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Nanocarbon Materials for Photodynamic Therapy and Photothermal Therapy Qian Li, Hong Ruan and Hongguang Li* Laboratory of Clean Energy Chemistry and Materials, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, China Abstract: Photodynamic therapy (PDT) and photothermal therapy (PTT) are two kinds of methodologies that can be applied to the treatment of cancer. They own some advantages over the existing strategies including chemo- and radiotherapy but at the same time, are also facing big challenges. During the past decades, great efforts have been devoted to overcome the bottlenecks and to push these two newly-emerging methodologies to practical applications. One of the big achievements is the utilization of nanocarbon materials in PDT and PTT. Nanocarbon materials include zero-dimensional fullerene, one-dimensional carbon nanotubes (CNTs), and two-dimensional graphene. Upon illumination, fullerene can generate reactive oxygen species (ROS) through both Type I and Type II photochemistry, which allows it a good candidate for PDT. CNTs and graphene generate significant amount of heat upon excitation with near-infrared light, which makes them suitable for PTT. In this review, recent developments of the application of nanocarbon materials in PDT and PTT are briefly summarized and discussed.
Keywords: Carbon nanotubes, fullerene, graphene, photodynamic therapy, photothermal therapy, tumor. 1. INTRODUCTION
2. FULLERENE IN PDT
Phototherapy, a form of light-based medical treatment, has been developed in the past decades for the treatment of various diseases. Photodynamic therapy (PDT) and photothermal therapy (PTT) are the two main kinds of phototherapy used for the treatment of diseases such as cancer [1]. PDT was based on the application of photosensitizer (PS) that generates reactive oxygen species (ROS) by exposure of propriety light; whereas, PTT employs photothermal (PT) agent to generate significant amount of heat upon illumination. Compared to traditional methodologies adopted in the treatment of cancer such as chemotherapy and radiotherapy, both PDT and PTT show reduced side effects and improved selectivity [2-4].
Fullerene (C60), which represents a third carbon allotrope after diamond and graphite, has fascinated scientists since its discovery in 1985 [7, 8]. Fullerene is a soccer-ball-shaped truncated icosahedron with 12 pentagons (due to C5-C5 single bonds) and 20 hexagons (C5-C6 double bonds) [9]. Both pristine fullerene and fullerene derivatives can generate ROS upon illumination, which makes them good candidates for PDT [4].
Nanocarbon materials including fullerene (Fig. 1), (1), carbon nanotubes (CNTs), (Fig. 1), (2) and graphene (Fig. 1), (3) have shown tremendous promise in phototherapy [5, 6]. Upon illumination, fullerene can generate ROS through both Type I (production of radicals) and Type II (production of singlet oxygen) photochemistry [5]. It is thus regarded as an alternative for traditional PS such as tetrapyrroles [5]. CNTs and graphene generate significant amount of heat upon excitation with near-infrared light, which makes them suitable for PTT [6]. In this review, we will give a brief review on the recent developments of functional nanocarbon materials and their applications in PDT and PTT.
*Address correspondence to th is author at the Laboratory of Clean Energy Chemistry and Materials, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, China; Tel: +86-931-4968829; Fax: +86931-4968163; E-mail:
[email protected] 2211-7393/14 $58.00+.00
2.1. Mechanisms The ability of fullerene to absorb visible light was attributed to the extended π -conjugated system present in the fullerene molecule [5]. Singlet excited state of fullerene is formed after fullerene absorbs light, which undergoes intersystem crossing to the triplet state. Part of the fullerene molecules in the triplet state are quenched by molecular oxygen and produce singlet oxygen, while others generate superoxide anion radical, especially with reducing agents (e.g. NADH). These are known as Type II photochemistry and Type I photochemistry, respectively (Fig. 2) [10-12]. 2.2. Advantages and Disadvantages Fullerene possesses some advantages over traditional PS such as tetrapyrroles. It is more photostable and less photobleaching. Particularly, it can generate ROS through Type I pathway. This is almost impossible for traditional photosensitizers such as tetrapyrroles [13]. As Type I pathway needs less oxygen than Type II pathway, fullerene is expected to be more effective in hypoxic tumors than tetrapyrroles [13, 14]. Moreover, the hydroxyl radicals (OH•-) generated in Type I pathway could be more cytotoxic than singlet oxygen (1O2) generated in Type II pathway [15]. © 2014 Bentham Science Publishers
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Fig. (1). Schematic representation of the structures of fullerene (1), carbon nanotube (2) and graphene (3). 1C * 60 1C * 60
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Of course, just like other PS, fullerene also shows some disadvantages. Without functionalization, fullerene is barely soluble both in water and biological media, which significantly hinders the biological applications of pristine fullerene [16]. Another concern is its relatively weak optical absorptions in the visible and NIR regions. However, these drawbacks could be overcome by suitable synthetic strategies applied on the pristine fullerene. In the former case, chemical modification and encapsulation methods can be employed while in the latter case, an antennae which can absorb visible and/or NIR light can be selected, as will be discussed in more details below separately.
