Macromolecular Research, Vol. 20, No. 9, pp 891-898 (2012) DOI 10.1007/s13233-012-0134-y

www.springer.com/13233 pISSN 1598-5032 eISSN 2092-7673

Reviews Nanotechnology and Carbon Nanotubes; A Review of Potential in Drug Delivery Edwin Kamalha*,1, Xiangyang Shi2, Josphat I. Mwasiagi3, and Yongchun Zeng1 1

College of Textile Science and Engineering, Donghua University, 210620 Shanghai, P. R. China College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 210620 Shanghai, P. R. China 3 School of Engineering, Moi University, Eldoret, Kenya

2

Received September 21, 2011; Revised December 30, 2011; Accepted January 2, 2012 Abstract: The need for affordable health care costs and the quest for better modes of treatment have increased research in novel drug delivery techniques. Efficient drug delivery systems (DDS) are judged on their ability to perform controlled and targeted drug delivery. Several nanomaterials such as carbon nanotubes (CNTs) are widely being investigated for biomedical use due to their unique properties, as well as several functional groups and incorporated targeting molecules. This review looked at nanotechnology as an emerging field in drug delivery. Several studies and findings with regards to the current functionalization of CNTs for drug delivery were explored. The conclusion reviewed the key notes. Keywords: drug delivery systems (DDS), carbon nanotubes (CNTs), single-walled nanotubes (SWNTs), multi-walled nanotubes (MWNTs), functionalization.

functionalization is necessary to add purity and also immobilize necessary biomolecules compatible with the drug to be delivered. It is mainly functionalization for cancer therapy with CNTs that is reported to have had more progress.5,6 However, such should be done to study more illnesses. With coordinated research, better alternatives with nanotechnology, are bound to be found. This review looks at the current use of nanotechnology and carbon CNTs in drug delivery. The functionalization of CNTs to impart to them demands in DDS has been reviewed in detail. Definition and Scope of Drug Delivery Systems. Drug delivery, encompasses the delivery vessel, the route, and the target site. This phenomenon is a combination of practices and/or devices aimed at effective drug therapy through controlled drug release.7 Flynn8 defines drug delivery as any means possible, to achieve regulated access of a drug to the targeted sites of the body. Other necessary features include; exclusive delivery to specific and inaccessible sites; protection of the body from unwanted deposition; a controlled rate and modality of delivery, and reduced amount of active principal used.9 New biologic drugs such as proteins and nucleic acids call for novel delivery alternatives with minimal side effects yet possessing better patient compliance. Researchers are continually investigating new ways to deliver

Introduction Earlier biomedical research on carbon nanotubes (CNTs) largely centered on functionalization and attachment of biomolecules on nanotubes for mainly characterizing and altering for use in some devices (as biosensors). The therapeutic importance and earnings from health care products, enjoyed by pharmaceutical companies, are incentives for research on new drug delivery technology. Challenges associated with current drug delivery systems (DDSs) include; difficult of travel through very restricted paths, drug decomposition before delivery, high cost, lower or very high release rates, low patient compliance and inconsistent dosage, to mention a few.1,2 Nanotubes and cellular study seem a great promise for usefulness in nanoparticle drug delivery systems (NPDDSs). Some nanotubes are small enough to suck out a nucleus from a cell and place it into another- a technique utilized during cloning, although nanotubes are even finer for more fine delivery. Large scale use of carbon nanotubes is still lacking due to associated challenges related to nanomaterials in general, and less deduction on CNTs’ toxicity.3,4 CNT *Corresponding Author. E-mail: [email protected] or [email protected] The Polymer Society of Korea

