Modification Strategies for Carbon Nanotubes as a Drug Delivery

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Modification Strategies for Carbon Nanotubes as a Drug Delivery System Peng Liu* State Key Laboratory of Applied Organic Chemistry and Institute of Polymer Science and Engineering, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China ABSTRACT: Carbon nanotubes (CNTs) are extensively explored in materials science due to their unique structure and consequent mystical properties. CNTs are enjoying increasing popularity as building blocks for novel drug delivery systems as well as for bioimaging and biosensing. The recent strategies to functionalize CNTs have resulted in the generation of biocompatible and water-soluble CNTs that are well suited for high treatment efficacy and minimum side effects for future cancer therapies with low drug doses. This review covers the latest advances in the strategies for the modification of CNTs (with inorganic nanoparticles, small organic molecules, polymers, or bioactive materials), with an emphasis on the development of functional biological nanointerfaces as drug vehicles, after a simple introduction of the toxicity of CNTs. The translation of these systems into clinical practice and an outlook into future approaches are also discussed.

1. INTRODUCTION Nanotechnology refers to the structures roughly in the 1−100 nm size ranges in at least one dimension in its strictest definition from the National Nanotechnology Initiative. It is the most rapidly developing research field in the last decades due to its potential applications in all fields that might affect our lives. A complete list of the potential applications of nanotechnology is too vast and diverse to discuss in detail, but without doubt, one of the greatest values of nanotechnology will be in the development of new and effective medical treatments,1 especially for the diagnosis and therapy of cancers.2 As one main member of the nanocarbon family, carbon nanotubes (CNTs), containing single-walled carbon nanotubes (SWCNTs), double-walled carbon nanotubes (DWCNTs), and multiwalled carbon nanotubes (MWCNTs), show many potential applications, such as in conductive and high-strength composites, energy storage and energy conversion devices, sensors, field emission displays and radiation sources, hydrogen storage media, and nanometer-sized semiconductor devices, probes, and interconnects.3 With the rapid development of nanotechnologies, colloidal nanocarriers in their various forms have the possibility of providing endless opportunities in drug delivery systems for therapeutic and diagnostic agents.4 Except for some pending concerns about their toxicity in vitro and in vivo, the functionalized CNTs appear to exhibit very low toxicity and are not immunogenic. It makes them promising carriers with great potential for the development of a newgeneration delivery systems for drugs and biomolecules. The functionalized CNTs have the capacity to cross biological barriers and can be eliminated via renal and/or fecal excretion. They can transport small drug molecules while maintaining and in some cases improvingtheir therapeutic efficacy.5 For biological and biomedical applications, the lack of solubility of CNTs in aqueous media has been a major technical barrier. A major drawback of CNTs that is particularly relevant to their compatibility with biological systems is their complete insolubility in all types of solvents.6 The recent expansion in methods to chemically modify and functionalize CNTs has © XXXX American Chemical Society

made it possible to disperse them in water, thus opening the path for their facile manipulation and processing in physiological environments. By now, various strategies, such as oxidization,7 organo-modification with small organic molecules8 or polymers,9 and dispersion with biocompatible surfactants, 10 have been developed for improving the dispersibility and biocompatibility of CNTs. As above-mentioned, the main strategy to obtain functional CNTs might be surface modification, besides the oxidization technique in which the cutting of CNTs must be the major aim as well as the introduction of oxygen-containing groups. Various substances containing the diagnostic and therapeutic reagents could be surface-modified onto the CNTs via covalent and noncovalent functionalization routes. In the former, the substances are usually modified onto the CNTs via the covalent bonds, so the hybrids obtained are relatively stable. This is rather a weakness for the diagnostic and therapeutic reagents. In some cases, the modified reagents need to be released from the CNT carriers, so the weaker bonds and some stable bonds that could be broken in certain environments are mainly adopted in the covalent functionalization route, especially with stimuli-responsive characteristics. As for the noncovalent functionalization, the diagnostic and therapeutic reagents are loaded via the ionic bond, hydrogen bond, hydrophobic interaction, or π−π stacking interaction. One important advantage of the noncovalent functionalization is that it would not damage the nanotube structure as it does with covalent functionalization. Therefore, the intrinsic optical properties of CNTs are largely retained after noncovalent functionalization, which is useful for biomedical imaging. Additionally, the noncovalent type of functionalization was reported to allow the controlled release of drugs.11 Because of Received: July 23, 2013 Revised: August 25, 2013 Accepted: August 29, 2013

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dx.doi.org/10.1021/ie402360f | Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

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Figure 1. Schematic illustration of Fe3O4 beads on MWCNTs via the solvo-thermal system.