Fullerene is a hydrophobic molecule, which hampered its potential application in PDT [12]. There are two main approaches for preparation of water-soluble fullerenes, including chemical modification and encapsulation methods.
which can be easily carried out at room temperature, has been widely used to prepare water-soluble C60 derivatives. Hu et al. reported that amino group of amino acid (e.g. L-phenylalanine) and folic acid could react with fullerene, and these derivatives (Fig. 3), (4, 5) have excellent selectivity to tumor cells [4]. Kwag et al. synthesized a watersoluble fullerene (6) via conjugation of glycol chitosan to C60, which shows highly increased tumor accumulation ability for in vivo tumor of KB tumor-bearing nude mice [9]. Another important type of C60 derivatives used in PDT is carboxyfullerene. They not only can be used as PS in PDT, but also are important intermediates to react with other water-soluble molecules. Sayes et al. demonstrated that C60[C(COOH)2]3 (7) is cytotoxic to human dermal fibroblasts cells at a LC50 value of 10 000 ppb [17]. Shi et al. constructed a multifunctional C60-iron oxide nanoparticlesPEG/hematoporphyrin monomethyl ether system (8) for cancer therapy, and methoxypolyethylene glycol amine was attached to C60[C(COOH)2]3 through amidation reaction [3].
The development of water soluble fullerenes through chemical modification has aroused much attention. Examples include L-phenylalanine-grafted fullerene, folic acid-grafted fullerene, glycol chitosan-grafted fullerene, carboxyfullerene, and PEG-conjugated fullerene (Fig. 3) [3, 4, 9, 12, 17]. Conjugation of free amine with C=C double bonds of fullerene,
All of these fullerene derivatives have been found to readily produce ROS upon photosensitization and the PDT effect is related to the number of the carbon-carbon double bonds destroyed by the addition of the functional groups and, to a lesser extent, to the addition pattern [12, 17-19]. It was found that fullerene monoadduct is normally more toxic than
2.3. Water-soluble Fullerenes
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Fig. (3). Schematic representation of the molecular structures of typical water soluble fullerenes: L-phenylalanine C 60 derivative (4), folic acid-conjugated fullerene (5), glycol chitosan-grafted fullerene (6), carboxyfullerene (7), and C60-iron oxide nanoparticles-PEG/ hematoporphyrin monomethyl ether system (●= iron oxide nanoparticles ●=hematoporphyrin monomethyl ether) (8).