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macromolecules that will facilitate the development of new biologic products such as bioblood proteins and biovaccines.10 Apart from the oral and injection routes commonly used, drugs can also be administered through; transdermal, transmucosal, ocular, pulmonary, and implantation.11 For alternative drug delivery mechanisms, the following materials may be added in their nano scale form: biologics, polymers, silicon-based materials, carbon-based materials, or metals.12 Nanotechnology and Drug Delivery. It is basic that the particle size has a direct effect on the efficiency and effectiveness of drug delivery. Nanostructure-aided drug delivery is potent in realizing nanomedicine through enhanced drug bioavailability, improved release time, and precision drug targeting.13 Micro-particles and nano-particles differ most vividly in the surface area to volume ratio, a factor that leads to many differences. For example, while within the human body, larger particles are more likely to lose drug payload during formulation unlike targeted nano-DDS which can increase drug payload while ultimately lowering the risk of adverse systemic side effects.14 Apart from efficient drug distribution, certainly, nanoscale drug carriers also have a drug efflux that will be proportionally more rapid than would be for larger particles.15 In general, due to their small physical dimensions, nanomaterial drug carriers are able to emerge through biological and physiological barriers that would be impossible for comparatively larger particles. Nano-drug delivery system passive targeting is achieved due to heterogeneous vasculature formation found in pathological processes such as tumors, resulting in enhanced permeation retention effects. The accumulation of nano-drug delivery systems at the targeted site results in enhanced drug payload. Active targeting is achieved using recognition molecules attached to nano-drug delivery system surfaces for specific ligand-receptor mediated interactions. Many desired physiologic targets may not be accessible to drugs due to some smaller structures like the blood brain barrier, branching pathways in the pulmonary area, and the narrowing at epithelial skin junctions. In contrast, nanoscale drug delivery systems can be implemented within such barriers including gene delivery vectors, and in stabilization of drug molecules that would otherwise degrade too rapidly.16 Particles of diameter below 100 nm give greater efficiency for delivery into the pulmonary system. Also, particles between 100 and 50 nm in size are said to have efficient uptake for gastrointestinal absorption and transcutaneous entry respectively.14,15,17 Such small particles traveling in the pulmonary tract however face greater chances of being exhaled.17,18 Hence, drug carriers with multilayers or larger compartments are suggested for pulmonary delivery. For instance, a formulation where the carrier housing outer layers may biodegrade as the carrier travels through the pulmonary tract can be sought. In such a case, the encapsulated drug is released as the drug carrier penetrates further into the lung, with more shedding. More advantages of nano892

structure-mediated drug delivery include the ability to deliver drug molecules directly into cells and the capacity to target tumors within healthy tissue.19 As opposed to microparticles which can only be taken up by phagocytic cells, nanoparticles may also enter through pinocytosis.20 Important also is the fact that nano-DDS surfaces can easily be modified using conventional chemical techniques to alter and tune pharmacokinetic or pharmacodynamic properties. For example, poly (ethylene glycol) (PEG), when linked onto surfaces of nanocarrier greatly increases their solubility and circulation time within the body. This reduces non-specific uptake and association by the reticuloendothelial system.12,17 Thus, the ability to alter the size, shape and makeup of nanostructures has considerable influence for current drug delivery formulations. Nanomaterials Currently in Drug Delivery. The choice of nanomaterials for drug delivery depends on the particular characteristics of the material, target site and likely impacts. Liposomes, usually fall within 100-200 nm in diameter and possess excellent biocompatibility as well as reduced toxic levels although they show some physical instability while in solution.21 Liposomes have a demerit of the wide physical dimension and are said to show low transfection efficiency in gene delivery. Dendrimers are comparatively smaller (10100 nm) and have added merits of a controllable size as well as ability for surface functionalizing. However, dendrimers exhibit high release rates, sensitivity to pH and some levels of cytotoxicity. Nano-particles of selected compatible materials have also been recently used. For example; gold and iron to mention, but a few. Nano-particles have also been used for contrast agents and providing fluorescence during imaging. Nano-particles practically have diameter below 100 nm.22 Nano-particles have a controllable size and also controlled release ability. Nano-particles though, also possess potential of toxicity especially promoting oxidation reactions in the body through free radicals they could give off. Fullerenes and CNTs have recently showed great potential for biomedical applications. Fullerenes are extremely smaller with a diameter about 1 nm and have high resistance to biochemical degradation in addition to ease of functionalization.23 Fullerenes however have high accumulation in the liver and would thus stay longer in the body with potential toxicity. Also, fullerenes have high binding to plasma proteins. Due to their demonstration of ability to enter the nuclei of cells, CNTs can serve effectively as carrier for drug delivery, basing on functionalizations they may undergo.24 Again, CNTs are of a size (80100 nm) where cells do not recognize them as harmful intruders. However, they have demerits of insolubility in aqueous media, self assembling into agglomerates and potential of toxicity.21,22 Figure 1 shows resultant systems with use of nanomaterials in drug delivery. Carbon Nanotubes and Drug Delivery. CNTs, and fullerenes, are carbon cylinders composed of benzene rings. CNTs can be used as drug delivery materials because they have larger inner volumes as compared to the dimensions of the tube Macromol. Res., Vol. 20, No. 9, 2012

Nanotechnology and Carbon Nanotubes; A Review of Potential in Drug Delivery

Figure 1. Scheme of nanosystems that may function as combined drug delivery and imaging agents for targeting T cells:22 (A) liposomal systems, (B) solid biodegradable nanoparticulates, and (C) macromolecular dendrimer complexes. PEG indicates poly(ethylene glycol); Gd-DTPA, gadolininum-diethylene triamine pentaacetic acid. Copyright 2007, American Association of Pharmaceutical Scientists. Reproduced with permission.

