [5] (Fig. 3)

Hollow tubes of very small dimensions with single or multiple walls, used in electronics industry.

Fig. (3). Nanotubes.

3.

Mega tubes [6] (Fig. 4)

Varying in dimensions than nanotubes as larger in diameter with walls of different thickness; application in transport of a variety of molecules of different sizes. Fig. (4). Mega tubes.

4.

Polymers [7] (Fig. 5)

Chain, two or three dimensional, formed under high pressure and temperature conditions.

Fig. (5). Polymers.

5.

Nano"onions" [8] (Fig. 6)

Spherical particles having multiple layers which surrounds buckyball core. Typical diameter is 3-5 nm; proposed for lubricants. Fig. (6). Nano"onions".

6.

Linked "ball-and-chain" dimers [9] (Fig. 7)

Two buckyballs linked by a carbon chains.

Fig. (7). Linked ball and chain dimers.

3. GENERAL PROPERTIES OF FULLERENES Pure fullerenes have better close packing than impure one. Derivatives of C60 show range of solubility [10]. Fluorinated derivatives are more soluble and some bromo derivatives are much less soluble. Fullerenes have low density (1.65 g/cc) relative to diamond (3.51 g/cc). Fullerenes are stable upto temperature of 1000°C. As the cage is entirely of sp2- hybridized carbons it gives electron withdrawing negative inductive (-I) effect so fullerenes are strongly electron-attracting i.e. (that is) fullerenes can readily react with nucleophiles. High strain energies contribute to

reactivity. Fullerenes can undergo various reactions [11] such as reduction, oxidation, hydrogenation, halogenation, nucleophilic reactions, radical reaction, transition metal complex reaction, regioselective reaction and so on. Fullerenes are susceptible to degradation or decomposition in presence of light [12] and oxygen. The intersystem crossing of singlet excited state to energetically lower triplet excited state results in decaying of C60. The triplet excited states are prone to many deactivation processes such as ground state quenching, quenching by molecular oxygen and transfer of electrons to molecules.

Fullerenes: Chemistry and its Applications


4. STABILITY OF FULLERENES Localization of electrons and ring strain affects stability of fullerenes. By applying huckel rule [13] to different fullerene derivatives like C50, C60, C70, C80 and C84, among these only C50 and C70 were predicated to be aromatic and C60 was less aromatic. As Huckel’s rule gives aromaticity in spherical systems than planar systems, only C60 was found to be more aromatic and highly stable. The highest stability of C60 is due to reduced strain in ring as twelve pentagons are isolated from each other [14]. When there are minimum bond orders in five-membered rings it indicates that all double bonds are in six-membered rings and none in five-membered rings. When meta position (i) of any two rings are fused with hexagonal ring, as in Fig. (8), this arrangement permits minimization of bond orders in five-membered rings. The degree of instability in C60 will occur when requirement of minimization of bond orders is not satisfied as there is para relationship between two pentagonal rings. It is significantly seen in higher fullerenes like C70, it is less stable than C60 which contains five arrangements of type (ii). This indicates that as number of carbon atoms increases, stability is going to decrease.

(i)

(ii)

meta

para

Fig. (8). Stability of fullerenes.

5. FULLERENE PRODUCTION There are various methods for fullerene production such as, 1) Electric Arc method, 2) Arc heating method, 3) Laser ablation method and 4) Formation of Fullerenes by pyrolysis of Hydrocarbons. These methods are generally used for large scale production. 5.1. Electric Arc Method Equipment bench top reactor by Wudl [15] (Fig. 9) was used for production of fullerenes in this method. The

Fig. (10). Arc heating of graphite.

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advantage is simple construction of reactor, low cost which makes them attractive for synthetic chemists [16]. A current (AC or DC) of 40-60 A° is applied to thin graphite rod supported by copper sleeve having sharpened tip results in evaporation of material of thin rod. The rod is consumed till the point where rod cannot make contact with the thick rod. Then power is shut off. By this technique, 5-10% of fullerene is obtained. (A)Vacuum system, (B) Pyrex jell bar, (C) graphite rod(3 mm), (D) graphite rod(4 mm), (E) copper electrode, (F) manometer

Fig. (9). Apparatus used by Wudl.

