carbon nanotubes

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Hindawi Publishing CorporationBioMed Research InternationalVolume , Article ID ,pageshttp://dx.doi.org/.//

Review ArticleCarbon Nanotubes: Applications in Pharmacy and Medicine

Hua He,1,2 Lien Ai Pham-Huy,3 Pierre Dramou,1 Deli Xiao,1

Pengli Zuo,1 and Chuong Pham-Huy4

China Pharmaceutical University, Nanjing , China Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University,

Nanjing , China Department of Pharmacy, Stanford University Medical Center, Palo Alto, CA , USA

Faculty of Pharmacy, University of Paris V, avenue de lObservatoire, Paris, France

Correspondence should be addressed to Chuong Pham-Huy; [email protected]

Received July ; Accepted July

Academic Editor: akeshi Noda

Copyright Hua He et al. Tis is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Carbon nanotubes (CNs) are allotropes o carbon, made o graphite and constructed in cylindrical tubes with nanometer indiameter andseveral millimeters in length. Teir impressive structural, mechanical, andelectronic properties are dueto their smallsize and mass, their strong mechanical potency, and their high electrical and thermal conductivity. CNs have been successullyapplied in pharmacy and medicine due to their high surace area that is capable o adsorbing or conjugating with a wide variety o

therapeutic and diagnosticagents (drugs, genes, vaccines, antibodies, biosensors, etc.). Tey have been rst proven to be an excellentvehicle or drug delivery directly into cells without metabolism by the body. Ten other applications o CNs have been extensivelyperormed not onlyor drug and genetherapies but also ortissue regeneration, biosensordiagnosis, enantiomer separation o chiraldrugs, extraction and analysis o drugs and pollutants. Moreover, CNs havebeen recently revealed as a promising antioxidant. Tisminireview ocuses the applications o CNs in all elds o pharmacy and medicine rom therapeutics to analysis and diagnosisas cited above. It also examines the pharmacokinetics, metabolism and toxicity o different orms o CNs and discusses theperspectives, the advantages and the obstacles o this promising bionanotechnology in the uture.

1. Introduction

Carbon nanotubes (CNs), discovered by Japanese scientistIijima in [], are now considered to be a top classsubject in academic researches as well as in various industrialareas. Tese nanomaterials are allotropes o carbon, madeo graphite, and have been constructed in cylindrical tubeswith nanometer scale in diameter and several millimeters inlength [, ]. Teir impressive structural, mechanical, andelectronic properties are due to their small size and mass,their incredible mechanical strength, and their high electricaland thermal conductivity [, ]. Carbon nanotubes havebeen rst used as additives to various structural materialsor electronics, optics, plastics, and other materials o nan-otechnology elds. Since the beginning o the st century,they have been introduced in pharmacy and medicine ordrug delivery system in therapeutics. Tanks to their high

surace area, excellent chemical stability, and rich electronicpolyaromatic structure, CNs are able to adsorb or conjugatewith a wide variety o therapeutic molecules (drugs, proteins,antibodies, DNA, enzymes, etc.). Tey have been proven to bean excellent vehicle or drug delivery by penetrating into thecells directly and keeping the drug intact without metabolismduring transport in the body []. Many studies havedemonstrated that when bonded to CNs, these moleculesare delivered more effectively and saely into cells thanby traditional methods []. Tis antastic discovery hasopened a new way or drug preparations that is completelydifferent with traditional techniques used in pharmaceuticalindustry beore and radically changed anterior conceptso pharmacology [, ]. It has been rst applied to bindantineoplastic and antibiotic drugs to carbon nanotubes orcancer and inection treatments, respectively. Ten, otherlinkages o biomolecules (genes, proteins, DNA, antibodies,


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BioMed Research International

vaccines, biosensors, cells, etc.) to CNs havee been alsoassayed or gene therapy, immunotherapy, tissue regenerationand diagnosis o different ailments []. Tereore, in a

very short time, CNs have become the ocus o attentionby scientists in a wide variety o disciplines. Tey maybe promising antioxidants or health protective effect and

ailment prevention in the uture []. However, it is notiedthat all these medicinal ndings are in an experimentalstage and are still not applied in men. Besides these mainapplications o CNs, they have been shown as a powerultool or enantiomer separation o chiral drugs and chemicalsin pharmaceutical industry as well as in laboratory and orextraction o drugs and pollutants in different media bysolid phase extraction beore analysis [,]. Our group hasrecently contributed to the development o different novelunctionalized CN techniques or drug delivery as well asor drug analysis and also to the study on the interactionsbetween CNs and albumin or drugs [].

