Nanomaterials for Photohyperthermia - Ingenta Connect

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Nanomaterials for Photohyperthermia: A Review Jonathan Fang and Yu-Chie Chen* Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300, Taiwan Abstract: The unique properties of nanomaterials have propelled the field of nanomedicine. Nanomaterials have been used as drug delivery, imaging, and photothermal agents for diagnosis and therapy of diseases. Recently, photohyperthermia has attracted great interest from researchers and is actively being investigated as an alternative method of therapy for cancer and even bacteria. Photohyperthermia, or photothermal therapy, is the process of a photothermal agent absorbing light and converting it into heat for the destruction of malignant cells, which is due to elevated temperatures. This technique is non-invasive, can target specific diseased cells for minimal adverse side effects, and can be used in conjunction with other cancer treatments, such as chemotherapy. In this review, we will discuss different nanomaterials that have been implemented as photothermal agents for the treatment of various cancer and bacterial cells. The review will mainly focus on gold nanoparticles, magnetic nanoparticles, and carbon nanotubes. However, other nanomaterials, such as semiconductor nanoparticles and polymer composites, will be briefly discussed. In addition, the photothermal mechanism, current developments, dual imaging and therapy, and future perspectives of nanoparticle-based photohyperthermia will be presented.

Keywords: Nanomaterials, photohyperthermia, photothermal agents, gold nanoparticles, magnetic nanoparticles, carbon nanotubes, theranostics. 1. INTRODUCTION The advent of nanotechnology has had a tremendous impact on many areas in science and engineering, especially in biotechnology and health care. Nanomaterials have greatly advanced the field of nanomedicine and have recently been used in areas such as drug delivery, imaging [1], cell targeting [2], and photothermal therapy [1, 2]. There are a wide variety of drug carriers that have been used for the delivery of therapeutic agents. Specifically, biodegradable polymeric nanoparticles [3-6] are a promising group of organic compounds that have been researched and utilized for drug delivery applications due to properties such as excellent biocompatibility and controlled, stimuli-responsive release capabilities. One class of these polymeric nanoparticles is polyesters [3], such as poly(lactic acid) (PLA) [4], poly(lactide-co-glycolide) (PLGA) [5], and poly(caprolactone) (PCL) [6], which have been used for the delivery of anti-cancer therapeutic agents [3-6]. In addition, non-polymeric nano-scale drug carriers, such as liposomes, have been used for the delivery of anti-HIV drugs [7]. These materials are excellent drug carriers due to their established biocompatibility and their ability to enhance drug bioavailability. Other nanomaterials that have been used for drug delivery are inorganic nanoparticles, such as silica nanoparticles [8, 9]. In contrast to drug delivery, photohyperthermia is an alternative therapeutic method that has recently attracted researchers and been investigated for the treatment of cancer and other infectious diseases. This technique relies on the use of photothermal agents that can convert light energy into heat for the purpose of destroying malignant cells. In this review, we will provide an overview on the nanomaterials that have been implemented as photothermal agents for photohyperthermia. 2. PHOTOHYPERTHERMIA Hyperthermia is the procedure of heating a region in the body affected by cancer or other diseases and killing the malignant cells, which is typically achieved when the temperature is raised to between 40°C and 44°C [10-12]. It is a therapeutic method that has been gaining interest due to its generally low toxicity [12], noninvasiveness, simplicity [13], and potential to treat tumors in areas *Address correspondence to this author at the Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300, Taiwan; Tel: +886-3-5131527; Fax: +886-3-5723764; E-mail: [email protected] 1873-4286/13 $58.00+.00