5.2. Arc Heating of Graphite This technique is developed by Smalley [17] (Fig. 10) which is used as an alternative to arc vaporization of graphite. There is a dissipation of electrical power in arc when the tips of two sharpened graphite rods are kept in close proximity but they are not in direct contact with other. When the electrodes are barely touching, known as “contactarcing” [18] this technique works more efficiently. This method also allows an efficient evaporation of carbon. The yield of obtained fullerenes by this process was found to be about 15%.

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Gokhale and Somani

Fig. (11). Laser ablation.

Fig. (12). Scheme for separation and purification.

5.3. Laser Ablation [19, 20] It is very powerful and useful technique for production of fullerene clusters. It involves laser ablation of graphite in helium atmosphere. Laser ablation is the process which involves removal of material from a solid (or occasionally liquid) surface with the help of irradiation using laser beam. As in this technique solvents are not used and operators are not exposed to chemicals, it is considered as environmentally friendly process. The material used in this process generally gets converted to plasma at higher laser flux. By carrying out this process at high temperature, this plasma cools more slowly and generated carbon clusters gets rearranged in stable fullerenes (Fig. 11). 5.4. Pyrolysis of Hydrocarbons Pyrolysis of hydrocarbons (preferably aromatics) can also be used to get fullerenes. The pyrolysis of naphthalene at 1000° C in an argon steam [21] was done first time to obtain fullerenes. The naphthalene skeleton is a small fragment of the C60 structure. The bowl-shaped corannulene [22] was used as precursors for C60, followed by naphthalene. Synthesis of fullerenes is also possible by laser pyrolysis which involves the use of benzene and acetylene as carbon source.

6. SEPARATION FULLERENE [23]

AND

PURIFICATION

OF

The first step involves extraction of soluble fullerenes from the crude carbon soot. Benzene was first used for extraction, but for safety reasons, it is replaced with toluene. Secondly, it is isolated by chromatographic separation using alumina as stationary phase and either pure hexane or hexane-toluene (95:5) as mobile phase. The general scheme is shown in Fig. (12). 7. CHARACTERIZATION The separation techniques can provide pure C60 or C70 molecules, but it is also important to verify the purity of obtained compounds. The techniques used for characterization of fullerenes are 7.1 13C NMR (Nuclear Magnetic Resonance) [24, 25] Solution phase 13C NMR is powerful probe of fullerene purity and structure. All 60 carbon nuclei are equivalent in C60, 13C NMR spectrum exhibit only one single peak in Fig. (13) whereas in C70 exhibit five distinct resonance (Fig. 13).



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Fig. (13). 13C NMR spectra of C60 and C70.

7.2. Mass Spectroscopy It is used for determination of composition and purity of fullerene compounds. It can be analyzed by FAB(Fast Atom Bombardment) [26, 27] and by laser desorption ionization [28] - Time of flight (TOF). The main reasons for selecting this type of mass spectrometry are: Laser ionization is a soft type of ionization which provides a broad mass range and fast data acquisition. 7.3. Optical Spectroscopy [29, 30] Pure C60 solutions exhibit deep purple color, C70 exhibit an intense wine red color and higher fullerenes show yellow to greenish color, which can be analyzed by UV-VIS (Ultraviolet-Visible) spectroscopy. In case of IR (Infrared spectroscopy), C60 shows four bands at 1428, 1183, 577 and 527 cm-1. 7.4. HPLC (High Performance Liquid Chromatography) [31] HPLC can be used to separate macroscopic quantities of fullerenes. It is also useful for determination of purity of fullerenes. 7.5. Single Crystal XRD (X-Ray Diffraction) [32] It is a non-destructive analytical method which provides information about the lattice structure of crystalline

substances, also about the unit cell parameters, bond-lengths, bond-angles, etc. 7.6. Thermal Methods [33] Analysis by thermal methods was done on fullerene derivatives and its nanofibres. Change in thermal stability of produced nanofibres with different polymer concentration in presence and absence of crosslinking agents was assessed by TGA (Thermogravimetry analysis) and DSC (Differential Scanning Calorimetry) methods. 8. REACTIONS OF FULLERENES Fullerenes can be used in various organic reactions to form new compounds. Fullerenes can undergo various reactions- Reduction, Addition reaction (cycloaddition), Hydrogenation, Transition metal complex reaction, Halogenation, Oxidation reaction, Regioselective multiple addition, etc. 8.1. Nucleophilic Addition As fullerenes gives -I effect, they can readily react with nucleophiles. C60 reacts with various nucleophiles such as carbon, nitrogen, phosphorous and oxygen to undergo nucleophilic additions. The reaction proceeds with formation of intermediate Nun C60n- by the initial attack of a nucleophile to C60. This intermediate is stabilized by various