In this paper, an overview o different applications o

CNs is ocused in the eld o pharmacy and medicine. Itbriey describes the structure o CNs and their differenttypes. It examines some main methodologies using CNs as

vehicle or drug and biomolecule delivery in the treatmentand diagnosis o different dreadul diseases. It enumeratessome recentresearcheso CNs as antioxidants and also somenovel analytical techniques using CNs as tools or enan-tioseparation o chiral drugs and or solid phase extraction odrugs and pollutants in different media. Pharmacokinetics,metabolism, and toxicity o CNs are also examined. Teperspectives o this promising bionanotechnology in theuture medicine are briey commented, in the conclusion.

2. Carbon Nanotubes: Structures,Types and Preparation

Carbon nanotubes (CNs) consist exclusively o carbonatoms arranged in a series o condensed benzene rings rolledup into a tubular structure. Tis novel articial nanomaterialbelongs to the amily o ullerenes, the third allotropic ormo carbon along with graphite and diamond which are bothnatural sp (planar) and sp (cubic) orms, respectively [,, ]. Based on the number o layers, structures o CNsare classied into two types: single-walled carbon nanotubes(SWCNs) and multiwalled carbon nanotubes (MWCNs)(Figure ).

SWCNs consist o a single graphene cylinder withdiameter varying between . and nm, and usually occuras hexagonal close-packed bundles (Figure ). MWCNsconsist o two to several coaxial cylinders, each made o asingle graphene sheet surrounding a hollow core. Te outerdiameter o MWCNs ranges rom to nm, while theinner diameter is in the range o nm, and their length is. to several m [,]. From a chemical reactivity pointo view, CN can be differentiated into two zones: the tipsand the sidewalls. An important actor that controls theseunique properties comes rom a variation o tubule structuresthat are caused by the rolling up o the graphene sheetinto a tube. Tere are three distinct ways or the molecule

0.2

5m

0.42nm

(a)

0.38nm

2100nm

(b)

F : Conceptual diagrams o single-walled carbon nanotubes(SWCN) (a) and multi-walled carbon nanotubes (MWCN) (b).Image rom ree internet access.

Tip

SidewallCarbon atom

F : A carbon nanotube with closed ends.

: Comparison between single-walled carbon nanotubes(SWCN) (A) and multi-walled carbon nanotubes (MWCN)(B) [].

SWCN MWCN

() Single layer o graphene Multiple layer o graphene

() Catalyst is required orsynthesis

Can be produced withoutcatalyst

() Bulk synthesis is difficult Bulk synthesis is easy

() More deection duringunctionalization

Less deection, but difficult toimprove

() Purity is poor Purity is high

() Less accumulation in body More accumulation in body

() Easy characterization and

evaluation

Difficult characterization and

evaluation() Easily twisted Difficult to twist

to do the rolling, depending upon its direction: armchair,zigzag, and chiral (Figure ). Detailed explanations o CNsstructures can be ound in several recent review articlescited herein [,]. Structures and characterizations oSWCNs and MWCNs aresummarized in able accordingto Singh et al. [].

Tree main techniques generally used or SWCNs andMWCNs production are:Arc-Dischargemethod (using arc-

vaporization o two carbon rods), Laser Ablation method


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Armchair

(a)

Zigzag

(b)

Chiral

(c)

F : Carbon nanotube structures o armchair, zigzag and chiral congurations. Tey differ in chiral angle and diameter: armchaircarbon nanotubes share electrical properties similar to metals. Te zigzag and chiral carbon nanotubes possess electrical properties similarto semiconductors.

(using graphite), and Chemical Vapor Deposition (usinghydrocarbon sources: CO, methane, ethylene, acetylene).Afer preparation, CNs are submitted to purication byacid reuxing, suractant aided sonication, or air oxidationprocedure in order to eliminate impurities such as amor-phous carbon, ullerenes, and transition metals introduced

as catalysts during the synthesis [, , ]. Pristine CNsare now synthesized and marketed by many chemical rmsworldwide.

3. Carbon Nanotubes: Functionalization forBiomedical Applications

Pristine CNs are not soluble in aqueous solutions becausethey have highly hydrophobic suraces. Surace unctional-ization is required to solubilize CNs, and to render bio-compatibility and low toxicity or their medical applications[]. Te unctionalization procedure o CNs can be dividedinto two main approaches, depending on the nature o thebiomolecule linked to carbon nanotube, that is, covalentattachment (chemical bond ormation) and noncovalentattachment (physioadsorption) [,].

Te covalent unctionalization o CNs is generallyobtained by oxidation with strong acids (HNO

3). During the

process, carboxyl (COOH) groups are ormed at the opensides (tips) and at the deects on the sidewalls o SWCNor MWCN, then, urther covalent conjugation with aminoacid. For the creation o COOH on the sidewalls o CNs,nitrene cycloaddition, arylation using diazonium salts or,-dipolar cycloadditions are usually employed [, ].Schematic illustration o covalent unctionalization o carbonnanotubes is summarized inFigure .