where surgical resection may not be viable [14]. The rationale for this type of treatment is based on the observation that direct cellkilling of tumors occurs at or above temperatures between 41°C and 42°C [11, 15-17]. Tumors are more susceptible to heat than healthy cells, making hyperthermia a viable treatment option [10]. Cell death from hyperthermia can be caused by several mechanisms, such as degradation of the cell wall membrane [13, 16], protein denaturation [13], and the production of reactive oxygen species, leading to necrosis and apoptosis [18]. Hyperthermia has been combined with chemotherapy [11, 15, 17, 19] and radiotherapy [17, 20, 21] for enhanced treatment of many different types of cancer. Multimodal cancer treatments have increased response rates and patient survival [17]. The types of cancers that have been treated with hyperthermia include melanoma, head and neck, esophageal [12], liver [14], cervical [21], breast [22], prostate [23], rectal [24], and ovarian cancer [25]. Hyperthermia has even been used to treat bone tumors [26] and patients with human immunodeficiency virus [27]. Energy sources that have been used for hyperthermia include magnetic fields [22], lasers [28], radiofrequency (RF) pulses [29], and ultrasound [30]. There have been plenty of reviews that have covered clinical hyperthermia, such as those by van der Zee [10], Wust et al. [11], Falk and Issels [12], and Christophi et al. [16]. In addition, cancer treatments that combine hyperthermia with chemotherapy (Takahashi et al. [19]) and radiotherapy (Horsman and Overgaard [20]) have been reviewed. Research on photohyperthermia, or photothermal therapy, for the treatment of cancer and bacteria has been recently gaining momentum. Photothermal therapy is the process of converting light energy into heat for the purpose of damaging and destroying diseased cells, such as cancer and bacteria. Surface plasmon resonance (SPR) can be described as resonant oscillations of free electrons of a particle irradiated by light [31]. When a photothermal agent, such as a gold nanoparticle, strongly absorbs incident light near its SPR peak, conduction band electrons decay to the ground state and releases heat in the process [32, 33]. The photothermal process is similar to that of another treatment method, photodynamic therapy (PDT), except that PDT undergoes photochemical processes that produce singlet oxygen, which introduces concerns over tissue oxygenation and cytotoxicity [2, 34, 35]. The majority of studies involving photothermal therapy have focused on treating or destroying various cancer cells, with some emphasis on killing bacteria. Photohyperthermia is rapidly emerging as an alternative to conven© 2013 Bentham Science Publishers

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rials were used for photothermal therapy. Figure 1 highlights the photothermal agents that will be discussed in this review.

tional therapies for cancer, such as antibody or drug therapy, and can be used in conjunction with these treatments to provide a synergistic therapeutic effect. Traditionally, monoclonal antibodies have been extensively investigated for treating tumors and other diseased cells but specific targeting of the malignant cells and nonspecific toxicity remains a problem [2]. Cell targeting has been used for diagnostic and therapeutic applications where a nanomaterial, such as a gold nanoparticle, is conjugated with an antibody or other biorecognition molecule to selectively bind to a specific receptor that is overexpressed on the surface of a cancer cell, which can then be destroyed by light-induced hyperthermia [36-44]. This type of targeted photothermal therapy has also been used with functional nanomaterials that have high binding affinity to bacteria for selective killing of bacteria [45-49]. Pitsillides et al. was one of the first to utilize this type of cell targeting for enhanced photothermal therapy by conjugating superparamagnetic iron oxide-doped latex microspheres and gold nanoparticles with antibodies specific to Tlymphocytes. The antibody-conjugated particles were then mixed with the lymphocytes and the particles that were selectively attached to the lymphocytes were irradiated with light to destroy the cells [2]. This non-invasive photothermal therapy method is able to selectively target and kill diseased cells with minimal side effects and damage to normal, healthy tissues and cells [31, 38, 40, 42, 50]. The effectiveness of photothermal therapy relies heavily on the photothermal agent, which are nanomaterials. For clinical applications, nanomaterials should be non-toxic, stable, hydrophilic, have long blood circulation time for high tumor uptake of nanomaterials via the enhanced permeability and retention (EPR) effect, selectively target diseased cells and tissues, have minimal aggregation, and have optimal properties for high accumulation at the tumor site while evading macrophages of the reticuloendothelial system (RES) [2, 38, 51]. The surface of nanoparticles are commonly modified with polyethylene glycol (PEG) to increase circulation time and reduce protein adsorption on the surface of the nano-carriers for slower degradation [3, 33, 51-53]. Nanomaterials may also possess dual functionality of imaging and photohyperthermia for both diagnostics and therapy, or theranostics [54]. The most widely used photothermal agents for photohyperthermia are gold nanomaterials, such as gold nanoparticles [39, 42], gold nanorods [40], and gold nanoshells [52], magnetic nanoparticles [55], and carbon nanotubes [56]. There have also been several instances where other nanomate-

