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the application of carbon nanotubes for targetted drug delivery system for cancer therapies

the application of carbon nanotubes for targetted drug delivery system for cancer therapies. OWner: Nanoscale Research Letters
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  NANO REVIEW Open Access  The application of carbon nanotubes in targetdrug delivery systems for cancer therapies Wuxu Zhang 1 , Zhenzhong Zhang 2* and Yingge Zhang 1* Abstract Among all cancer treatment options, chemotherapy continues to play a major role in killing free cancer cells andremoving undetectable tumor micro-focuses. Although chemotherapies are successful in some cases, systemictoxicity may develop at the same time due to lack of selectivity of the drugs for cancer tissues and cells, whichoften leads to the failure of chemotherapies. Obviously, the therapeutic effects will be revolutionarily improved if human can deliver the anticancer drugs with high selectivity to cancer cells or cancer tissues. This selective deliveryof the drugs has been called target treatment. To realize target treatment, the first step of the strategies is to buildup effective target drug delivery systems. Generally speaking, such a system is often made up of the carriers anddrugs, of which the carriers play the roles of target delivery. An ideal carrier for target drug delivery systems shouldhave three pre-requisites for their functions: (1) they themselves have target effects; (2) they have sufficiently strongadsorptive effects for anticancer drugs to ensure they can transport the drugs to the effect-relevant sites; and (3)they can release the drugs from them in the effect-relevant sites, and only in this way can the treatment effectsdevelop. The transporting capabilities of carbon nanotubes combined with appropriate surface modifications andtheir unique physicochemical properties show great promise to meet the three pre-requisites. Here, we review theprogress in the study on the application of carbon nanotubes as target carriers in drug delivery systems for cancertherapies. Keywords:  carbon nanotubes, cancer therapies, drug delivery systems, target chemotherapy Introduction Cancers are a kind of the diseases that are hardest tocure, and most cancer patients definitely die even whentreated with highly developed modern medicinal techni-ques. Surgery can remove cancer focuses but cannot dothe same for the micro-focuses and neither can extin-guish the free cancer cells that are often the srcin of relapse. Chemotherapy with anticancer drugs is themain auxiliary treatment but often fails because of theirtoxic and side effects that are not endurable for thepatients. Over the past few decades, the field of cancerbiology has progressed at a phenomenal rate. However,despite astounding advances in fundamental cancer biol-ogy, these results have not been translated intocomparable advances in clinics. Inadequacies in the abil-ity to administer therapeutic agents with high selectivity and minimum side effects largely account for the discre-pancies encompassing cancer therapies. Hence, consid-erable efforts are being directed to such a drug delivery system that selectively target the cancerous tissue withminimal damage to normal tissue outside of the cancerfocuses. However, most of this research is still in thepreclinical stage and the successful clinical implementa-tion is still in a remote dream. The development of sucha system is not dependent only on the identification of special biomarkers for neoplastic diseases but also onthe constructing of a system for the biomarker-targeteddelivery of therapeutic agents that avoid going into nor-mal tissues, which remains a major challenge [1]. Withthe development of nanotechnology, few nanomaterial-based products have shown promise in the treatment of cancers and many have been approved for clinicalresearch, such as nanoparticles, liposomes, and polymer-drug conjugates. The requirements for new drug * Correspondence:; 1 Institute of Pharmacology and Toxicology and Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Academy of MedicalScience, Zhengzhou, Henan, People ’ s Republic of China 2 Nanotechnology Research Center for Drugs, Zhengzhou University,Zhengzhou, Henan, People ’ s Republic of ChinaFull list of author information is available at the end of the article Zhang  et al  .  Nanoscale Research Letters  2011,  6 :555 © 2011 Zhang et al; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons AttributionLicense (, which permits unrestricted use, distribution, and reproduction in any medium,provided the srcinal work is properly cited.  delivery systems to improve the pharmacological profileswhile decreasing the toxicological effects of the delivereddrugs have also envisaged carbon nanotubes (CNTs) asone of the potential cargos for the cancer therapy.CNTs belong to the fullerene family of carbon allotropeswith cylindrical shape. The unique physicochemicalproperties [2,3] of CNTs with easy surface modification have led to a surge in the number of publications in thisinteresting field. Apart from their uses in the cellularimaging with diagnostic effects in nanomedicine [4,5], CNTs are promising drug carriers in the target drugdelivery systems for cancer therapies. Unlike other nao-carriers, such as liposomes/micelles that emerged in the1960s and nanoparticles/dendrimers that emerged in1980s, it has emerged no more than 20 years for carbonnanotubes to be envisaged as target drug carriers. Inthis chapter, the works that