corresponding multi-adducts [17]. On the other hand, the addition pattern also affects the PDT efficiency [12, 18, 19]. For example, Chin et al. demonstrated that the singlet oxygen quantum yield of non-homoconjugated derivatized C60 was higher than that of homoconjugated C60 derivates with the same number of double bonds [19]. An alternative way to increase the solubility of fullerene in aqueous solutions is to incorporate fullerene into watersoluble supramolecular structures such as liposomes, micelles, dendrimers, cyclodextrin and self-nanoemulsifying systems [13]. In this strategy, the solubility of fullerene in water can be improved by hindering the hydrophobic fullerene core inside the modifying agent. However, in this case the contact of fullerene with oxygen might also be screened, which will influence the effect of PDT [12, 20]. In order to solve this problem, Metanawin et al. reported that C60 loaded on the surfaces of micelle cores allowed generation of significant amount of ROS [20]. 2.4. Attachment of Antennae Fullerene mainly absorbs blue and green light. To extend absorption spectrum of fullerene further into longer wavelengths, attaching light-harvesting antennae to fullerene is a promising way. For example, attaching fullerene with porphyrin (Fig. 4), (9) could extend absorption spectrum of fullerene further into the red wavelengths and produce biological photodamage under low oxygen concentration [13, 21, 22]. The antennae of CPAF-C2H (10) and [CPAF(C2MC3N6+)2]-(I-)10 (11) attached covalently to fullerene with a small distance of < 3.0 Ǻ also can facilitate photon absorption at longer wavelength white light [23].
3. GRAPHENE AND CNTS IN PTT Both graphene and CNTs have attracted much attention from scientists around the world for their unique physical, chemical, and thermal properties. Graphene, discovered in 2004, is a single-atom-thick planar sheet of carbon atoms packed in a honeycomb crystal lattice [24]. CNTs are among the most investigated materials before the invention of graphene. CNTs were first discovered in 1991 and can be described as hollow tube rolled from graphene sheet [25]. 3.1. Mechanisms Graphene and CNTs have strong absorption in the NIR region and can transform light into heat, which makes them excellent materials for PTT. Thermal therapy, also called hyperthermia, has been used to treat diseases in the past few decades. Typically in cancer treatment, 41 °C–47 °C is usually employed to promote selective cell death [26]. Since the poor blood supply in tumors led to reduced heat tolerance, cancer cell is more prone to die compared to normal cells [27]. Loosening cell membranes and denaturing proteins can be induced in cancer cells during hyperthermia [28]. 3.2. Advantages and Disadvantages Graphene and CNTs exhibit both advantages and limitations in hyperthermia. Some of the advantages that graphene and CNTs possess are as follows. Graphene and CNTs have the ability to load hydrophobic drugs, which supplies a way to combine PTT with PDT or chemotherapy [29-31]. Graphene and CNTs can strongly absorb NIR light, which allows sufficient tissue penetration [29, 32]. Compared to
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Fig. (4). Fullerenes with antennae: with porphyrins (9, M = 2H or Zn); C60(>CPAF-C2H) (10); C60[>CPAF-(C2MC3N6+)2]-(I-)10 (11).
magnetic iron oxide nanoparticles usually used in hyperthermia, graphene and CNT show higher rate of heating and do not require the removal of metallic materials [33]. Besides these advantages, Graphene and CNTs also show some limitations in PTT. Again, they are very hydrophobic and easily form irreversible agglomerates in polar solvents. On the other hand, hyperthermia was hampered by thermoresistance. Thus effective execution of apoptosis at mild temperature should be investigated. 3.3. Water-soluble Graphene and CNTs In order to use graphene and CNTs in biomedicine, they should exhibit high solubility and stability in physiological solutions. Graphene oxide (GO, Fig. 5), (12) and carboxyl graphene (CXYG, 13), which are soluble in water, are usually applied as platform for biomedical applications [34, 35]. GO is often prepared by Hummers’ method. It contains a large number of reactive groups such as epoxy hydroxyl and carboxylic acid, which can be conjugated with various functional groups. As GO and CXYG form aggregates in the presence of high concentration of salts, linear PEG, branched PEG and hyaluronic acid (HA) can be used as graphene surface modifiers (Fig. 5). Zhang et al. demonstrated that CXYG functionalized with linear polyethylene glycol (PEG) exhibits high solubility and stability in physiological solutions [31]. Yang et al. reported that branched PEG-modified GO sheets showed highly efficient tumor passive targeting and low retention in reticuloendothelial systems [36]. The structure of PEG-conjugated GO has been schematically shown in (Fig. 5) (14). Li et al. reported that GO functionalized with hyaluronic acid (HA, 15) demonstrated aqueous solubility and targeting to HA receptors overexpressed on cancer cells [37]. Oxidizing CNTs with strong acid can form carboxylic acid groups, which is viewed as the basic reaction for the preparation of CNTs derivates [38]. Similar to GO and CXYG, oxidized CNTs (16) are soluble in water, but it tends to aggregate in the physiological solution. Polymers, such as linear/branched PEG and HA, can be attached to oxidized CNTs to enhance water-solubility and biocompatibility (Fig. 6) [39, 40]. Bottini et al. reported that PEG modified CNTs