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C 60

Gokhale and Somani

H+

RLi or RMgBr

H R

R

RLi- MeLi

RMgBr- EtMgBr

BuLi

PhMgBr

Me3SiCCLi

CH=CH (CH 2)2 MgBr

Li-fluorenide

Me3SiCH2 MgCl

Fig. (14). Addition of nucleophile on C60. EtOO C

Br

EtOOC

EtOOC

C OO Et

BrC H 2(C OOEt) 2

Toluene, NaH

Fig. (15). Bingel reaction.

reactions such as (a) the addition of electrophiles E, (b) addition of neutral electrophiles EX such as alkylhalogenides, (c) internal addition reaction to give methanofullerenes and cyclohexenofullerenes; or by (d) an oxidation. Nucleophilic addition reactions are of various types, such as addition of carbon nucleophiles, addition of cyanide, addition of hydroxides and alkoxides, addition of phosphorus, silicon, germanium nucleophiles and addition of macromolecular nucleophiles as in case of fullerene polymers. 8.1.1. Addition of Carbon Nucleophiles I) C60 can react with Organolithium (R-Li) and Grignard compounds (R-Mg-X) using alkyl, phenyl or alkenyl compounds to form primary intermediates as the anions RC60-. To obtain maximum yield, organolithium compounds as nucleophiles are used [34]. Different Grignard reagents can be used, given in Fig. (14). II) Bingel reaction [35]- It is a classic example of nucleophilic addition reaction which was first discovered by Bingel, 1993 using bromo derivative of diethyl malonate in presence of a sodium hydride as base to form methanofullerenes (Fig. 15). The reaction mechanism involves abstraction of proton by base to form carbanion or enolate which reacts with electron deficient fullerene double bond as shown in Fig. (15), followed by displacement of bromine in an intramolecular ring closure. 8.1.2. Addition of Cyanide [36] The negative shift of reduction potential results due to addition of alkyl nucleophile. To compensate this potential addition of strong electron withdrawing group is necessary such as addition of cyanide. C60 reacts with LiCN or NaCN to form monoadduct anion which can be quenched with various nucleophiles (Fig. 16).

8.2. Cycloaddition As double bonds of C60 exhibit a dienophilic character various cycloaddition reactions are possible. The reactivity of the diene is mainly responsible for the various conditions for cycloadduct formation. 8.2.1. [4+2] Cycloaddition Many [4+2] cycloaddition reactions with C60 are done under thermal conditions. The reaction of cyclopentadiene [37] and C60 gives the monoadduct in comparatively high yield at room temperature as shown in Fig. (17). The anthracene cycloadduct is formed when excess of diene is refluxed in toluene (Fig. 17). 8.2.2. [3+2] cycloaddition To obtain pyrazoline intermediate C60 reacts with diazomethane in toluene. Extrusion of N2 form this intermediate results in two different bridged fullerenes [38], as shown in Fig. (18). 8.3. Hydrogenation [39] Hydrogenation of fullerenes can be done easily and by various processes. C60H18 and C60H36 are common examples of hydro fullerenes. Due to large strain in ring completely hydrogenated fullerene, C60H60 is hypothetical. The prolonged hydrogenation by direct reaction with hydrogen gas at high temperature results in cage formation which leads to instability of highly hydrogenated fullerenes. Fullerenes are easily hydrogenated by several methods. Examples of hydro fullerenes are C60H18 and C60H36. Completely hydrogenated C60H60 is only hypothetical because of large strain. Finally there is collapse of cage structure which forms polycyclic aromatic hydrocarbons.


Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 4 NC

Na + -

NaCN, r.t. C 60

ODCB/DMF

F 3CCOOH, r.t NC

p-ToSCN, r.t.

F3CSO2Me

H

NC

NC

C H3

Fig. (16). Addition of cyanide.

C yclopen tad iene, Toluen e

A nthracen e, Toluen e

r.t.

ref lux

Fig. (17). [4+2] cycloaddition. N N

CH 2N 2, toluene r.t.

-N 2

Fig. (18). [3+2] cycloaddition.