Te noncovalent unctionalization o CNs can be carriedout by coating CNs with amphiphilic suractant moleculesor polymers (polyethyleneglycol). Te large aromatic (-electrons) hydrophobic surace o carbon nanotubes makesthem idealpartners or noncovalent interactions with suitablecomplementary molecules and macrobiomolecules (DNA).

Tese interactions can take place both on the inside andoutside o CNs. However, macromolecules cannot be linkedon their inside [,,].

Schematic noncovalent unctionalization o CNs is illus-trated inFigure .

Afer unctionalization, CNs become hydrophilic andare ready to be linked with drugs or biomolecules (genes,DNA, proteins, enzymes, biosensors, etc.) or their deliv-ery into the target cells or organs. Detailed techniques ounctionalization and linkage can be ound in our recentpublications and in the others cited herein [,,,].

4. Applications of Carbon Nanotubes inPharmacy and Medicine

Te main applications o CNs in pharmacy and medicineinclude drug, biomolecule, gene delivery to cells or organs,tissue regeneration, and biosensor diagnostics and analysis.Tey are summarized inFigure .

For drug delivery, the general process using CNs can bebriey resumed as ollows. Drug is xed on the surace orthe inside o unctionalized CNs. Te conjugate obtained isthen introduced into the animal body by classic ways (oral,injection) or directly to the target site through the use oa magnetic conjugate, or example, guided by an external


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CNTs

CONHRCONHR

RNHOC

COOH

ClOC

COOH

CONHR

CONHR

CONHR

COOH

COOH

COOH

HOOC

HOOC

COCl

COCl

COCl

COCl

COCl

RHNOC

ClOC

(b)

(a)

SOCl2

RNH2

HNO3/H2SO4

F : Covalent unctionalization o CNs by (a) oxidation reaction by strong acid and (b) urther attaching hydrophilic molecules byamidation reactions.

SWCNT

(b)

(a)

F : Noncovalent unctionalization o CNs with (a) suractants such as protein adsorption and (b) polymers such as DNA wrapping.

magnet to the target organ, such as lymphatic nodes. Te cellingests the drug CN capsule and nally the nanotube spillsits contents into the cell and thus the drug is delivered [].Schematic illustration o drug delivery process is described inFigure .

Generally, unctionalized CNs possess the ability tocarry molecules o interest across the cytoplasmic mem-brane and nuclear membrane without producing a toxiceffect; thereore, the drug CN conjugate proves to be saerand more effective than drug used alone by traditionalpreparation. Afer reaching the targeted cell, they are twopossibilities to deliver the drug: the drug enters the cells

without internalization o the CN carrier or both the drugand the CN carrier enters the cells. Te latter internalizationmethod is more effiectiv than the rst one, because aferentering the cells, the intracellular environment degradesthe drug carrier conjugate releasing drug molecules in situ,that is, inside the cells. While, in the non-internalizationmethod, the extracellular environment helps to degrade drugcarrier conjugates and the drug then crosses itsel the lipidmembrane to enter the cells, thereby, there is a possibility odrug degradation during this penetration by itsel. Tere aretwo possible mechanisms o CN internalization: either viathe endocytosis pathway or via the insertion and diffusion


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FunctionalizedCNTs

CNTs intherapeutics

CNTs indiagnosis and

analysis

Cancer therapy

Infection therapy

Gene therapy

Tissue generation

Neurodegenerativediseases

As antioxidants

Biosensor vehiclesfor diagnosis

Enantioseparationof chiral drugs

Extraction ofdrugs and

biochemicals

By drug delivery

By immunotherapy

By hyperthermia

therapy

F : Schematic o carbon nanotube applications in therapeutics and biomedical diagnosis and analysis.

pathway, that is, via the endocytosis-independent pathway.However, the mechanism o the last pathway is still not well-known [,,].

Briey, the explanations about the ability o CNs tocross cell membranes or drug delivery are due to thesimple hydrophobic interaction, - stacking interaction,electrostatic adsorptionand covalentbondsin theirstructure,but also by adsorption into the hollow cylinder, which isconducive to increase the adsorptive capacity []. Besides,CNs have a capacity not only to penetrate into the cellsto promote the cellular uptake o therapeutic moleculesbut also to keep them intact during transportation andcellular penetration. Te last property permits the decrease

o the dosages o drugs used, and consequently their toxicity,especially or anticancer drugs.

.. Carbon Nanotubes Used for Cancer Terapy

... By Drug Delivery. CNs can be used as drug carriersto treat tumors [,]. Te efficacy o anticancer drugsused alone is restrained not only by their systemic toxicityand narrow therapeutic window but also by drug resistanceand limited cellular penetration. Because CNs can easilyacross the cytoplasmic membrane and nuclear membrane,anticancer drug transported by this vehicle will be liberatedin situ with intact concentration and consequently, its action

in the tumor cell will be higher than that administered aloneby traditional therapy. Tus, the development o efficientdelivery systems with the ability to enhance cellular uptake oexisting potent drugs is needed. Te high aspect ratio o CNsoffers great advantages over the existing delivery vectors,because the high surace area provides multiple attachmentsites or drugs [].