(17) have favorable pharmacokinetic and toxicology profiles [39]. Shi et al. conjugated CNT with HA (18) to target cancer cells [40]. 3.4. Combination of PTT with PDT or Chemotherapy The PTT effect is hampered by thermoresistance, which helps in protecting cancer cells from thermal stress [41]. Harsh thermal treatment (e.g. over 48 °C) is often used to prevent such phenomenon. However, it may lead to inflammatory disease and cancer metastasis. The combination of PTT with PDT or chemotherapy offers a promising way to enhance the PTT effect with minimal side effects. The combination of PTT with chemotherapy (thermochemotherapy) has aroused wide attentions. In traditional thermochemotherapy, nontargeted heating sources are often used. Recently, CNTs and graphene are adopted for their local heating. Zhang et al. reported that thermochemotherapy treatment with a noncovalently associated doxorubicin (DOX)-GO complex, demonstrates a synergistic effect compared to PTT or chemotherapy alone [31]. Ali-Boucetta et al. reported that such complex also demonstrates higher therapeutic efficacy than DOX and DOX-pluronic complex [42]. Combination of PDT and PTT is also a promising way to improve the therapeutic efficacy. It not only provides nanocarriers for hydrophobic PS, but also results in higher therapeutic efficacy. Tian et al. reported that a noncovalently associated Chlorin e6 (Ce6)-GO complex remarkably improves cellular uptake of Ce6 and shows a synergistic effect in therapeutic efficacy [29]. Shi et al. reported that a noncovalently associated hematoporphyrin monomethyl ether (HMME)-CNT complex showed a synergistic effect without obvious toxic effects to normal organs [40]. 4. PERSPECTIVES Based on the efforts of scientists in materials science and life science, it is generally accepted that nanocarbon materials including fullerene, CNTs and graphene are good candidates for phototherapy. Fullerene, which comprises both Type I and Type II photochemistry during PDT process, is more effective in hypoxic tumors than traditional tetrapyrrole
62 Pharmaceutical Nanotechnology, 2014, Vol. 2, No. 2
Li et al. CONH-PEG
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Fig. (5). Water-soluble graphene for photothermal therapy: graphene oxide (GO, 12), carboxyl graphene (CXYG, 13), PEG-conjugated graphene (14) and HA-conjugated graphene (15). COOH CONH
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Fig. (6). Water-soluble CNTs for photothermal therapy: oxidized CNT (16), PEG-conjugated CNT (17, R represents reactive functional groups at the distal end of the projected PEG chains) and HA-conjugated CNT (18).
Nanocarbon Materials for Photodynamic Therapy and Photothermal Therapy
PS. Graphene and CNTs have high absorption in the NIR region and can transform light into heat, which makes them excellent materials for PTT. Of course, just like other reagents for PDT such as tetrapyrroles and those for PTT such as various nanoparticles, nanocarbon materials also show some disadvantages. Future work on these interesting materials should focus on enlarging their advantages while at the same time, trying to minimize their disadvantages. Typically, increasing water solubility of the nanocarbon materials can be achieved by the attachment of hydrophilic functional groups and/or by encapsulation method. Besides the consideration of water solubility, attachment functional groups which can increase the absorption of nanocarbon materials and/or specifically target cancer cells are highly desired. Finally, combination of two or more therapeutic methods should be a promising way to further increase the therapeutic effect.
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CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest.
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ACKNOWLEDGEMENTS
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The authors are grateful for the financial support by the Hundred Talents Program of Chinese Academy of Sciences (Y20245YBR1).
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Received: July 17, 2014
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Accepted: September 22, 2014