carbon layers of the tubes. It demonstrated that they are suited as nanocontainers and nanocarriers and can release the drug to initialize its medical virtue. Su et al. established CNTs as excellent near-infrared controllable delivery vehicles for small-molecule compounds (SMCs) as selective cell-killing agents.20 The cell-homing indole-loaded CNTs (indole@CNTs) (CIDs) were formed by labeling indole@CNTs with EphB4-binding peptides. CIDs can selectively target EphB4-expressing cells and release indole onto cell surfaces by near-infrared (NIR) irradiation. Released indole molecules exhibit significant cell-killing effects without causing local overheating. The MWCNTs were also used as nanoreserviors for drug loading, and their controlled release was demonstrated.21 After the MWCNTs were treated with acid sonication to open their ends and make their outer and inner surfaces more hydrophilic, the anti-inflammatory drug dexamethasone (Dex) was filled into the opened MWCNTs. The open ends of the drug-filled CNTs were then sealed with polypyrrole (PPy) films formed through electropolymerization in order to prevent the unwanted release of the drug. The coating can effectively store drug molecules and release the bioactive drug in a controlled manner using electrical stimulation. The Dex released from the PPy/CNT film was able to reduce lipopolysaccharide induced microglia activation to the same degree as the added Dex. It is known that the encapsulation of anticancer agents inside CNTs could provide protection from external deactivating agents.22 The inhibition of prostate cancer cells’ (PC3 and DU145) viability from tubes encapsulating cisplatin (CDDP, cis-diamminedichloroplatinum, a platinum-based chemotherapy drug) proved the efficiency of the produced delivery system.23 However, the open ends of the CNTs leave the encapsulated drugs exposed to the environment and eventually allow their uncontrolled release before reaching the desired target.

this, the noncovalent functionalization strategy has been widely used in developing CNT-based nanomedicine.

2. OXIDIZED CNTS The CNTs could be purified to remove metal seeds via oxidation with various oxidants, electrochemical oxidation, or thermal annealing.12 Meantime, the carboxyl acid groups have been introduced onto the CNTs during the oxidation process so that the dissolution (especially in water) and biocompatibility of the oxidized CNTs could be improved obviously, making them potential nanovehicles for precise and controlled drug and gene delivery, as well as markers for in vivo biomedical imaging. Multiwalled carbon nanotubes (MWCNTs) were purified and functionalized in a mixture of concentrated acids (3:1 H2SO4:HNO3) at room temperature via sonication in a water bath to introduce carboxylic acid groups onto the MWCNTs’ surface. A high drug loading capacity of 48 wt % was achieved for aspirin by suspending the functionalized MWCNTs in an alcohol solution.13 Chen et al. prepared the carboxylated MWCNTs with a nitric acid treatment and evaluated their ability for loading of the anticancer drug epirubicin hydrochloride (EPI) by forming supramolecular complexes with EPI via π−π stacking.14 By increasing the pH or decreasing the temperature, the adsorption capacity of EPI on the carboxylated MWCNTs increased. Wang et al. investigated the adsorption and desorption of doxorubicin (DOX) on the carboxylated MWCNTs.15 The carboxylated MWCNTs possessed a huge adsorption capacity for DOX (9.45 g/g). It was found that the adsorption process was very slow, and the presence of serum facilitated the release of DOX from the drug-loaded MWCNTs. The carboxylated single-walled carbon nanotubes (SWCNTs) were investigated for the small interfering RNA (siRNA) delivery in parallel with an efficient commercial system.16 The results from the inhibition of gene expression for both transfection systems were confirmed at protein level. Therefore, the carboxylated SWCNTs combined with suitable tumor markers, like p53 siRNA, TNF-α siRNA, or VEGF siRNA, can be used for the efficient delivery of siRNA. Encapsulation of functional molecules into the hollow chambers of CNTs can not only stabilize the encapsulated molecules but also generate new nanodevices.17,18 Carboplatin, a therapeutic agent for cancer treatment, was filled into the CNTs as feasible carriers by a wet-chemical approach after the CNTs were opened by treatment with nitric acid.19 Microscopic analysis revealed that many spherical carboplatin clusters with a mean diameter of 1−2 nm had been aligned to the inner

3. INORGANIC NANOPARTICLES MODIFIED CNTS 3.1. Magnetic Nanoparticles. The MWCNTs were uniformly coated with the magnetic nanoparticles (MNs) with a particle size of about 6.0 nm via an in situ solvo-thermal method at 180 °C.24 The CoFe2O4/MWCNT nanocomposites exhibited superparamagnetic characteristics, high hydrophilicity, and low levels of cytotoxicity on HeLa and L929 cells. The DOX loading capacity was found to be 18.8%. An appreciable release of DOX from the superparamagnetic nanocomposites was observed over a 73 h period (26% within 25 h and 30% over 73 h) in an acidic solution of pH 5.2, whereas the DOX on B