Many anticancer drugs have been conjugated with unc-tionalized CNs and successully tested in vitro and in

vivo such as epirubicin, doxorubicin, cisplatin, methotrexate,quercetin, and paclitaxel [,,].

For avoiding the harmul effect o anticancer drug onhealthy organs and cells, our group [] has linked epirubicin

with a magnetic CNs complex obtained by xing a layero magnetite (Fe3O4) nanoparticles on the surace o thenanotubes with necklace-like type and on the tips o short-ened MWCNs []. Other authors have used the epirubicinmagnetic CNs complex or lymphatic tumor targeting. Sucha system can be guided by an externally placed magnet totarget regional lymphatic nodes [].

For the same previous reason, chemotherapeutic agentscan be bound to a complex ormed by CN and antibodyagainst antigen overexpressed on the cancerous cell surace.By the attraction o antigen-antibody, the CNs can be takenup by the tumor cell only beorethe anticancer drug is cleavedoff CNs; thus, targeting delivery is realized []. A major


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Chemical receptor

Cell receptorsFunctionalized CNT

Biodegradablecap

Released drug

Cell

Drug

(c)

(a)

(f)

(b)

(d)

(e)

F : Schematic illustration o the drug delivery process. (a) CN surace is linked with a chemical receptor (Y) and drugs () are loadedinside, (b) open end o CN is capped, (c) drug-CN carrier is introduced in the body and reaches the target cells due to chemical receptoron CN surace, (d) cell internalizes CN by cell receptors (V) via endocytosis pathway or example, (e) cap is removed or biodegrades insidethe cell, then drugs are released.

obstacle to effective anticancer therapy is the multidrug resis-tance caused by enhanced efflux o anticancer drugs by theoverexpressed p-glycoprotein, resulting in poor anticancereffect []. Li and coworkers [] have shown that SWCNscan be unctionalized with p-glycoprotein antibodies andloaded with the anticancer agent doxorubicin. Comparedwith ree doxorubicin, this ormulation demonstrated highercytotoxicity by .-old against KR leukemia cells.

Te in vivo administration o SWCN paclitaxel conju-gate in a murine breast cancer model has been observed withhigher efficacy in suppressing tumor growth and less toxiceffects to normal organs [,]. Te higher therapeutic effi-

cacy and lower side effects could be attributed to prolongedblood circulation, higher tumor uptake, and slower release odrug rom SWCNs [].

... By Antitumor Immunotherapy. Some studies havedemonstrated that CNs used as carriers can be effectivelyapplied in antitumor immunotherapy [,]. Tis ther-apeutic consists o stimulating the patients immune systemto attack the malignant tumor cells. Tis stimulation canbe achieved by the administration o a cancer vaccine or atherapeutic antibody as drug. Some authors have validatedthe use o CNs as vaccine delivery tools []. Yangs groupobserved that the conjugate o MWCNs and tumor lysate

protein (tumor cell vaccine) can considerably and specicallyenhance the efficacy o antitumor immunotherapy in amouse model bearing the H liver tumor []. In vitro,the conjugate o CNs and tumor immunogens can act asnatural antigen presenting cells (such as mature dendriticcells) by bringing tumor antigens to immune effector cells; this action is due to the high avidity o antigenon the surace and the negative charge. Te complementsystem activation effects o CNs and also their adjuvanteffects may play a role in the stimulation o antitumorimmunotherapy; however, the mechanism remains unknown[,].

... By Local Antitumor Hyperthermia Terapy. Te hyper-thermia therapy using CNs has been recently suggestedas an efficient strategy or the cancer treatments. SWCNsexhibit strong absorbance in the near-inrared region (NIR; nm). Tese nano-materials are considered as potentcandidates or hyperthermia therapy since they generatesignicant amounts o heat upon excitation with NIR light[]. Te photothermal effect can induce the local thermalablation o tumor cells by excessive heating o SWCNsshackled in tumor cells such as pancreatic cancer. Someprogress in the technique has been achieved in recent years,and it has shown easibility in clinical application.


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.. Carbon Nanotubes for Infection Terapy. Because o theresistance o inectious agents against numerous antiviral,antibacterial drugs or due to certain vaccine inefficacy inthe body, CNs have been assayed to resolve these prob-lems. Functionalized CNs have been demonstrated to beable to act as carriers or antimicrobial agents such as the

antiungalamphotericin B [, ]. CNs can attach covalentlyto amphotericin B and transport it into mammalian cells.Tis conjugate has reduced the antiungal toxicity about% as compared to the ree drug []. Our group hassuccessully combined an antimicrobial agent Pazuoxacinmesilate with amino-MWCN with high adsorption and willbe applied to experimental assays or inection treatment[].