-N 2

CN

7

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Gokhale and Somani

Fig. (19). Birch- Huckel reduction. HO O

OH O O

O O

O

OH O

HO

CH 3

N O

N O

NH 3 O

O

O

O O

O

O

OH N

O

OH O

O

O

O N

O

CH 3

Derivative 1- Dendrofullerene Derivative 2- Trans isomer of derivative 1

Fig. (20). Fullerenes derivatives.

E.g. (Example) - Birch-Huckel Reduction, Fig. (19) Hydrogenation of C60 was done with Lithium (Li) in liquid ammonia (Liq.NH3). The major products of this are the isomers of C60H18 and C60H36 (Fig. 19) 9. APPLICATIONS OF FULLERENES 9.1. Biological Applications 9.1.1. Antiviral Activity Although tremendous advances in the therapy of AIDS are done, there are several major problems associated with current antiviral drugs and its treatment such as, quick mutation of Human HIV (Human Immunodeficiency Virus), developed resistance and high toxicity leads to urgent need to develop new antiviral drugs. HIVP (HIV Protease) is basic and important enzyme required for the virus survival which is an aspartic protease enzyme, specific for HIV proteins and does not react directly or indirectly with human proteases. The activation of RT (Reverse Transcriptase), RNAse, Integrase and Protease is done by the cleavage of polyprotein by HIVP. The HIVP active site is a cylindrical hydrophobic cavity having diameter of around 10 A° which has two amino acidic residues, 25 and 125 aspartate [40].

It was suggested that fullerene derivatives acts as antiHIV agents by fitting smartly in the active site of the viral protease due to strong Van der Waals interactions on hollow surface of enzyme. The hydrophobic interactions between C60 and regions of cavity plays role in holding the inhibitor tightly [41]. Earlier studies have showed that derivatives of fullerenes can inhibit HIVP and can form complex with the same (Fig. 20). As shown in Fig. (20), Dendrofullerene 1 was found to have the highest anti-protease activity and Derivative 2 which is trans-2 isomer strongly inhibits the replication of HIV-1 [42]. Fulleropyrrolidines having two ammonium groups was found to active against HIV-1 and HIV-2. A series of fullerene derivatives (Derivatives 3-7, Fig. 21) was synthesized to elucidate the structural parameters which affect the antiviral activity. The results showed that trans fullerene derivatives are more active than cis where the equatorial fullerene derivative is totally inactive [43] (Fig. 21). The fullerene derivatives of cationic and anionic type inhibit the replication of HIV-RT and hepatitis C virus. Anionic type of fullerenes was found to possess antioxidant


N


I-

N

I

-

N

9

I-

N I

-

I3 (tran s-2)

N

N

4(t ra ns -3 )

I

I-

I

-

5(t ra ns -4 )

N

-

N N

I-

N

I6(e qu it ori al )

7(c is-3 )

Fig. (21). Series of Fulleropyrrolidines.

activity and cationic type showed antibacterial and antiproliferative properties. Cationic and anionic type fullerene derivatives inhibit HIV- RT and hepatitis C virus replication [44]. 9.1.2. Antioxidant and Neuroprotective Activity The fullerenes have capability to react with oxygen species such as O2•- (Super oxide) and •OH (Hydroxyl) radicals [45] which can attack on lipids, proteins, DNA and other macromolecules without any consumption of itself, this is the main reason for the neuroprotective activity showed by fullerenes. As evidences has proved this feature of fullerenes, they are considered as world’s most efficient and powerful radical scavenging agent and termed as radical sponges [46]. Fullerenes also act as medical antioxidant, are able to localize within the cell to mitochondria and other cell compartment sites. In disease condition production of cellular ROS (Reactive Oxygen Species) can result in apoptosis, a scheduled cell death. So fullerene derivatives can prevent apoptosis by neutralization of ROS. 9.1.3. Fullerenes in Drug and Gene Therapy [47] As there is inhibition by three membrane barriers namely, cell membrane, endosomal membrane and nuclear membrane there is major challenge of transport of any compound into nucleus of intact cell. To make transport easy, various carriers are used such as nanoparticles. Fullerenes belong to