3. PHOTOTHERMAL AGENTS 3.1. Gold Nanomaterials 3.1.1. Gold Nanoparticles Modern synthesis of gold colloids can be traced back to the 1850s when Michael Faraday reduced gold chloride with phosphorus to form small gold particles [57]. Gold colloids or nanoparticles are typically synthesized through the reduction of chloroauric acid (HAuCl4) by a reducing agent, such as sodium citrate [58] and sodium borohydride (NaBH4) [59]. Gold nanoparticles have been used in biology for labeling, sensing, molecular and drug delivery, and hyperthermia [36]. Drug targeting and gene therapy applications arise from delivery of deoxyribonucleic acid (DNA) and therapeutic drugs into the cell, which is due to cellular uptake of gold nanoparticles [36]. Gold nanoparticles are also easily biofunctionalized with antibodies or other biomolecules, such as antibiotics or adenoviral vectors, thus making them ideal candidates for immunotargeting therapy [38-42] and gene therapy [60]. Covalent bonding between a thiol group and gold has been extensively exploited for bioconjugation of gold nanoparticles with thiol-modified ligands or biomolecules [36, 37]. Gold nanoparticles are excellent photothermal agents due to their tunable optical properties in the nearinfrared (NIR) and infrared (IR) regions [32, 33], biocompatibility [33, 61], efficient light absorption [34], ease of synthesis [39], nontoxicity, and stability [42]. Figure 2 shows the mechanism for selective photothermal destruction of a cancer cell through specific antibody-antigen binding. Upon laser irradiation, gold nanoparticles that are attached to the cell membranes can form overlapping microbubbles in the surrounding liquid, which causes cellular damage and cell death [43]. In most cases, the antibody-conjugated nanoparticles bind directly to the overexpressed receptors on the surface of the cell. Gold nanospheres, the simplest type of gold nanoparticle, have optical absorption in the visible region between 500 nm and 600 nm [31]. An important optical property of gold nanoparticles is that it can absorb significantly more light (up to six orders of magnitude) than typical NIR organic dyes, such as indocyanine green and Rhodamine 6G [34, 41, 45, 62]. Furthermore, the photo-stability of gold nanoparticles is much higher than that of

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Fig. (1). Diagram outlining the various nanomaterials used for photohyperthermia.

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Fig. (2). Schematic of selective photothermal destruction of a cancer cell: (a) A primary antibody specifically attaches to a surface protein on the cell membrane. Then, a gold nanoparticle conjugated with a secondary antibody binds to the primary antibody for nanoparticle attachment to the cancer cell. (b) Upon laser irradiation, heat emanates from the nanoparticles and bubble formation ensues, thus damaging the membrane and causing cell death (Reprinted with permission from Zharov VP, Galitovskaya EN, Johnson C, Kelly T. Synergistic enhancement of selective nanophotothermolysis with gold nanoclusters: potential for cancer therapy. Lasers Surg Med 2005; 37: 219-226, John Wiley & Sons, Inc., Copyright 2005 Wiley-Liss, Inc.).

organic dyes [41, 62, 63]. Gold nanomaterials have been extensively used for photothermal therapy of various cancers, such as oral squamous cell carcinoma [35, 39, 40], breast cancer [38, 41-43, 64, 65], hepatocellular carcinoma [44, 66], colon cell carcinoma [62, 67], and myeloid leukemia [68]. Some researchers have also used gold nanoparticles for the selective killing of pathogenic bacteria, such as Staphylococcus aureus [46], Salmonella typhimurium [47], Escherichia coli, and vancomycin-resistant Enterococcus (VRE) [48]. Huang et al. [34] and Kennedy et al. [69] have provided reviews on the use of gold nanoparticles for photothermal therapy. Zharov et al. [42] demonstrated in vitro photothermal treatment of human breast cancer cells by using 40 nm gold nanoparticles conjugated with goat antimouse immunoglobulin G with laser irradiation. Primary F19 monoclonal antibodies were selectively attached to the proteins on the surface of the cancer cells. The secondary antibody, goat antimouse immunoglobulin G, was specifically bound to the primary antibody to allow for selective nanoparticle attachment to the cell. Finally, the nanoparticles accumulated on the cell membrane and aggregated to form large nanoclusters on the membrane. These large, aggregated nanoclusters shifted optical absorption from the visible, for gold nanoparticles, to the NIR region. In addition, these nanoclusters enhanced photothermolysis due to laser-induced formation of overlapping microbubbles, which would cause more cellular damage than just a single nanoparticle [43]. For 532 nm laser irradiation, both single 40 nm gold nanoparticles and aggregated gold nanoclusters significantly reduced cancer cell viability. However, nearly complete destruction of the cancer cells was only observed with the gold nanoclusters. For 1,064 nm NIR laser irradiation, this photothermal discrepancy between gold nanoparticles and nanoclusters was even more pronounced as the single gold nanoparticles had no effect on the cancer cells while the gold nanoclusters destroyed most of the cells. These results support the assertion that aggregated nanoclusters were much more effective photothermal agents than single gold nanoparticles. They also determined that the optimal nanoparticle and nanocluster sizes were 30 – 40 nm and 100 – 200 nm, respectively. Optimal cell killing was observed when the nanoclusters were located near or inside the cell membrane. Nanoclusters that penetrated the membrane and reached inside the cell showed reduced or no cellular damage. A possible reason for this difference is that nanoclusters inside the cell may be randomly distributed within the cell while nanoclusters at or