Functionalized CNs can also act as vaccine deliveryprocedures [, ]. Te linkage o a bacterial or viralantigen with CNs permits o keeping intact antigen con-ormation, thereby, inducing antibody response with theright specicity []. Te xation o unctionalized CNs

with B and cell peptide epitopes can generate a multi-valent system able to induce a strong immune response,thereby becoming a good candidate or vaccine delivery[, ]. Tus, unctionalized CNs can act a good car-rier system or the delivery o candidate vaccine antigens.Besides, CNs themselves might have antimicrobial activitysince bacteria may be adsorbed onto the suraces o CNs,such as the case o E. coli. Te antibacterial effect wasattributed to carbon nanotube-induced oxidation o theintracellular antioxidant glutathione, resulting in increasedoxidative stress on the bacterial cells and eventual cell death[].

.. Carbon Nanotubes for Gene Terapy by DNA Delivery.Gene therapy is an approach to correct a deective gene whichis the cause o some chronic or hereditary diseases by intro-ducing DNA molecule into the cell nucleus. Some deliverysystems or DNA transer include liposomes, cationic lipidsand nanoparticles such as CNs recently discovered [,,].

When bound to SWCNs, DNA probes are protectedrom enzymatic cleavage and intererence rom nucleicacid binding proteins, consequently, DNA-SWCNcomplex exhibits superior biostability and increasessel-delivery capability o DNA in comparison to DNAused alone [, , ]. Indeed, stable complexes betweenplasmid DNA and cationic CNs have demonstratedthe enhancement o gene therapeutic capacity comparedwith naked DNA. CNs conjugated with DNA wereound to release DNA beore it was destroyed bycells deense system, boosting transection signicantly[,,].

Te use o CNs as gene therapy vectors has shownthat these engineered structures can effectively transport thegenes inside mammalian cells and keep them intact becausethe CN-gene complex has conserved the ability to expressproteins []. Pantarotto and coworkers [] have developednovel unctionalized SWCN-DNA complexes and reportedhigh DNA expression compared with naked DNA.

.. Carbon Nanotubes for issue Regeneration and ArticialImplants. Te knowledge advances o cell and organ trans-plantation and o CN chemistry in recent years have con-tributed to the sustained development o CN-based tissueengineering and regenerative medicine. Carbon nanotubesmay be the best tissue engineering candidate among numer-

ous other materials such as natural and synthetic polymersor tissue scaffolds since this nanomaterial is biocompati-ble, resistant to biodegradation, and can be unctionalizedwith biomolecules or enhancing the organ regeneration. Inthis eld, CNs can be used as additives to reinorce themechanical strength o tissue scaffolding and conductivity byincorporating with the hosts body [,,,].

Indeed, MacDonald et al., [] have successully com-bined a carboxylated SWCNs with a polymer or collagen(poly-l-lactide or poly-D,L-lactide-co-glycolide) to orm acomposite nanomaterial used as scaffold in tissue regenera-tion. Other tissue engineering applications o CNs concern-ing cell tracking and labeling, sensing cellular behavior, and

enhancing tissue matrices are also studied recently [,].For example, it has been reported that CNs can effectivelyenhance bone tissue regenerations in mice and neurogeniccell differentiation by embryonic stem cells in vitro [,].

.. Carbon Nanotubes for Neurodegenerative Diseases andAlzheimer Syndrome. As a promising biomedical material,CNs have been used in neurosciences [,,,]. Becauseo their tiny dimensions and accessible external modica-tions, CNs are able to cross the blood-brain barrier by

various targeting mechanisms or acting as effective deliverycarriers or the target brain. Yang et al. [] have observedthat SWCNs were successully used to deliver acetylcholine

in mice brainsaffected by Alzheimers disease with high saetyrange. Many other unctionalized SWCNs or MWSCNshave been used successully as suitable delivery systems ortreating neurodegenerative diseases or brain tumors [,,]. Overall, the results o these studies have indicated thatconjugates o CNs with therapeutic molecules have bettereffects on neuronal growth than drugs used alone.

.. Carbon Nanotubes as Antioxidants. Te theory ooxygen-ree radicals has been known about fy years ago.However, only within the last two decades, has there beenan explosive discovery o their roles in the developmento diseases, and also o the health protective effects oantioxidants []. Nevertheless, the potential role o CNs asree-radical scavengers is still an emerging area o research.Some scientists have recently reported that CNs and inparticular carboxylated SWCNs are antioxidants in natureand may have useul biomedical applications or preventiono chronic ailments, aging, and ood preservation [, ].Francisco-Marquez et al. observed that the presence oCOOH groups would increase the ree radical scavengingactivity o SWCNs and that carboxylated SWCNs areat least as good as, or even better, ree radical scavengersthan their nonunctionalized partners []. Teir antioxidantproperty hasbeen used in anti-aging cosmetics andsunscreencreams to protect skin against ree radicals ormed by the


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body or by UV sunlight [, ]. More investigations odifferent CN orms in the uture are needed to developtheir precious effect o ree radical scavenger or biomedicaland environmental applications, since ree radicals are wellknown to be very damaging species [,].