Figure 2. (a) A single-wall carbon nanotube ball-and-stick model.27 Reproduced with permission from Precision Engineering. Copyright 2004 Elsevier. (b) Model of a fullerene (C60) molecule.28 Copyright 2000, National Academy of Sciences, USA.

that can be filled with desired chemical and biological species.25 Also notable is that CNTs have distinct inner and outer surfaces that can be differentially modified for functionalization. Hence, the outer surface of CNTs can be immobilized with biocompatible materials while the inside can be filled with the desired biochemical payload. In addition, insertion (otherwise known as encapusulation) of species inside the tube is possible due accessibility to their inner surface through the open mouths CNTs possess. Van der waals and hydrophobic forces are important for the insertion process.26,27 Figure 2, shows two hollow, cage-like structures of nanotubes and fullerenes. Methods for producing Fullerenes and CNTs include: elecMacromol. Res., Vol. 20, No. 9, 2012

tric arc discharge (EAD); laser ablation (LA); chemical vapor deposition (CVD); or combustion processes.29After surface functionalization, CNTs can be internalized within mammalian cells, and may be used as vaccine delivery structures when linked to peptides.30,31 A modeling of water molecules flow through CNTs, with use of molecular dynamics (MD) simulations, suggests their potential use as small molecule transporters.32-34 Simulations involving DNA transport through CNTs indicate potential use as a gene delivery tool.26 CNTs have also been studied for composite structures in drug delivery especially with natural biomaterials. For example, temperature-stabilized hydrogels for drug delivery applications incorporate CNTs35 while tissue-selective targeting and intracellular targeting of mitochondria have been achieved with use of fullerene structures.36 Other experiments with fullerenes reported that they exhibit antioxidant and antimicrobial behavior which give longer life ability.37 Functionalization of CNTs for Drug Delivery. As already indicated, CNTs are classified into two,38 namely: (a) SWNTsSingle-walled carbon nanotubes and (b) MWNTs- Multiwalled carbon nanotubes (Figure 3). SWNTs are composed of a single layer, with a diameter range of up to 1nm. In contrast, MWNTs are formed by multiple layers of grapheme sheets and have much larger diameters (10-100 nm). SWNTs exhibit superior and attractive optical properties than MWNTs, implying different use in biological systems.39-42 CNTs are hydrophobic in nature, completely insoluble in all solvents, generating some health concerns and toxicity problems.21 Also, the purification processes after production may not be enough to render CNTs less harmful. Thus, functionalization of CNTs with biocompatible groups highly influences the ability to use them in biological activity.42 To this effect, several strategies have emerged to render CNT more water-miscible. Reductive chemical treatment of CNTs under strong acid-based oxidation generates carboxylic groups on their surfaces. Other treatments have involved use of diazo-

Figure 3. Carbon nanotube structures.43 URL http://www.nanotechnologies.qc.ca (Accessed on 2011, Aug 02). Reproduced with permission. 893

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nium chemistry to attach addends to the CNT side walls through covalent linkage. Functionalized CNTs can conveniently be linked with active molecules including peptides, nucleic acid, proteins and therapeutic agents for targeted delivery and therapeutic purposes.44 For example; antifungal agents (such as amphotericin B) or anticancer drugs (such as methotrexate) have been covalently linked to carbon nanotubes with a fluorescent agent.45 With multiple functionalizations on the side wall or tips of CNTs, several molecules can be carried at once; a strategy important in cancer treatment. CNTs can be functionalized via two routes; covalent functionalization and noncovalent functionalization.40 Covalent Functionalization. The most common of covalent reactions to functionalize CNTs is oxidation; where carboxyl groups are formed at the ends of tubes and the defects on the sidewalls using oxidizing agents such as nitric acid.38 Hydrophilic polymers such as poly(ethylene glycol) (PEG) can give added functionality if attached to oxidized CNTs, yielding CNT-polymer conjugates of better stability in intended biological environment. Portney and Ozkan;46 Martin and Kohli25 among others, used covalently PEGylated SWNTs produced by this strategy for both in vitro and in vivo applications. Cylcoaddition has also been applied as a covalent reaction and mainly takes place on the aromatic sidewalls of CNTs rather than at the nanotube ends or defects as in the oxidation case.47 Photochemical reaction of CNTs with azides can be used to achieve cycloadditions.48 Alternatively, reaction with carbene generating compounds via the Bingel reaction respectively may also be applied.49,50 The commonly used 1,3-dipolar cycloaddition reaction on CNTs involves addition of azomethine-ylide generated by condensation of an α-amino acid and an aldehyde, to the graphitic surface, giving a ring coupling to the CNT sidewall.51-53 Further conjugation of biological molecules such as peptides or drugs can be achieved by introduction of functional groups such as aminoterminated PEG via a modified α-amino acid.54 It is important to note that due to the disruption in nanotube structure, intensities of Raman scattering and photo properties of SWNTs are drastically decreased after covalent modification, thus reducing their potential optical applications.55 Figure 4 illustrates covalent functionalization mechanisms. Noncovalent Functionalization. Noncovalent functionalization of CNTs is mainly achieved by coating CNTs with molecules of amphiphilic nature and does not alter electronic and physical properties of CNTs owing to the maintained intrinsic sp2-hybridized state CNT sidewalls. Only the length is reduced a little due to sonication.44 Chen et al.57,58 utilized the π-π interaction between pyrene and the nanotube surface to noncovalently functionalize CNTs using pyrene derivatives (Figure 5(a)). Chen et al.58 also showed that proteins can be immobilized on SWNTs functionalized by an amine-reactive pyrene derivative. Due to π-π stacking between aromatic DNA base units and the nanotube surface, single-stranded DNA molecules have been widely 894