inside the cell membrane can directly disrupt the membrane, thus causing more damage [43]. Composite gold nanoparticles have also been synthesized and utilized for photothermal therapy of cancer cells. For example, Day and co-workers [64] were the first to employ antibody-conjugated gold-gold sulfide (GGS) nanoparticles for in vitro imaging, specific targeting, and photothermal destruction of breast cancer cells. Chloroauric acid was combined with sodium thiosulfate to form these nanoparticles, which were less than 50 nm in diameter and strongly absorbed in the NIR region. For imaging purposes, GGS nanoparticles can undergo two-photon photoluminescence and has been demonstrated to have higher brightness than gold nanoshells. Pulsed NIR lasers were used instead of continuous ones to reduce energy usage and to minimize damage to normal, healthy tissues for in vivo use. Laser power of 1 mW was used to image cancer cells targeted with antibody-conjugated nanoparticles while 50 mW was needed to photothermally induce cell death. Zhang et al. [66] coated chitosan, an abundant polysaccharide, on to gold nanoparticles for enhanced stability and photothermal killing of hepatocellular carcinoma (HepG2) cells when compared to unmodified gold nanoparticles. In addition, the surface charge of these nanoparticles was tunable by modifying the chitosan coating, which enables targeting of charged cell membranes. Bacteria are becoming increasingly more resistant to antibiotics so alternative methods, such as photothermal therapy, for diagnosis and treatment are needed [45]. S. aureus is a pathogenic bacterium that is responsible for diseases such as skin and wound infections, toxic shock syndrome, septic arthritis, endocarditis, and osteomyelitis [46]. Zharov et al. [46] utilized photothermal therapy to kill S. aureus using relatively small (10 – 40 nm) gold nanoparticles conjugated with anti-Protein A, which is specific to S. aureus. Killing of this bacteria was achieved after 100 pulses from a 532 nm laser with 12 ns pulses at 0.1 – 5 J/cm2. Using transmission electron microscopy (TEM) and photothermal imaging (PTI), they estimated that an average of approximately 40 – 60 nanoparticles attached to an individual bacterium but the maximum number of nanoparticles that can attach to S. aureus may be much higher. Increasing the number of gold nanoparticles bound to S. aureus would lower the minimum laser energy required to achieve killing of bacteria. There is tremendous potential to lower the laser fluence levels to 100 mJ/cm2, which is the safety standard for medical lasers.