have been carried out withCNTs in the field of cancer therapy are briefly introduced. Physicochemical properties of CNTs Carbon nanotubes are a huge cylindrical large moleculesconsisting of a hexagonal arrangement of sp 2 hybridizedcarbon atoms (C-C distance is about 1.4  Ǻ ). The wall of CNTs is single or multiple layers of graphene sheets, of which those formed by rolling up of single sheet arecalled single-walled carbon nanotubes (SWCNTs) andthose formed by rolling up of more than one sheets arecalled multi-walled CNTs (MWCNTs). Both SWCNTsand MWCNTs are capped at both ends of the tubes ina hemispherical arrangement of carbon networks calledfullerenes warped up by the graphene sheet (Figure 1A).The interlayer separation of the graphene layers of MWCNTs is approximately 0.34 nm in average, eachone forming an individual tube, with all the tubes hav-ing a larger outer diameter (2.5 to 100 nm) thanSWCNTs (0.6 to 2.4 nm). SWCNTs have a betterdefined wall, whereas MWCNTs are more likely to havestructural defects, resulting in a less stable nanostruc-ture, yet they continue to be featured in many publica-tions due to ease of processing. As for their use as drugcarriers, there remain no conclusive advantages of SWCNTs relative to MWCNTs; the defined smaller dia-meter may be suitable for their quality control while thedefects and less stable structure make their modificationeasier. CNTs vary significantly in length and diameterdepending on the chosen synthetic procedure. SWCNTsand MWCNTs have strong tendency to bundle togetherin ropes as a consequence of attractive van der Waalsforces. Bundles contain many nanotubes and can beconsiderably longer and wider than the srcinal onesfrom which they are formed. This phenomenon couldbe of important toxicological significance [6,7]. CNTs exist in different forms depending upon the orientationof hexagons in the graphene sheet and possess a very high aspect ratio and large surface areas. The availablesurface area is dependent upon the length, diameter,and degree of bundling. Theoretically, discrete SWCNTshave special surface areas of approximately 1300 m 2 /g,whereas MWCNTs generally have special surface areasof a few hundred square meters per gram. The bundlingof SWCNTs dramatically decreases the special surfacearea of most samples of SWCNT to approximately 300m 2 /g or less, although this is still a very high value [8,9]. The markedly CNTs have various lengths from severalhundreds of nanometers to several micrometers and canbe shortened chemically or physically for their suitability for drug carriers (Figure 1B) [10] by making their two ends open with useful wall defects for intratube drugloading and chemical functionalization (Figure 1B). Functionalization of CNTs As drug carriers, the solubility of CNTs in aqueous sol- vent is a prerequisite for gastrointestinal absorption,blood transportation, secretion, and biocompatibility andso on; hence, CNT composites involved in therapeuticdelivery system must meet this basic requirement. Simi-larly, it is important that such CNT dispersions shouldbe uniform and stable in a sufficient degree, so as toobtain accurate concentration data. In this regard, thesolubilization of pristine CNTs in aqueous solvents isone of the key obstacles in the way for them to be devel-oped as practical drug carriers owing to the rather hydro-phobic character of the graphene side walls, coupled withthe strong  π - π  interactions between the individual tubes.These properties cause aggregation of CNTs into bun-dles. For the successful dispersion of CNTs, the mediumshould be capable of both wetting the hydrophobic tubesurfaces and modifying the tube surfaces to decreasetube ’ s bundle formation. To obtain desirable dispersion,Foldvari et al. have proposed four basic approaches [11]:(1) surfactant-assisted dispersion, (2) solvent dispersion,(3) functionalization of side walls, and (4) biomoleculardispersion. Among the above described approaches, func-tionalization has been the most effective approach. Inaddition, functionalization has been shown capable of decreasing cytotoxicity, improving biocompatibility, andgiving opportunity to appendage molecules of drugs, pro-teins, or genes for the construction of delivery systems[12]. Up to now, there have been a lot of literatures onthe functionalization of CNTs with various molecules(Figure 2A). The functionalization can be divided intotwo main subcategories: non-covalent functionalizationand covalent functionalization (Figure 2B). Non-covalent functionalization Many small, as well as large, polymeric anticanceragents can be adsorbed non-covalently onto the surface Zhang  et al  .  Nanoscale Research Letters  2011,  6 :555 2 of 22  Figure 1  The formation of SWCNT and its physical and chemical treatment for use as drug carriers . ( A ) The schematic illustration of thestructure formation of SWCNTs with the two ends closed. ( B ) The schematic illustration of the strategy for the preparation of the CNT-baseddrug delivery systems. Figure 2  The modification of CNTs . Schematic illustration of modification of CNTs with various molecules. 1, Dhar et al. [70]; 2, Jia et al. [13]; 3, Georgakilas et al. 2002 [16]; 4, Peng et al. 1998; 5, Liu et al. [91]; 6, Gu et al. 2008; 7, Son et al. 2008; 8, Klingeler et al. 2009. Zhang  et al  .  