Figure 4. Schemes of covalent functionalization of carbon nanotubes. (a) Acid refluxing to open CNT ends. It involves oxidation and substitution reactions. CNTs are then conjugated with hydrophilic polymers (e.g., PEG) or other functional molecules.56 Copyright 2010 Elsevier. Reproduced with permission. (b) Photoinduced addition of azide compounds with CNTs.48 Copyright 2005, American Chemical Society. (c) Bingel reaction on CNTs.49 Copyright 2003, American Chemical Society. (d) 1,3-dipolar cylcoaddition on CNTs.51 Copyright, American Chemical Society, “R” in the figure represents a hydrophilic group. Based on such functionalizations, conjugation of bioactive molecules can be done.

used to solubilize SWNTs (Figure 5(b)). Gannon et al.59 has reported that porphyrin derivatives of aromatic nature were used for noncovalent functionalization of CNTs especially for hydrophobic effects, and polar heads for water solubility. For biological applications, such functional groups should be able to bioconjugate with intended biological molecules and form functional CNT aggregates for different biological applications.12 It has however been reported that interaction of the targeted drug with the surrounding biological environment as well as the carrier could induce detrimental effects on the drug and the body molecules themselves.61,62 This has necessitated the study of the effect of encapsulation of drugs using CNTs and fullerenes for DDS. In one study, CNTs were used to protect and control the release of loaded molecules; hence a prolonged effect of the loaded drugs.64 β-Carotene (a natural pigment and photonic Macromol. Res., Vol. 20, No. 9, 2012

Nanotechnology and Carbon Nanotubes; A Review of Potential in Drug Delivery

Figure 5. Schemes of noncovalent functionalization of carbon nanotubes. (a) Left: Proteins are anchored on the SWNT surface via pyrene π-π stacking on a nanotube surface. Right: A transmission electron microscope (TEM) image of an SWNT conjugated with proteins.57,58 Copyright 2001, American Chemical Society. (b) Simulation of an SWNT coated by a single-stranded DNA via π-π stacking.30,60 Copyright 2005, The National Academy of Sciences, USA.30 (c) An SWNT functionalized with PEGylated phospholipids. Any of linear PEG (l-PEG), or branched PEG (br-PEG) can be used in this method.38 Copyright 2005, The National Academy of Sciences, USA.

tool) was incorporated inside CNTs, to prevent its fast degradation, under light exposure as earlier on reported by Chen and Huang.65 In another study by Yudasaka et al.66 CNTs were heated at 550 oC to open the tips of the tubes followed by loading an anticancer drug (hexamethylmelamine-HMM) inside SWNTs using a “two-step nanoextraction” procedure. The CNTs were sealed at each ends with fullerenes (C60) as shown in Figure 6(a). Transmission electron Microscope (TEM) images and extensive Raman analysis confirmed storage of the drug in the constructed CNT vessels. Fullerenes C60 molecules and HMM molecules were identified in the test specimen while in the control, they were absent; revealing CNTs filled with C60.67,68 Earlier on Yudasaka et al.66 had reported the possibility of opening the “nano-bottles” and subsequently extracting the entrapped drug, using CH2Cl2 to dissolve C60 and HMM drug. IR analysis confirmed the effective release. CNTs usually show a broad signal within a range of 400-4000 cm-1. Particular peaks were detected at 2900 cm-1 in the HMM-loadedCNTs and they disappeared once the drug was released as reported by Yanagi et al.68 The absence of these peaks, reasonably attributable to HMM’s methyl groups, implied the Macromol. Res., Vol. 20, No. 9, 2012