.. Carbon Nanotubes as Biosensor Vehicles for Diagnosticand Detection. A biosensor is an analytical device, usedor the detection o an analyte that combines a biologicalcomponent with a physicochemical detector. Te use o CNsin biosensing nanotechnology is recent and represents a mostexciting application area or therapeutic monitoring and in

vitro and in vivo diagnostics. For example, many searchershave coupled CNs with glucose-oxidase biosensors orblood sugar control in diabetic patient with higher accu-racy and simpler manipulation than biosensors used alone[, , ]. Other CN-enzyme biosensors such as CN-based dehydrogenase biosensors or peroxidase and catalasebiosensors have also been developed or different therapeutic

monitoring and diagnostics [,].For electrical detection o DNA, the assay sensitivity was

higher with alkaline phosphatase (ALP) enzyme linked toCNs than with ALP alone. Te sensitivity o the assay usingSWCN-DNA sensor obtained by integration o SWCNswith single-strand DNAs (ssDNA) was considerably higherthan traditional uorescent and hybridization assays. TisCN-biosensor-linked assay can be modied or antigendetection by using specic antibody-antigen recognition.Tus, it could provide a ast andsimple solution ormoleculardiagnosis in pathologies where molecular markers exist, suchas DNA or protein [,].

Moreover, CNs have been assayed to detect some

organophosphoric pesticides by using acetylcholine esteraseimmobilized on CN surace with electrochemical detection[, , ]. Owing to their length scale and unique structure,the use o CNs as biosensor vehicle is highly recommendedto develop sensitive techniques or diagnostics and analysesrom the laboratory to the clinic.

.. Carbon Nanotubes for Enantioseparation of Chiral Drugsand Biochemical. In pharmaceutical industries, % o thedrugs currently in use are chiral products and % othe last ones are marketed as racemates consisting o anequimolar mixture o two enantiomers []. Recently, USFood and Drug Administration (FDA) recommended theassessments o each enantiomer activity or racemic drugsin body and promoted the development o new chiraldrugs as single enantiomers []. Tereore, a wide rangeo new technologies or chiral separation has been devel-oped, among them carbon nanotechnology. Silva et al. []have recently used a microcolumn packed with SWCNas chiral selector or separation o carvedilol enantiomers,a -blocker, with uorescent detection. Yu et al. [] havedeveloped a chiral stationary phase o MWCN cross-linkedwith hydroxypropyl--cyclodextrin or enantioseparation oracemic clenbuterol, a bronchodilator, with-high-resolutionactor. It is also notied that CNs are chiral orms due tothe helical winding o the graphitic rings around the tube

axis. However, they might not be effective enantio-specicadsorbents. In contrast, chiral selector modied CNs havebeen successully assayed to separate enantiomers rom manyracemic drugs [].

.. Carbon Nanotubes for Solid Phase Extraction of Drugs

and Biochemicals. Due to their strong interaction with othermolecules, particularly with those containing benzene rings,CNs suraces possess excellent adsorption ability. Non-unctionalized or unctionalized CNs have been investi-gated as Solid phase Extraction (SPE) adsorbents used aloneor in conjugation with classical SPE sorbents (C silica,XAD- copolymer) or the analytical extraction o drugs,pesticides or natural compounds in different media suchas biological uids, drug preparations, environment, plants,animal organs, and so orth [,]. In several comparativestudies CNs exhibit similar or higher adsorption capacitythan silica-based sorbents or macroporous resins. Manyapplications o CNs in SPE can be ound in different

recent review articles dealing with general aspect [, ].For examples, many drugs such as benzodiazepines, sulon-amides, non-steroidal anti-inammatory (NSAI), barbitu-rates, antidepressants, propranolol, cinchonine and quinine,and so orth, have been extracted by SPE using eitherSWCNs or MWCNs as adsorbents in different matricescited above, then analyzed by different physicochemicaltechniques []. Recently, our group [] has developed anovel molecularly imprinted magnetic solid phase extractionmaterials xed on magnetic carbon nanotubes as support orthe extraction and determination o an antibiotic, gatioxacin(GFX), in serum samples coupled with HPLC. Te resultso this novel adsorbent phase showed excellent specic

recognition toward GFX. Moreover, it was easily separatedrom the suspension by an external magnet, giving a bestselective extraction o drug rom biological uids [].