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were successfully attached to the side walls of SWCNTs via the nitrene cycloaddition to form a nanovehicle for the delivery of boron to tumor cells for an effective boron neutron capture therapy in the treatment of cancer.30 The water-soluble nanotubes were found to be tumor-specific and thus absorbed preferentially by EMT6 tumor cells, making them effective boron delivery agents for boron neutron capture therapy (BNCT) in cancer treatment. Thus, grafting various small organic molecules or polymers has been used as the main approach for the surface modification of the CNTs. 4.1. Small Organic Molecule-Modified CNTs. Different generation alkylated dendrons with numerous positively charged tetraalkyl ammonium salts at their periphery were introduced onto the MWCNTs.31 The positive charges on the MWCNTs’ surface, coupled with the unique ability of the CNTs to penetrate cell membranes, make the alkylated dendron-modified CNTs (dendron-MWCNTs) potentially ideal vectors for siRNA delivery. It was found that the cytoplasmic delivery of the nucleic acid was remarkably increased throughout the different dendron generations. The grafting of drugs onto the CNTs can be used as a new tool and a useful method for potential drug delivery. c,c,t[Pt(NH3)2Cl2(OEt)(O2CCH2CH2CO2H)] was tethered to the surface of the SWCNTs through peptide linkages formed by the reaction of the SWCNT-tethered amines with the carboxylate moiety.32 Its cytotoxicity was found to be >100fold lower than the free platinum(IV) complex. The Pt(IV) complex of the formula c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)(O2CCH2CH2CONH-PEG-FA)], containing a folate derivative (FA) at an axial position, was prepared and attached to the surface of amine-functionalized single-walled carbon nanotubes (SWCNT-PL-PEG-NH 2) through multiple amide linkages to use the SWCNTs as a “longboat delivery system” for the platinum warhead, carrying it to the tumor cell and releasing cisplatin upon intracellular reduction of Pt(IV) to Pt(II), targeting human cells that highly overexpress the folate receptor (FR).33 The ability of the modified SWCNTs to selectively destroy FR(+) vs FR(−) cells demonstrated its ability to target tumor cells that overexpress the FR on their surface. The SWCNTs delivered the folatebearing Pt(IV) cargos into FR(+) cancer cells by endocytosis, demonstrated by localization of the fluorophore-labeled SWCNTs using fluorescence microscopy. The drugs were covalently grafted onto the SWCNTs by the initial conversion of carboxylic groups in the SWCNTs obtained by the oxidization to corresponding acryl chlorides.34 The active acyl chlorides in the functionalized SWCNTs were subsequently mixed with chemotherapeutic agents having −NH−, −NH2, and −OH functional groups to afford the formation of the relevant amide and ester, respectively. The covalent grafting of drugs increases the solubility of the SWCNTs in both aqueous and organic solvents. The releasing of the covalently grafted drugs can occur smoothly from the covalent SWCNT-drug conjugates during long time intervals via the hydrolysis reaction, which involves breaking amide bonds in acidic buffer. The antitumor agent 10-hydroxycamptothecin (HCPT) was covalently bonded onto the MWCNTs with hydrophilic diaminotriethylene glycol as the spacer with 16% drug content.35 The MWCNT−HCPT conjugates could be readily internalized by cells in vitro and exhibited relatively long blood circulation and high tumor accumulation in vivo, with the superior antitumor effect of the conjugates in comparison to its

the CoFe2O4/MWCNT nanocomposites remained stably bound at pH 7.4 and 6.3. Xiao et al. prepared the magnetic multiwall carbon nanotubes (MMWCNTs) via a simple solvo-thermal process for a magnetic targeted drug delivery system (Figure 1).25 The size (100−350 nm), location, and denseness of the Fe3O4 beads fixed on the MWCNTs, as well as the MWCNTs structure, could be easily altered by controlling the reaction parameters. EPI was strongly and rapidly adsorbed onto the WMWCNTs by π−π stacking interactions between EPI and the MMWCNTs with a drug loading capacity of 96.15 mg/g. The accumulative drug release rate at acidic media was higher than that in the neutral solution, which is mainly attributed to the decrease of both π−π stacking interactions and hydrophobic interactions at low pH. Due to their magnetic properties, high adsorption surfaces, and excellent adsorption capacities, the MMWCNTs synthesized in this study are suitable to be applied to a magnetic targeted drug delivery system. Vermisoglou et al. fabricated the magnetic carbon nanotubes which consist of the monodisperse, inherently open-ended MWCNTs loaded with magnetic iron-based nanoparticles encapsulated within the tube’s graphitic walls by a combined action of templated growth and a ferrofluid catalyst/carbon precursor.26 The hybrid nanotubes are stable under extreme pH conditions because of the particle protection provided by the graphitic shell. They are promising for high capacity drug loading given that the magnetic functionalization did not block any of the active sites available for drug attachment, either from the CNT internal void or on the internal and external surfaces. Additionally, the hybrid nanotubes exhibit enhanced hydrophilic characteristics, as shown by water adsorption measurements, which make them suitable for biological applications. The poly(acrylic acid) functionalized multiwalled carbon nanotubes (PAA-g-MWCNTs) decorated with magnetite nanoparticles (Fe3O4) were also prepared as the magnetic lymphatic-targeting drug delivery system.27,28 3.2. Carbon Nanotubes Bottle. Li et al. designed a “carbon nanotubes bottle” structure (Figure 2).29 After the