successful removal of C60 and the extraction of the guest molecule, hence suggesting that CNTs could be further functionalized at their sidewalls for an improved targeting while protecting the encapsulated molecules.” Hampel et al.69 and co-workers discovered yet another fascinating method to encapsulate a carboplatin drug inside CNTs. Hampel’s group improved on drug loading by using MWNTs. Heat and strong acidic treatment were used to open CNTs while drug incorporation was by wet chemical approach relying mainly on capillary forces. Capillarity is an intrinsic property of opened CNTs affected by surface kinetics between the liquid and solid surface of CNTs. Chaban et al.70 reported on heat-assisted release of drug molecules encapsulated into a CNT, by near-infrared radiation. The researchers utilized the property of CNTs to absorb near-infrared (NIR) radiation within a spectral range of 800-1,100 nm, and also biological organisms being transparent to NIR radiation. Extra energy conferred to the CNT by NIR, facilitates diffusion of a drug molecule into and its release from the CNT. The energy can also serve to reduce interaction between the drug molecule and the tube. Using ciprofloxacin (CIP) as a drug, Chaban et al.70 further inves895

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Figure 6. (a) Preparation of ‘‘carbon nano-bottles’’ loaded with antitumor agents and C60 using a controlled nano-extraction strategy. C60 filled at the extremities of CNTs can act as ‘‘cap’’ to seal the CNTs.63 Copyright 2008, John Wiley and Sons. Reproduced with permission. (b) ‘‘Window mechanism’’ for the encapsulation of atoms inside the fullerene cage. (A) C60 or buckminsterfullerene. (B) C60 with an atom inside. (C) C60 with an atom inside and with a bond broken (open window). (D) Same molecule as in (C) but with the atom moving out through the window.28 Copyright 2000, The American Academy of Sciences.

tigated the rates of energy transfer between a CNT, water, and the drug molecule in addition to studying the temperature, concentration and diffusion dynamics of the CNT encapsulated drug molecules. Molecular dynamics simulation results revealed a fast deposition of energy to CIP and water by the CNT on heating the CNT. The simulations support the idea that optical heating of CNTs can assist in releasing encapsulated drugs. This property of near infrared absorption by CNTs was also utilized to destroy cancer cells using SWNTs functionalized with pristine, treated with a phospholipid (PL) modified PEG on one side and folic acid (FA) on the other side. The PL-PEG-FA/SWNT complex was mainly taken up by cancer cells, since tumor cells show high reception for folate. Using a laser of 808 nm wavelength to induce localized heating, the tumor cells that had internalized the CNTs were destroyed.71

Conclusions Nanotechnology has slowly gained use in several fields such as energy, filtration, tissue engineering, information and communication, diagnostics, catalysis, construction and textiles, among others. The medical area is one of great emergence as nanomaterial size plays a vast role, offering unique properties. Several nanostructures structures are complex in nature. Their chemistry, physical and chemical makeup, in addition to several chemical interactions especially during functionalization is a matter of necessary study. Many researchers have reported outcomes after chemical treatments while neglecting underlying mechanisms and associated effects. The specific routes of entry and exit for CNTs and the mechanisms of releasing drugs into the mainstream body or to targeted parts have not been explored in detail. During purification and functionalization of CNTs, the use of cata896

lysts involving metals such as iron (Fe), may carry residual ions (free radicals) on CNTs. These may cause or support oxidation processes in the body, hence damaging body cells. Hence, more research on these processes is essential. For clinical applications, the strength of CNTs as a possible success in nano-drug delivery systems cannot be underestimated. Despite the underlying challenges, reports show a significant advance in nano-drug delivery systems. Both noncovalent and covalent functionalizations are being utilized although noncovalent routes seem to outnumber. Many studies and reviews appear to be similar which means the principles being used are still few and related. Theoretical models have been presented, suggesting possibilities of encapsulating drug molecules into the hollow structure of CNTs for drug delivery. However, significant practical studies especially on humans are still needed to strengthen the feasibility of the encapsulation technique in CNT based drug delivery. One such area is the mechanism of releasing encapsulated drugs and disposal of CNTs from the body. It is an area requiring contentious study. Despite several unanswered questions about the long-term effects of CNTs, functionalized CNTs represent an emerging and new trend of materials for encapsulation, delivering, and release of biomolecules into biological cells.

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