Many other applications o CNs in SPE have beenperormed or the analysis o diverse pesticides (carbouran,iprobenos, parathion-methyl, etc.), phenolic preservatives,and natural compounds (piperine rom pepper). Moreover,CNs can be utilized or the extraction o inorganic ions andorganometallic compounds as well as or the preparation ostationary phases o GC or LC columns [,].

5. Pharmacokinetics and Metabolism ofCarbon Nanotubes

Studies in pharmacokinetics and metabolism o diverse ormso CNs have been investigated and some review articlesabout them have been reported in the literature recently [, ,]. Te biodistribution and pharmacokinetics o nanopar-ticles depend on their physicochemical characteristics suchas surace unctionalization, solubility, shape, aggregation,and chemical composition. In the literature, two studieswere perormed with water soluble CNs (SWCN or/andMWCN) or their biodistribution in mice [,]. Noneo these studies reports toxic side effects or mortality. Both

experiments have used either 125Iodine or 111Indium as radiotracers or observing their biodistribution in mice [, ].In


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the rst one, 125I-hydroxylated-SWCN (125I-SWCN-OH)was administrated by different routes (intraperitoneal, IV, SC,or oral).Tis study reported that the CNbiodistribution wasnot signicantly inuenced by the administration route and

that the 125I-SWCN-OH distributed quickly throughout thewhole body with % o the unchanged nanotubes excreted

intotheurineand%intheeces[, ]. Te preerred organsor accumulation were the stomach, kidneys, and bone. Notissue damage or distress was reported. Second study used

two orms o111Indium-unctionalized SWCN or MWCNby IV administration only in mice. Te biodistributionproles obtained were ound very similar or both types ounctionalized CNs which showed an affinity or kidneys,muscle, skin, bone, and blood min afer administration[, ]. However, all types o CNs were rapidly clearedrom all tissues and a maximum blood circulation hal-lie o. h was determined []. Both SWCN and MWCN wereound to be excreted through the renal route and observedto be intact in the excreted urine by transmission electron

microscopy [].Nevertheless, some scientists have recently shown thatCNs can be broken down by myeloperoxidase (MPO), anenzyme ound in neutrophils o mice []. Teir discoveriescontradict what was previously believed, that CNs are notbroken down in the body. Tis action o how MPO convertsCNs into water and carbon dioxide can be signicantto medicine and thus represents a breakthrough in nan-otechnology and nanotoxicology, since it clearly shows thatendogenous MPO can break down CN [].

6. Toxicity of Carbon Nanotubes

Te results o CN toxicological assays ound in the literatureseem to be contradictory. Some preliminary in vitro testshave showed that CNs are toxicologically benign to certaincells, while other urther studies have indicated that CNs,especially raw materials are potentially dangerous to manyliving systems [, , , ]. It is notied that phar-macological activities o CNs conjugated with therapeuticmolecules are still not applied in men and consequently theirclinical toxicity is also not evaluated.

.. In Vitro oxicological Studies of Carbon Nanotubes. Somein vitro cytotoxicity assessments o water dispersible single-walled carbon nanotubes (SWCN) on A cells, a humanlung cell line, conrmed that there was no intracellularlocalization o SWCN in A cells and demonstrated thatSWCN could induce an indirect cytotoxicity by alterationo cell culture medium which caused a alse-positive toxiceffect []. Dumortier et al. [] observed that watersoluble SWCNs marked with uorescein were nontoxic tocultures o mouse B- and -lymphocytes and macrophagesand preserved the unction o these immune cells. Otherstudies aimed to evaluate the potential toxicity and thegeneral mechanism involved in two diameter kinds o watersoluble multiwalled carbon nanotubes (MWCN)-inducedcytotoxicity in C rat glioma cell line []. Results demon-strated that smaller size o MWCN seemed to be more

toxic than larger one. MWCN-induced cytotoxicity in Crat glioma cells was probably due to the increased oxidativestress. However, pristine, water insoluble CNs, have beenound to be highly toxic in vitro to many different typeso cells, including human keratinocytes, rat brain neuronalcells, human embryonic kidney cells, and human lung cancer

cells [, ]. It is notied that these insoluble pristineCNs cannot be used as carriers or drug and gene deliveryin therapeutics, but are only ound in the workplace o CNproduction.