Figure 2. Schematic model of the carbon nanotubes bottle.

encapsulation of cisplatin, a FDA-approved chemotherapeutic drug, into oxidized MWCNTs, the 1-octadecanethiol modified gold nanoparticles (ODT-f-GNPs) were used to cap the open ends of the MWCNTs encapsulating the CDDP (CDDP@ MWCNTs). A rapid release of encapsulated drugs occurred mainly within the first hour, and 89% of encapsulated CDDP was released at pH 7.4 during 6 h from the uncapped MWCNTs. The presence of caps decreased the rate of CDDP release from the MWCNTs sealed by the ODT-f-GNPs, especially in the first 1 h, although about 40% of CDDP still remained inside the capped CDDP@MWCNTs.

4. ORGANO-MODIFIED CNTS The enhancement of the water solubility of CNTs through side-wall derivation with biologically important moieties has been of special interest. The substituted C2B10 carborane cages C



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native formulation (clinical HCPT injection) and low toxicity to the living mice. Heparin was immobilized onto the MWCNTs via the indirect center-point attachment or the direct end-point attachment through its reducing end methods.36 The blood compatibility of the heparin-immobilized MCWNTs via the direct end-point attachment (Figure 3) was greatly enhanced compared to the other approach. Their plasma-based anticoagulant activity was also prolonged. Figure 4. Structure of the FA−MWCNT@Fe.

ibility, and biofunctionalities while preserving their desired properties.43 It makes the polymer-modified CNTs potential vehicles for the smart drug delivery systems (DDS). The poly(ethylene glycol) (PEG)-conjugated multiwalled carbon nanotubes (PEGylated MWCNTs) were explored as drug carrier to overcome multidrug resistance.44 It is reported that the PEGylated MWCNTs could penetrate into mammalian cells without damaging the plasma membrane, and its accumulation did not affect cell proliferation and cell cycle distribution. More importantly, the PEGylated MWCNTs accumulated in the multidrug-resistant cancer cells as efficiently as in the sensitive cancer cells. Furthermore, the PEG-grafted branched polymer-coated SWCNTs exhibited remarkably long blood circulation (t1/2 = 22.1 h) upon intravenous injection into mice, far exceeding the previous record of 5.4 h. The ultralong blood circulation time suggests greatly delayed clearance of nanomaterials by the reticuloendothelial system (RES) of mice, a highly desired property for in vivo applications of nanomaterials, including imaging and drug delivery.45,46 Doxorubicin (DOX) was immobilized onto the SWCNTs stabilized-ready with functional polyethylene glycol (H2N− PEG−NH2) through hydrazone bonds (Figure 5).47 The acid cleavability of the hydrazone bonds formed between the DOX molecules and the hydrazinobenzoic acid (HBA) segments of the SWCNTs provides a strong pH-responsive drug release and facilitates effective DOX release near the acidic tumor microenvironment, thus reducing its overall systemic toxicity. Compared with the SWCNT−DOX conjugate formed by

Figure 3. Schematic representation of the fabrication of heparinimmobilized MCWNTs via the direct end-point attachment.

Bianco et al. developed a strategy for the bifunctionalized MWCNTs by covalently functionalizing MWCNTs via 1,3dipolar cycloaddition of azomethine ylides with orthogonally protected amino functions that can be selectively deprotected and subsequently modified with drugs (amphotericin B (AmB)37 or methotrexate (MTX)38) and fluorescent probes. The covalent linkage of different drugs to CNTs is expected to be an approach to modulate the therapeutic action of the agent, thus obtaining new conjugates with interesting properties. Increasing evidence suggests that the folate receptor (FR) can be exploited for therapeutic applications. The up-regulation of folate receptors on malignant cells to target pharmaceuticals linked to folic acid in cancer tissues in vivo was wellcharacterized.39 The folate-decorated CNT-mediated drug delivery system has attracted significant attention. FA could be noncovalently functionalized onto the individualized magnetic CNTs with a layer of magnetite nanoparticles on the inner surface of the nanotubes to improve drug delivery to cancer cells in the lymph nodes.40 Chemotherapeutic agents, such as 5-fluorouracil (5-FU) and cisplatin, were incorporated into the pores of the functionalized CNTs using nanoprecipitation. By using an externally placed magnet to guide the drug matrix to the regional targeted lymph nodes, the CNTs can be retained in the draining targeted lymph nodes for several days and continuously release chemotherapeutic drugs. On the basis of the combination of the highly specific biological affinity probe of folic acid (FA) and the magnetically guided probe of iron NPs on the CNTs, the folate and iron bifunctionalized multiwall carbon nanotube (FA−MWCNT@ Fe) were prepared by conjugating folate and iron nanoparticles with the oxidized MWCNTs and applied as a dual-targeted drug nanocarrier to deliver DOX into HeLa cells with the assistance of an external magnetic field (Figure 4).41 The nanocarrier has a sufficient load capacity (32 μg/mg for DOX) and a prolonged release property. Furthermore, both biologically (active) and magnetically (passive) targeting capabilities toward HeLa cells in vitro were with a ca. 6-fold higher delivery efficiency of doxorubicin than free doxorubicin. Lu et al. reported a similar folate and Fe3O4 bifunctionalized MWCNTs dual-targeted drug nanocarrier to deliver DOX with higher saturation magnetization by using the poly(acrylic acid) (PAA)-grafted MWCNTs.42 4.2. Polymer-Modified CNTs. Modifying CNTs with polymer could efficiently improve their solubility, biocompat-