Khan et al. [47] conjugated popcorn-shaped gold nanoparticles with a monoclonal M3038 antibody specific to S. typhimurium DT104, a bacterium that is resistant to five common antibiotics. Antibody-conjugated gold nanoparticles were incubated with bacteria and irradiated with a laser (670 nm, 200 mW/cm2), which killed almost 100% of the bacteria within 20 min. Laser irradiation without nanoparticles did not significantly kill any bacteria, even after 40 min. Huang et al. [48] demonstrated photothermal killing of a variety of pathogenic bacteria with polygonal gold nanoparticles conjugated with vancomycin, which binds directly to the cell wall of many strains of bacteria. The vancomycin-conjugated gold nanoparticles had a maximum absorption peak at 830 nm, were incubated with bacteria, and irradiated with a NIR laser (808 nm, 200 mW/cm2) for 5 min. Photothermal treatment was performed on eight different bacterial strains with less than 1% of the bacteria surviving after 5 min of NIR irradiation. In comparison to the study by Khan et al. [47], Huang and co-workers used a laser wavelength in the NIR region and achieved photothermal killing of bacteria with the same laser power but within a shorter irradiation time. 3.1.2. Gold Nanorods Gold nanorods are cylindrical, rod-shaped nanoparticles that have been investigated for their optical properties [32] and applications in drug delivery [32, 33], sensing [33], imaging [33, 41], and photothermal therapy [40, 44, 49, 68, 70]. Due to its ease of synthesis, flexibility in producing nanorods of varying aspect ratios, and relatively high yield, one of the most widely used synthesis routes for gold nanorods is the seed-mediated growth method with the assistance of surfactants such as cetyltrimethylammonium bromide (CTAB) (Fig. 3a), which was developed by Murphy’s group [33, 35, 71]. Properties of gold nanorods that make them excellent photothermal agents are their ease of preparation and bioconjugation, high absorption cross-section, and tunable optical absorption into the NIR and IR regions (from its longitudinal plasmon band) where there is minimal light absorption by tissue and water, thereby avoiding damage to normal, healthy tissue (Fig. 3b) [32, 33, 35, 40]. The aspect ratio of the gold nanorods plays an important role in affecting the absorption peak and photothermal efficiency of these nanomaterials. In contrast to gold nanospheres, gold nanorods have two surface plasmon resonance peaks, one coming from its short axis and one from its long axis [32]. Figure 3b shows that the longitudinal absorption peak of gold nanorods red-shifts to the NIR with increasing aspect ratio, which is an established phenomenon [32, 72, 73]. In addition, increasing the aspect ratio should also enhance the photothermal efficiency of gold nanorods since the higher surface area enables more absorption of light for conversion to heat. However, nanorods with very high aspect ratios may be too large and unsuitable for in vivo use. Alkilany et al. [32] have recently reviewed the status of gold nanorods as photothermal agents for photohyperthermia and drug delivery while Choi et al. [33] have recently discussed their use in photohyperthermia and imaging for cancer treatment. Dickerson et al. [35] utilized PEGylated anti-EGFR gold nanorods for in vivo destruction of subcutaneous squamous cell carcinoma. Mice were injected with HSC-3 human squamous carcinoma cells and PEGylated anti-EGFR nanorods, which circulated through the body for 24 h prior to NIR irradiation at 808 nm. Irradiation for 10 – 15 min at 1.7 – 1.9 W/cm2 was needed for tumor control with minimal damage to surrounding normal tissue. The control treatment (phosphate-buffered saline injection and no NIR irradiation) did not inhibit tumor growth while NIR laser treatment with gold nanorods severely stunted tumor growth. Researchers have commonly exploited the folate receptor, which is overexpressed by a variety of cancer cells, for tumor targeting [74-76]. Jin et al. [44] investigated the use of folateconjugated gold nanorods for the photothermal destruction of hepatocellular carcinoma, a tumor that overexpresses folate receptors. The gold nanorods had an aspect ratio of approximately 4 and had


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transverse and longitudinal absorption peaks at 520 nm and 760 nm, respectively. Folate conjugation of the gold nanorods caused a red shift in the optical absorption of the nanorods. HepG2 cells were incubated with the nanorods and fluorescence imaging confirmed that the folate-conjugated gold nanorods specifically attached to the cancer cells. Finally, the HepG2 cells, with and without gold nanorods, were irradiated with a laser (650 nm, 200 mW/cm2) for 10, 20, and 30 min. Photothermal therapy was able to reduce cell viability to approximately 50% and below 20% for 20 and 30 min of irradiation, respectively. In comparison, cells that were not in the presence of the folate-conjugated gold nanorods were not visibly damaged under the same irradiation conditions. However, the lengthy irradiation time needed to achieve significant destruction of cancer cells may be a concern for in vivo use. Hauck et al. [68] combined gold nanorod photohyperthermia with chemotherapy for enhanced cancer treatment. The gold nanorods had average dimensions of 29.1 nm by 8.8 nm. NIR irradiation (808 nm, 2 W/cm2) raised the solution temperature in the cells with gold nanorods to above 46.4 ± 1.9°C, which is above the threshold for cellular death. After 8 days of culturing, all the cells that underwent NIR irradiation and gold nanorod treatment either died or became apoptotic. The chemotherapeutic drug cisplatin was also administered in conjunction with photothermal therapy. The cytotoxic drug dosage with NIR photothermal heating was only about 33% of the therapeutic drug dosage needed to achieve similar cytotoxicity without heating. A synergistic effect between nanoparticlebased photohyperthermia and chemotherapy was demonstrated where the combination of both treatments were more effective than either treatments used alone. Composite gold nanorods have also seen use in dual imaging and photothermal treatment of cancer cells, as demonstrated by Wang et al. [77] and Ke et al. [78]. Wang and co-workers [77] combined modified gold nanorods with iron oxide nanoparticles to produce nanocomposites for in vitro magnetic resonance imaging (MRI) and NIR photothermal destruction of breast cancer cells. These magnetic gold nanorods were shown to be better contrast agents than unmodified iron oxide nanoparticles. SK-BR-3 cells were destroyed by the accumulation of nanocomposites on the surface of the membrane and NIR irradiation (785 nm, 4.53 W/cm2) for 5 min. Ultrasound is an alternative imaging method that is safe, simple to use, and relatively inexpensive [78]. Due to these advantages, Ke and co-workers [78] developed ultrasound contrast agents composed of PLA microcapsules loaded with gold nanorods to enable both ultrasound imaging and photothermal therapy. PLA microcapsules possess echogenic properties suitable for ultrasound while the gold nanorods enable NIR photohyperthermia. In vivo ultrasound imaging was performed on the kidneys of a rabbit injected with gold nanorod-PLA microcapsules. They also demonstrated in vitro photothermal destruction of human cervical cancer cells under high intensity NIR irradiation for 10 min. However, the average size of these nanorod-composites was greater than 2 m, which could be impractical for in vivo use. Important concerns regarding the clinical use of gold nanorods include particle stability, storage, and biocompatibility, especially since the surfactant CTAB is coated on the nanorod surface during synthesis so there are possible toxicity issues with desorbed CTAB. Khlebtsov et al. [70] demonstrated long-term storage of gold nanorods and used them to probe photothermal therapy on mice injected with Ehrlich carcinoma tumors. The nanorods had an average length and diameter of 41.1 nm and 10.2 nm, respectively, and had a plasmon resonance peak at 820 nm. In addition, the gold nanorod powder was stable as they retained their properties for almost 6 months at room temperature. For in vivo photohyperthermia, 0.4 mL solutions containing gold nanorod concentrations of 100 mg/L and 400 mg/L were injected into tumor-bearing mice, which corresponded to doses of 2 and 8 mg of gold/kg of animal, respectively. NIR irradiation (810 nm, 4 W/cm2) on tumors with nanorods for 5