.. In Vivo oxicological Studies of Carbon Nanotubes.According to the interesting review article about CN tox-icity recently published by Yang et al., [] many in vivotoxicological assessments have been perormed by IV or SCinjections and gastrointestinal exposure with unctionalizedor dispersed SWCNs or/and MWCNs in different animals(rats, mice). Te available saety data collectively indicatethat CNs are o low toxicity via various exposure path-

ways or biomedical applications. CNs induced meaningultoxicity only when a very high dosage ( mg/kg) underPolyethylene-Glycol-MWCNs (PEG-MWCNs) orm wasadministrated in mice [, ]. Te toxicity o SWCNsis closely related to the oxidative stress in despite o theadministration routes []. On the other hand, when CNshave been used as tissue engineering materials or cell growthby implanting subcutaneously, CNs exhibited very goodbiocompatibility and did not arise any serious toxicity, except

very limited inammation []. However, Folkmann et al.[] reported that SWCNs can induce oxidative damages toDNA in mice afer oral gavage and Fraczek et al. [] oundthat implanted SWCNs and MWCNs induced inamma-

tion. In contrast, other reports on the toxicity o CNs toskin suggested that CNs were biocompatible to skin withgood biocompatibility afer subcutaneously planting [].For the carcinogenicity evaluations, akanashi et al. []also observed that MWCNs injected into the subcutaneoustissue o rasH mice did not develop neoplasms. However,other scientists ound that CNs introduced into the abdom-inal cavity o mice showed asbestos-like pathogenicity [].Indeed, there are several parameters affecting the toxicity oCNs in vivo. Metal impurities might contribute partiallyto the oxidative stress and thus, careul purication oCNs is necessary. Chemically unctionalized CNs showhigher biocompatibility than pristine CNs. Tus, Yang

et al. [] concluded that unctionalized CNs are generallybiocompatible and low toxic or the biomedical purposes.More toxicity evaluations are encouraged to give the saetythreshold value o different CNs andclariy the toxicologicalmechanism.

.. Human oxicity of Carbon Nanotubes. As applications ounctionalized CNs linked with therapeutic molecules arestill not assayed in man or clinical studies, most publicationsound in the literature suggested that pristine CNs couldbe the source o occupational lung diseases in workers oCN industries like asbestos pathology previously observedin man [,,]. Based on several rodent studies in which


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test dusts were administered intratracheally or intrapharyn-geally to assess the pulmonary toxicity o manuacturedCNs, these authors concluded that CNs were capable oproducing inammation, epithelioid granulomas, brosis,and biochemical changes in the lungs [,]. In arecent publication in [], Ali-Boucetta et al. reported

that the asbestos-like reactivity and pathogenicity reportedor long, pristine nanotubes can be completely alleviatedi their surace is modied and their effective length isreduced as a result o chemical treatment, such as withtri(ethylene glycol) (EG). However, opinions about thepotential hazards o exposures to pristine CNs and theirresidual metal impurities are still discussed. Moreover, theapparent similarity between multi-walled carbon nanotubes(MW-CNs) and asbestos bers has raised many questionsabout their saety prole. Despite their immense potentialbenets in therapeutics, the toxicity o CNs is a majorconcern that needs to be more clearly explained and appre-hended.

7. Conclusion and Perspectives

Tis minireview reveals many spectacular benets o car-bon nanotubes during their recent applications in differentareas o pharmacy and medicine. Te discovery o thisbionanotechnology has opened new alternatives more effec-tive than the ancient drug delivery methods since CNscan pass through cell membranes, carrying drugs, genes,biomolecules, vaccines, and so orth deep into the target cellsor organs previously unreachable. Another novel approachis the use o collagen CNs materials as scaffolds in tis-sue generation and articial implants because CNs resistbiodegradation and are a powerul engineering candidateover other existing materials used to repair deective organs.Besides, CNs combined with biosensors or other materialshave proven excellent implements or the therapeutic moni-toring and the diagnosis o diseases as well as or the analysiso drugs in different areas. It is also advisable to developthe ree radical scavenger potential o unctionalized CNsor health maintenance. Overall, this nanotechnology couldrevolutionize the therapeutic concepts in the utureand give aglimmer o hope or thetreatment o many incurablediseases.

However, despite many surprising results o CNsobtained during the beginning o this research eld, there arestill tremendous opportunities to be explored and signicantchallenges and risks to be solved. Tereore, more imagina-tion and innovation are needed to elaborate different neworms o CNs and their conjugates with high efficacy andsaety or medicinal use in the uture. For example, uturepreparation o CNs should be attached with new sensitivemarkers so that they could directly reach the target cells orscientists could easily drive them rom the exterior to thetarget organ in order to avoid side effects on the other healthytissues.

In the same time, many hurdles o this nanotechnologyhave to be solved or elucidated. Te human toxicity odifferent orms o CNs or short- and long-term treatmentis the rst vital concern when they will be assayed in clinic.

Some preliminary toxicological studies in vitro and in ani-mal that were recently perormed have shown controversialresults. Careully optimizing the physicochemical parametersto minimize the toxicity o CNs is highly avorable. Moretoxicological investigations o different orms o CNs rompristine CNs to unctionalized CNs and their conjugates

are highly recommended beore theycould be effectively usedin clinical study and then marketed worldwide.

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