Figure 5. Model structure of the SWCNT−HBA−DOX. D



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Figure 6. Schematic representation of the supramolecular stacking of DOX on carbon nanotubes.

Figure 7. Schematic representation of the nanotube−doxorubicin conjugate.

CNTs via the “grafting to” approach as an in vitro gene transfer agent with high transfection efficiency and relatively low toxicity.51 The glycoprotein-stabilized SWCNTs were found to be involved in glycan−receptor interactions, thus binding to the surface of cell membrane, with no significant toxicity at the concentration of 0.1 mg/mL. Their cytotoxicity assay reveals that the cell growth is promoted at very low concentrations, and the increase in concentration leads to the decrease in cell viability. Chaudhuri et al. reported the delivery of doxorubicin using a nanotechnology-based platform that could significantly reduce the systemic toxicity of the drug, keeping its therapeutic efficacy in a mouse melanoma tumor model52 by conjugating a doxorubicin prodrug to the PEG modified SWCNTs (PEG-gSWCNTs) via a carbamate linker that could enzymatically cleave to realize the temporal release of the active drug (Figure 7). It was found that the treatment with the nanotube− doxorubicin conjugate abrogated the tumor growth without the systemic side effects associated with free doxorubicin in an in vivo melanoma model. The CNT−doxorubicin conjugate (CNT−Dox) nanovector can be harnessed for the delivery of chemotherapeutics to melanoma, with increased therapeutic index. The physical loading of PTX onto the side walls of the CNTs was achieved by immersing the PEG-g-SWCNTs and PEG-gMWCNTs in a saturated solution of PTX in methanol, and loading capacities of 26% (w/w) and 36% (w/w) for the PEGg-SWCNTs and the PEG-g-MWCNTs, respectively, were achieved.53 The PTX-loaded PEG-g-SWCNTs and PEG-gMWCNTs exhibited good dispersibility in aqueous solution, and the individual CNTs could be observed in TEM images. PTX could be released from the drug-loaded PEG-g-CNTs several times faster than from the free PTX. Heister et al. systematically investigated the PEG conjugation for the fine-tuning of the functionalization chemistry of the CNTs for drug delivery applications, in particular with regard to

supramolecular interaction, the SWCNT−HBA−DOX featured high weight loading and prolonged release of DOX and thus improved its cytotoxicity against cancer cells. Functionalization partitioning of SWCNTs, imparting multiple chemical species such as PEG, drugs, and fluorescent tags, with different functionalities onto the surface of the same nanotubes was developed.48 PEG was modified onto the SWCNTs to obtain water-soluble SWCNTs, which allow for surprisingly high degrees of π-stacking of aromatic molecules, including a cancer drug (doxorubicin) with ultrahigh loading capacity, a widely used fluorescence molecule (fluorescein), and combinations of molecules.49 Binding molecules to nanotubes and their release can be controlled by varying the pH. The strength of the π-stacking of aromatic molecules is dependent on nanotube diameter, leading to a method for controlling the release rate of molecules from SWCNTs by using nanotube materials with suitable diameter. Dai’s group also reported the in vivo SWCNT drug delivery for tumor suppression in mice by conjugating paclitaxel (PTX) to the branched PEG chains on the SWCNTs via a cleavable ester bond50 without causing obvious toxic effects to normal organs. The water-soluble SWCNT−PTX conjugate affords higher efficacy in suppressing tumor growth than clinical Taxol in a murine 4T1 breast cancer model owing to prolonged blood circulation and 10-fold higher tumor PTX uptake by SWCNT delivery, likely through enhanced permeability and retention. The cancer chemotherapy agent DOX also could be loaded onto the branched PEG functionalized SWCNTs via the supramolecular π−π stacking for in vivo drug delivery applications (Figure 6). It afforded a significantly enhanced therapeutic efficacy and a marked reduction in toxicity compared with free DOX. To obtain biocompatible water-dispersible CNTs for the in vitro uses, the cationic block glycopolymers (P(APMA31-bLAEMA32) and P(APMA38-b-GAPMA20)) were covalently grafted on the carboxylic groups present on the surface of the E