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Fig. (3). (a) Diagram outlining the synthesis of gold nanorods, (b) TEM images and absorption spectra of gold nanorods with varying aspect ratios. Optical absorption shifts to the NIR and IR regions with higher aspect ratios (Reprinted from Alkilany AM, Thompson LB, Boulos SP, Sisco PN, Murphy CJ. Gold nanorods: their potential for photothermal therapeutics and drug delivery, tempered by the complexity of their biological interactions. Adv Drug Deliv Rev 2012; 64: 190-199, Copyright 2012, with permission from Elsevier).

min decreased the tumor volume but undamaged areas on the tumor periphery continued to grow and tumor volume increased at later times. The higher dose (8 mg of gold/kg of animal) reduced tumor volume by half and had a much longer delay in tumor growth, approximately 12 days, in comparison to the lower dose (2 mg/kg), where tumor growth occurred after less than 5 days. Gold nanorods have also been implemented for the selective targeting and photothermal destruction of a pathogenic bacterium, Pseudomonas aeruginosa [49]. The multi-drug resistant P. aeruginosa is a leading cause of infection and mortality among people with impaired immune functions [49]. Norman et al. [49] synthesized antibody-conjugated gold nanorods for specific targeting of P. aeruginosa (PA3) cells. Nanorods themselves were not toxic to the P. aeruginosa isolate bacterial cells for over a 24 h period. Antibody-conjugated nanorods bound the bacterial cells much more than bare nanorods. Upon NIR irradiation (785 nm, ~50 mW), the nanorods significantly reduced cell viability by 75%. PA3 cells treated with only nanorods, NIR radiation, or neither had approximately 80% cell viability, demonstrating the effectiveness of both nanorods and NIR light. 3.1.3. Gold Nanoshells Gold nanoshells can be considered as composite gold nanoparticles and like gold nanorods, have been investigated for their optical properties [79, 80] and applications to photothermal therapy [38, 41, 62, 65, 67]. These composite nanoparticles were developed by Halas’ group over a decade ago. Gold nanoshells are composed of a dielectric or semiconducting core, such as silica, covered by a gold