class of inorganic nanoparticles having small size (~ 1 nm). The fullerene core being very hydrophobic, fullerenes can become water-soluble and be capable of carrying drugs and genes for the cellular delivery by attaching hydrophobic moieties. The derivatives of fullerenes are able to cross cell membrane to bind to mitochondria. 9.1.4. Diagnostic Application The important property of fullerenes of distribution and relocation in selected organs provide an opportunity for targeting a specific organ. The fullerene derivatives can be used as X-ray contrast agents. The formation of endohedrals metallofullerenes [48] results due to entrapment of metal atoms inside the cavity of fullerene sphere. The endohedrals have application in nuclear magnetic field. The toxic heavy radio metal are unable to exit from fullerenes cage once it has been placed. This property suggests the application of fullerenes as radiotracers in vivo. 9.1.5. Antimicrobial Activity [49] The fullerenes found to have potential antimicrobial activity due to its possible intercalation into biological membranes. The different strains of fungi and bacteria such as Candida albicans, Bacillus subtilis, Escherichia coli and Mycobacterium avium showed positive results.

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9.2. Pharmaceutical Application CNTs (Carbon Nanotubes) - other allotropes of carbon having structure in nano scale with length-to-diameter ration greater than 1, 00, 000 known as CNTs (Carbon Nanotubes). 9.2.1. Carrier for Drug Delivery [50] Carbon nanotubes with different functionalities are reported for targeting of Amphotericin B to Cells. The intracellular penetration was enhanced when doxorubicin with nanotubes have given. Due to their nanosize carbon nanotubes finds an application in tablet manufacturing as lubricants or glidants. 9.2.2. Genetic Engineering [51] CNT and CNH (Carbon nanohorns) are used to manipulate genes and atoms in the development of bioimaging genomes, proteomics and tissue engineering in genetic engineering. Nanotubes and nanohorns have ability to adhere various antigens on their surface which can be used as source of antigen in vaccines. Therefore the use of nanotubes as source of antigen can avoid use of dead bacteria which is sometimes dangerous. 9.2.3. Preservative [52] Their antioxidant property can be used to preserve formulations which are prone to oxidation. They are used as preservative in anti-aging cosmetics and with zinc oxide in formulations to prevent oxidation. 9.2.4. Artificial Implants [53] Generally the body exhibits rejection reaction for implants with the post administration pain. This can be overcome by use of miniature sized nanotubes and nanohorns get attached with other proteins and amino acids. Due to their high tensile strength, carbon nanotubes filled with calcium and arranged or grouped in the structure of bone can act as bone substitute or in form of artificial joints.

Gokhale and Somani

such programs are based on limited amount of identified exposure and uncertainties of the quality of exposure and toxicity. There is no suitable data obtained for chronic exposure and their endpoints such as carcinogenicity, etc. Therefore, it is unrealistic to make any generalizations about exposure and toxicity of fullerenes. Also, new testing parameters need to be invented for conscious evaluation of toxicity of fullerenes. 11. FUTURE ASPECTS The unique applications of fullerenes are due to extraordinary structure of fullerenes. Due to its poor solubility in common organic solvents, spectroscopic analysis of products, purification, separation and assessment of purity will become quite difficult. The high cost and low availability of fullerenes necessitates working on a very small scale. 12. CONCLUSION Over the past few years, many new findings and important aspects of these carbon molecules have been accumulated to develop a new exciting scientific field. The direct application of fullerene and their derivatives to biological targets finds promising applications in medicine. The associated low toxicity of fullerenes is sufficient to attract the researchers for investigation of these interesting molecules. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS Declared none. REFERENCES

9.2.5. Diagnostic Tool [54, 55]

[1]

Due to their ability of fluorescence with specific biomolecules, protein-encapsulated or protein filled nanotubes have been tried as implantable biosensors. For the study of cells and biological systems, Nanosize robots and motors with nanotubes can be used.

[2] [3]

10. TOXICITY OF FULLERENES

[5]

There are number of factors that may be responsible for toxicity of fullerenes including its crystal structure, surface modifications and preparation methods. Generally greater the solubility of fullerene sample, lesser the toxicity associated with exposure. But these above mentioned factors may drive the water solubility of fullerenes [56]. As per the review of Fathi moussa [57] shows that pristine C60 is not relatively toxic. The evidences have been showed that fullerenes have no acute or sub-acute toxicity in large population of living organisms. Various risk assessment programs [58] have been done to evaluate toxicity of fullerenes. The conclusions of

[4]

[6] [7]

[8]

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Received: April 04, 2015

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Revised: June 26, 2015

Accepted: August 12, 2015