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therapeutic efficacy, biocompatibility, and stability.54 The effect of the binding conditions during the drug loading step (e.g., pH, temperature, and light), the binding onto nanotubes, and the PEG conjugation approaches on the therapeutic activity of the drugs were studied. They found that a stable dispersion was of minor importance for the therapeutic success of the system. Furthermore, the attachment of folate as a targeting agent significantly enhanced cytotoxicity, thereby achieving higher cell killing at lower drug concentrations combined with certain selectivity for cancerous cells. A low cost, effective novel drug delivery system was developed by modifying MWCNTs with a polysaccharide (mannose) for site-specific delivery of AmB formulation to macrophages to overcome the side effects of free AmB and improving the patient compliance.55 The AmB-loaded mannosylated MWCNTs were found to be nanometric in size (500 nm) with tubular structure and good entrapment efficiency (75.46 ± 1.40%). They also exhibited better cell uptake activity as performed on J774 cells. The different cationic polymers (polyethyleneimine (PEI), poly(Lys:Phe, 1:1) (PLP), and 1,2-distearoyl-sn-glycero-3phosphoethanolamine-N-[amino(polyethylene glycol) 2000 (DSPE−PEG−NH2)) were noncovalently coated onto the pristine or oxidized and opened double-walled carbon nanotubes (DWCNTs) to enhance the cell transfection efficiency of the lysosomotropic antimalarial drug chloroquine.56 The oxidized and opened DWCNTs were selected for optimum chloroquine loading together with polyethyleneimine (PEI) as the optimum cationic coating agent for plasmid DNA binding and delivering it to human cells. Using the optimized system, there was no cytotoxicity of the functionalized DWCNTs at the concentrations needed for optimum gene delivery. Cisplatin was conjugated to the carboxyl functional groups of the dendritic blocks of polycitric acid−polyethylene glycol− polycitric acid (PCA−PEG−PCA) linear−dendritic copolymers, and then the prodrugs interacted with the MWCNTs noncovalently, producing the hybrid nanomaterial-based drug delivery systems (HNDDSs).57 Therein, the functionalized MWCNTs were used as biocompatible platform for the delivery of therapeutic agents and diagnostics and the PCA− PEG−PCA linear−dendritic copolymers were used as watersoluble, biocompatible, and highly functional hybrid materials with a linear PEG block and two dendritic PCA blocks that improve the solubility and functionality of MWCNTs, respectively. The HNDDSs are able to transport small molecules such as anticancer drugs both by their functional groups and their cavity. Zhang et al. described a system based on polysaccharide (sodium alginate (ALG) and chitosan (CHI)) modified SWCNTs for the controlled release of DOX, including FA as a targeting group.58 FA can be additionally tethered to the SWCNTs to selectively deliver DOX into the lysosomes of HeLa cells with much higher efficiency than the free DOX. The complete system displays excellent stability under physiological conditions, but at the reduced pH typical of the tumor environment and intracellular lysosomes and endosomes, the DOX is efficiently released and enters the cell nucleus and induces cell death. The FA-tethered CHI was used to wrap the SWCNTs for a highly effective targeted DDS denoted as the FA/CHI/ SWCNTs for tumor-targeting chemotherapy.59 The DOXloaded FA/CHI/SWCNTs (DOX/FA/CHI/SWCNTs) had high therapeutic payloads and much less in vivo toxicity than