shell of nanoscale thickness [79, 80]. Production of gold nanoshells typically involves synthesis of the silica core nanoparticles via the Stober method, adsorbing an amino-functionalized silane onto the particles, growing and covalently binding gold colloids on the aminated particle surface, and finally reducing gold from HAuCl4 in the presence of formaldehyde to form the gold shell [65, 67, 79]. One attractive feature of gold nanoshells for photothermal therapy is its tunable plasmon resonance whereby increasing the ratio of the core to the total radius shifts the plasmon resonance peak from the visible region to the NIR and IR regions (Fig. 4) [79, 80]. Another useful property is the strong absorption and scattering observed from gold nanoshells, which makes it a good contrast agent for imaging applications [41]. Likewise with other nanomaterials, gold nanoshells are PEGylated for in vivo photothermal therapy for enhanced biocompatibility [41], extended blood circulation time [41, 52], and minimizing nanoshell aggregation [65]. Lal et al. [52] has reviewed the status of gold nanoshells for photothermal therapy and as contrast agents for imaging. Halas and co-workers have extensively investigated the use of gold nanoshells for photohyperthermia. For example, Hirsch et al. [65] was one of the earliest to utilize gold nanoshells for NIR photothermal therapy of breast carcinoma cells in vitro and in vivo. The PEG-modified nanoshells had an average core diameter of 110 nm, an average shell thickness of 10 nm, and an absorbance peak at 820 nm. Cells treated with both NIR light (820 nm, 35 W/cm2 for 7 min) and nanoshells were destroyed while cells treated with only

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NIR light or only nanoshells maintained viability. Similar results were observed in vivo at lower power (4 W/cm2) and shorter irradiation time (less than 6 min). Magnetic resonance temperature imaging revealed that for in vivo photothermal therapy with nanoshells, tumors experienced an average temperature increase of 37.4 ± 6.6°C for NIR irradiation times between 4 – 6 min. Thus, the tumors were heated to temperatures that were significantly above the threshold temperature to induce cellular death. Finally, maximal penetration depths between 4 – 6 mm were reached for photothermal therapy of tumors in mice. Heating depths beyond 1 cm have been observed elsewhere and deeper penetration depths are possible at lower nanoshell concentrations, longer irradiation times, or higher laser power [65]. In addition, theranostics was also demonstrated in several studies with nanoshells typically having a core diameter between 110 nm and 130 nm [38, 41, 67]. Bardhan et al. [38] and Loo et al. [41] both used antibody-conjugated gold nanoshells for both imaging and photothermal therapy of human breast cancer cells. Bardhan and co-workers [38] conjugated gold nanoshells with antibodies specific to human epidermal growth factor receptor 2 (HER2), which is overexpressed by SKBr3 breast cancer cells. They also grew a thin dielectric layer around the nanoshell and incorporated NIR fluorophores and iron oxide nanoparticles into the thin layer for dual fluorescence optical imaging (FOI) and MRI. In vivo experiments were performed where nanoshells were injected into tumor-bearing mice to observe their biodistribution and to track the fate of the nanoshells up to 72 h, which is when they exited the body. It was discovered that nanoshells accumulated mostly at the tumor site with some expected accumulation at the liver and spleen,