Nanoscale Research Letters  2011,  6 :555 3 of 22  of pristine CNTs. Forces that govern such adsorptionare the hydrophobic and  π - π  stacking interactionsbetween the chains of the adsorbed molecules and thesurface of CNTs. Since many anticancer drugs arehydrophobic in nature or have hydrophobic moieties,the hydrophobic forces are the main driving forces forthe loading of such drugs into or onto CNTs. The pre-sence of charge on the nanotube surface due to chemi-cal treatment can enable the adsorption of the chargedmolecules through ionic interactions [13,14]. Aromatic molecules or the molecules with aromatic groups can beembarked on the debunching and solubilization of CNTs using nucleic acids and amphiphilic peptidesbased on the  π - π  stacking interactions between theCNT surface and aromatic bases/amino acids in thestructural backbone of these functional biomolecules.Noncovalent functionalization of CNT is particularly attractive because it offers the possibility of attachingchemical handles without affecting the electronic net-work of the tubes.Oxide surfaces modified with pyrene through  π - π stacking interactions have been employed for the pat-terned assembly of single-walled carbon nanomaterials[15]. The carbon graphitic structure can be recognizedby pyrene functional groups with distinct molecularproperties. The interactions between bifunctional mole-cules (with amino and silane groups) and the hydroxylgroups on an oxide substrate can generate an amine-covered surface. This was followed by a coupling stepwhere molecules with pyrene groups were allowed toreact with amines. The patterned assembly of a singlelayer of SWCNT could be achieved through  π - π  stack-ing with the area covered with pyrenyl groups. Alkyl-modified iron oxide nanoparticles have been attachedonto CNT by using pyrenecarboxylic acid derivative aschemical cross-linker [16]. The resulting material hadan increased solubility in organic media due to the che-mical functions of the inorganic nanoparticles.Surfactants were initially involved as dispersing agents[17] in the purification protocols of raw carbon material.Then, surfactants were used to stabilize dispersions of CNT for spectroscopic characterization [18], optical lim-iting property studies, and compatibility enhancement of composite materials.Functionalized nanotube surface can be achieved sim-ply by exposing CNTs to vapors containing functionali-zation species that non-covalently bonds to thenanotube surface while providing chemically functionalgroups at the nanotube surface [19]. A stable functiona-lized nanotube surface can be obtained by exposing it to vapor stabilization species that reacts with the functio-nalization layer to form a stabilization layer against des-orption from the nanotube surface while depositingchemically functional groups at the nanotube surface.The stabilized nanotube surface can be exposed furtherto at least another material layer precursor species thatcan deposit as a new layer of materials.A patent [20] is pertinent to dispersions of CNTs in ahost polymer or copolymer with delocalized electronorbitals, so that a dispersion interaction occurs betweenthe host polymer or copolymer and the CNTs dispersedin that matrix. Such a dispersion interaction has advan-tageous results if the monomers of the host polymer/copolymer include an aromatic moiety, e.g., phenylrings or their derivatives. It is claimed that dispersionforce can be further enhanced if the aromatic moiety isnaphthalenyl and anthracenyl. A new non-wrappingapproach to functionalizing CNTs has been introducedby Chen et al. [21]. By this approach, the functionaliza-tion can be realized in organic and inorganic solvents.With a functionally conjugated polymer that includesfunctional groups, CNT surfaces can be functionalizedin a non-wrapping or non-packaging fashion. Throughfurther functionalization, various other desirable func-tional groups can be added to this conjugated polymer.This approach provided the possibility of further tailor-ing, even after functionalization. A process registered by Stoddart et al. [22] involves CNTs treated with poly{(5-alkoxy-m-phenylenevinylene)-co-[(2,5-dioctyloxy-p-phe-nylene) vinyl-ene]} (PAmPV) polymers and their deriva-tives for noncovalent functionalization of the nanotubeswhich increases solubility and enhances other propertiesof interest. Pseudorotaxanes are grafted along the wallsof the nanotubes in a periodic fashion by wrapping of SWCNTs with these functionalized PAmPV polymers.Many biomolecules can interact with CNTs withoutproducing of covalent conjugates. Proteins are animportant class of substrates that possess high affinity with the graphitic network. Nanotube walls can adsorbproteins strongly on their external sides, and the pro-ducts can be visualized clearly by microscopy techni-ques. Metallothionein proteins were adsorbed onto thesurface of multi-walled CNT, as evidenced by high-reso-lution transmission electron microscopy (TEM) [23].DNA strands have been reported by several groups tointeract strongly with CNT to form stable hybrids effec-tively dispersed in aqueous solutions [24,25]. Kim et al. [26] reported the solubilization of nanotubes with amy-lose by using dimethyl sulfoxide/water mixtures. Thepolysaccharide adopts an interrupted loose helix struc-ture in these media. The studies of the same group onthe dispersion capability of pullulan and carboxymethylamylase demonstrated that these substances could alsosolubilize CNTs but to a lesser extent than amylose.There are also some literatures that reported severalother examples of helical wrapping of linear orbranched polysaccharides around the surface of CNT[27]. Zhang  et al  .  Nanoscale Research Letters  2011,  6 :555 4 of 22
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