the free DOX. The DDS displayed excellent stability under physiological conditions, but can efficiently release DOX at the reduced pH typical of the tumor environment, and intracellular lysosomes and endosomes could effectively kill the HCC SMMC-7721 cell lines and depress the growth of liver cancer in nude mice, showing superior pharmaceutical efficiency to simple extracellular exposure or intravenous injection of the DOX itself. Li et al. prepared a drug delivery system via a MWCNT vehicle by noncovalently functionalizing MWCNTs with chitosan oligomers (CS) with a molecular weight of 4000− 6000 Da to make them water-soluble.60 Then a cancer ancillary drug tea polyphenols (TP) was conjugated mainly via the hydrogen bond between CS and TP molecules, making MWCNTs an efficient vehicle for drug delivery. The release of drug molecules can be realized by pH variation and gammaradiation, leading to new methods for controlling drug release from a carbon nanotube carrier. Chen et al. designed a targeted drug delivery system (TDDS) of epidermal growth factor−chitosan−carboxyl−single-walled carbon nanotubes−ETO (EGF/CHI/SWCNT−COOHs/ ETO) using the modified SWCNTs as the carrier, the EGFfunctionalized SWCNTs as the targeted moiety, and etoposide (ETO) as the drug.61 Its drug loading capacity was 25−27%. The cell death induced by the EGF/CHI/SWNT−COOHs/ ETO was as much as 2.7 times that due to ETO alone. ETO could be released from the EGF/CHI/SWNT−COOHs/ETO at low pH and taken up by tumor cells. It indicated that the TDDS had a greater anticancer effect than the free ETO in vitro. 4.3. Biofunctionalized CNTs. Most recently, nanotubes− biomolecule conjugates attracted intense interest as delivery vehicles of biologically active molecules (such as protein, DNA, and RNA) in view of possible biomedical applications, including vaccination and gene delivery.62,63 The recent strategies to functionalize CNTs with bioactive glycoconjugates (such as glycoproteins, glycolipids and glycodendrimers) have resulted in the biocompatible and water-soluble CNTs well suited for highly selective interactions with proteins and living cells as building blocks for cell signaling, gene delivery, bioimaging, biosensors, and bone tissue engineering constructs.64 Dai et al. developed a novel functionalization scheme for SWCNTs to afford nanotubes−biomolecule conjugates with the incorporation of cleavable bonds to enable controlled molecular releasing from nanotube surfaces, thus creating “smart” nanomaterials with high potential for chemical and biological applications.65 By investigating the transporting, enzymatic cleaving and releasing of DNA from SWCNT transporters, and subsequent nuclear translocation of DNA oligonucleotides in mammalian cells, a highly efficient delivery of siRNA by SWCNTs and achievement more potent RNAi functionality than a widely used conventional transfection agent was revealed. They also developed SWCNTs as nonviral molecular transporters for the delivery of siRNA into human T cells and primary cells by adsorbing the phospholipids (PLs) grafted amine-terminated polyethylene glycol (PL−PEG2000− NH2) onto the SWCNTs.66 Then the thiol-modified siRNA cargo molecules were linked to the amine groups on the sidewalls of the SWCNTs through cleavable disulfide bonds (Figure 8). It was found that the nanotubes could deliver siRNA to afford efficient RNAi of CXCR4 and CD4 receptors F



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on human T cells and peripheral blood mononuclear cells (PBMCs).

Figure 9. Schematic illustration of the designed vehicles for tumortargeted drug delivery.

The [cis-Pt(NH3)2]-moiety was covalently attached to CNTs containing surface-modified carboxylic groups. Targeting was achieved by the epidermal growth factor (EGF) conjugated to the CNT and release of the cytotoxic Pt(II) moiety was accomplished by aquation (Figure 11).72 The cisplatin and EGF were attached to the SWCNTs to specifically target squamous cancer, and the SWCNT−cisplatin without EGF was nontargeted control. Li et al. designed the antibody of P-glycoprotein (P-gp) (anti-P-gp) functionalized water-soluble single-walled carbon nanotubes (Ap-SWCNTs) loaded with doxorubicin, DOX/ApSWCNTs, via the biocompatible diimide-activated amidation reaction for challenging the multidrug resistant leukemia cells (K562R).73 DOX noncovalently adsorbed could be controllably released into target cells via the exposure of near-infrared radiation (NIR). And the induced cytotoxicity of DOX to the multidrug resistant leukemia cells (K562R) has been significantly enhanced by loading DOX on the Ap-SWCNTs. Taghdisi introduced sgc8c aptamer (this aptamer targets leukemia biomarker protein tyrosine kinase-7) to complex between Dau (daunorubicin) and the SWCNTs to enhance targeted delivery of Dau to acute lymphoblastic leukemia Tcells (Molt-4).74 A high drug loading capacity, near 157%, was achieved. The loaded drug was released from the drug-loaded nanotubes (Dau-aptamer-SWCNTs) in a pH-dependent manner (6-fold higher release rate at pH 5.5). Dau flow cytometric analysis and cytotoxicity showed that the Dauaptamer-SWCNTs tertiary complex was internalized effectively to Molt-4 cells, but not to U266 cells. Furthermore, the tertiary complex was less cytotoxic in U266 cells when compared to Dau alone. Karchemski et al. designed a new drug delivery system, in which drug-loaded liposomes were covalently attached to the partially carboxylated MWCNTs to form a CNT−liposomes conjugate (CLC) via the amide linkage (Figure 12).75 The novel approach combines the efficient cell uptake of CNTs with the well-known high drug loading capacity of nanoliposomes. CLC could deliver a high dose of drug into target cells using a low concentration of CNTs; thus, CNT-related toxicity should be significantly reduced. It is possible to bind different drugs to the CNTs by binding liposomes loaded with different contents on the same CNTs.

Figure 8. Functionalization of SWCNTs with PL-PEG2000-NH2 for the conjugation of thiol-siRNA through disulfide linkages.

Pan et al. established an approach for the CNT−protein conjugate from the pyridyldithio functionality-decorated MWCNTs.67 Bovine serum albumin (BSA) was easily covalently conjugated onto the MWCNTs via stimuliresponsive covalent linkages through the disulfide-exchange reaction at mild conditions. The protein conjugated on the surface of MWNT can be controlled to release in the presence of a suitable concentration of glutathione. The pyridyldithio functionality-decorated MWCNT is expected to provide a platform for further conjugating many biological molecules onto carbon nanotubes. Highly efficient loading of the fluorescein (FAM) labeled short double strands DNA (20 base pairs) (dsDNA-FAM) was achieved with the positively charged SWCNTs. Then the dsDNA-FAM modified SWCNTs were encapsulated with the folic acid modified phospholipids for active targeting into tumor cell. 68 The multifunctionalized SWCNTs could efficiently target mouse and mammalian tumor cells in which FRs are overexpressed. Poly(amido amine) (PAMAM) dendrimer-modified MWCNTs proved to be good gene transporters for mammalian cell lines and antisense therapy. The loading amount of FITClabeled antisense c-myc oligonucleotides (as ODN) absorbed increased and higher transfection efficiencies and inhibition effects on tumor cells were achieved accordingly, with the increasing of generation of the PAMAM dendrimer.69 Chen et al. designed a novel SWCNT-based tumor-targeted drug delivery system that consisted of a functionalized SWCNT linked to tumor-targeting modules as well as prodrug modules (Figure 9).70 Its cytotoxic form inside the tumor cells upon internalization and in situ drug release was activated by conjugation of prodrug modules. The attachment of tumorrecognition modules (biotin and a spacer) to the nanotubes surfaces could provide the targeting characteristics. Heister et al. developed a novel functionalization approach to equip the oxidized SWCNTs with three different agents (anticancer drug DOX, a monoclonal antibody which recognizes carcinoembryonic antigen (CEA), and a fluorescent marker NHS−fluorescein) at noncompeting binding sites for multimodal drug delivery (Figure 10).71 The triple functionalized SWCNTs can successfully transport a potent anticancer drug to human cancer cells with subsequent translocation of the drug to the nucleus, whereas the SWCNTs remain in the cytoplasm.

5. CONCLUSION AND FUTURE PERSPECTIVE Various chemistries have been developed to functionalize CNTs with inorganic, organic, polymer, or bioactive materials to make them soluble, biocompatible, and targeted, in terms of applying CNTs in nanomedicine. Properly modified CNTs G



Review

Figure 10. Schematic illustration of the doxorubicin−fluorescein−BSA antibody−SWCNT complexes.

The in vivo toxicological and pharmacological studies undertaken so far indicate that the functionalized CNTs can be developed as nanomedicine, contrary to nonfunctionalized, pristine CNTs. Though it is still too early to establish CNTs for clinical use, these novel carriers are undoubtedly interesting and deserve further investigation. A detailed understanding of the pharmacological and toxicological properties of CNTs and a balanced evaluation of risk-to-benefit ratio are required before they can be recommended for routine clinical use. Although remarkable strides have already been made for the CNT-mediated drug delivery systems over the past few years, much more work is clearly needed before we will see CNTs enter the clinic in earnest. The long-term toxicity remains as the most important issue still to be overcome. Further systematic investigations using different animal models with various dosages and incubation times are required, although many works strongly suggest that appropriately functionalized CNTs are nontoxic in vitro to cells and in vivo to mice. Despite the fact that several groups have succeeded in using CNTs for in vitro delivery of drugs, demonstrations of in vivo delivery remain elusive. Also, special attention should be paid to optimize the surface functionalization of CNTs for specific biomedical applications, where the surface chemistry is designed to minimize toxicity and also engineer the specificity, such as structure (single-walled, double-walled, and multiwalled CNTs), length and aspect ratio, surface area, degree of aggregation, extent of oxidation, surface topology, bound functional group(s), and method of manufacturing. There will be some limitations to these nanomaterials because they are not biodegradable. They have been shown to be excreted in vivo and so could be cleared from the body once it is no longer needed. The CNT excretion rates and accumulation in organs and any reactivity with the immune system will determine the CNT safety profile and, consequently, any further pharmaceutical development. Therefore, the parameters such as degree of aggregation, biodistribution, and clearance pathways of these CNT-mediated drug delivery systems also need to be established.

Figure 11. Schematic illustration of the SWCNT−cisplatin−EGF drug delivery system.

Figure 12. Schematic illustration of the CNT-liposomes conjugate (CLC).

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seem to have a high propensity to cross cell membranes. They can be charged with biologically active moieties, which can then be delivered to the cell cytoplasm. The chemistry of CNTs offers the possibility of introducing more than one function on the same tube, so that targeting molecules, contrast agents, drugs, and reporter molecules can be used at the same time.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax/Phone: 86-931-891-2582. Notes

The authors declare no competing financial interest. H



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Review

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ACKNOWLEDGMENTS This project was granted financial support from the National Nature Science Foundation of China (Grant No. 20904017), and the Program for New Century Excellent Talents in University (Grant No. NCET-09-0441).

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Modification Strategies for Carbon Nanotubes as a Drug Delivery

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