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which was probably minimized by the PEG functional group on the nanoshell. O’Neal et al. [62] demonstrated NIR photothermal destruction of CT26.WT murine colon carcinoma cells in vivo with gold nanoshells with no tumor recurrence observed for several months. They synthesized gold nanoshells with a 110 nm diameter silica core and an 8 – 10 nm thick gold shell, yielding an absorption peak between 805 – 810 nm. PEG-coated gold nanoshells circulated in the bloodstream for 6 h for sufficient accumulation in the tumors. Mice that underwent photothermal treatment had complete resorption of the tumor within 10 days and remained healthy past 90 days. In addition to silica gold nanoshells, composite gold nanoshelliron oxide nanoparticles (IONPs) were also synthesized for magnetic separation and photothermal destruction of cancer cells and bacteria. For example, Fan et al. [50] synthesized and conjugated gold nanoshell-IONPs with an S6 aptamer, which is specific to the HER2 receptor. The gold nanoshell-IONPs were incubated with breast cancer cells and irradiated with a 670 nm laser at 2 – 3 W/cm2, which killed most of the cells within 10 min. After 13 min of treatment, all the cancer cells were killed while only 12% of the normal cells died. Larson et al. [81] also synthesized antibodyconjugated gold nanoshell-IONPs and demonstrated dual functionality of MRI imaging and photothermal destruction of breast cancer cells. The iron oxide core provided enhanced MRI contrast while the gold shell enabled photothermal therapy. Core shell nanoparticles were 45 ± 14 nm in size with a plasmon peak centered at 540 nm. One 7 ns, 400 mJ/cm2 pulse at 700 nm was sufficient to kill the cells labeled with the antibody-conjugated nanoparticles while the unlabelled cells (PEGylated hybrid nanoparticles) remained unharmed, even after 600 pulses. Finally, IONPs were also used for magnetic separation and photohyperthermia for the selective killing of bacteria. Huang et al. [82] synthesized and conjugated gold nanoshell-iron oxide (Fe3O4@Au) nanoeggs with vancomycin to bind various bacteria. Figure 5 shows the synthesis steps and TEM images of the nanoeggs at the various stages. Fe3O4@Au nanoeggs had a maximum absorption at 840 nm. They were able to elevate the temperature of a nanoegg suspension from 23°C to 55°C under NIR irradiation (808 nm, 250 mW/cm2) for 3 min, demonstrating high photothermal potential. The nanoegg-attached bacteria aggregated when a magnet was placed near them and nearly all the bacteria were destroyed under the same irradiation conditions with less than 1% of the bacteria surviving. 3.1.4. Optimal Dimensions for Gold Nanomaterials Despite the multitude of photohyperthermia studies that have been carried out with gold nanomaterials, there is still a limited understanding of the relationship between nanomaterial parameters and efficiency of photothermal therapy [63]. Khlebtsov et al. [63] has performed theoretical simulations to determine which gold nanoparticle structures will yield maximum absorption, thus making them optimal photothermal agents. For example, maximum photothermal effects from gold nanospheres irradiated with a 515 nm laser was observed for nanospheres of sizes ranging from 20 – 40 nm. For peak absorption near 800 nm, gold nanorods should have a major size ranging from 50 – 70 nm with an aspect ratio around 3.5. Finally, to obtain peak absorption near 800 nm, gold nanoshells should have a silica core diameter ranging from 50 – 100 nm and a shell thickness ranging from 3 – 8 nm. However, there are some drawbacks with some of these gold nanostructures. For example, visible light radiation is not ideal for clinical applications as light penetration through tissue is severely limited and damage to surrounding tissues can occur. Gold nanorods are commonly synthesized and coated with CTAB, which may cause some hindrance towards bioconjugation. In addition, cytotoxicity of free CTAB molecules should be considered although researchers have replaced CTAB with more biocompatible molecules for in vivo use. Citing photothermal studies that were mentioned above, Jin et al. [44] replaced the CTAB coating on gold nanorods with folate to target


Fang and Chen

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Fig. (5). (a) Diagram showing the synthesis of Fe3O4@Au nanoeggs. TEM images of the nanomaterial at various stages: (b) magnetic IONPs, (c) magnetic IONPs encapsulated by silica nanoeggs, (d) iron oxide-silica nanoeggs bound to gold seeds, (e) Fe3O 4@Au nanoeggs. (f) Color change indicating the evolution of Fe3O4@Au nanoeggs after adding formaldehyde to the iron oxide-silica nanoeggs-gold seeds (Reprinted with permission from Huang WC, Tsai PJ, Chen YC. Multifunctional Fe3O4 @Au nanoeggs as photothermal agents for selective killing of nosocomial and antibiotic-resistant bacteria. Small 2009; 5: 51-56, John Wiley & Sons, Inc., Copyright 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim).

tumor cells that overexpress folate and Khlebtsov et al. [68] PEGylated the nanorods to remove the CTAB. Taking it a step further, Vigderman et al. [83] not only replaced the CTAB with a cationic thiol, (16-mercaptohexadecyl) trimethyl-ammonium bromide (MTAB), but also enhanced the uptake of nanorods by cancer cells. The cationic MTAB bound nanorods through gold-sulfur binding and replaced virtually all of the CTAB. These nanorods were tested with breast cancer cells and they discovered that MTAB nanorods displayed no cytotoxicity and a cellular uptake of approximately 2 million nanorods per cell while limited uptake was observed with PEGylated nanorods. Finally, gold nanoshells with 3 – 8 nm thick shells can be difficult to synthesize and may be prone to destruction from high temperatures induced by laser heating. An important observation is that gold nanoparticles can also achieve strong NIR absorption when formed as nanoclusters and are more stable, less expensive, and easier to synthesize than nanorods and nanoshells [43, 63]. Puvanakrishnan et al. [84] recently published a study investigating the effect of particle size and shape on tumor targeting for gold nanorods and nanoshells injected into mice. Nanoparticles typically accumulate in tumors through EPR, taking advantage of the tumors’ leaky vasculature. Gold nanorods of dimensions 24 nm by 7 nm and 120 nm diameter gold nanoshells with a 15 nm thick shell were used for their experiments. Biodistribution studies focused on the accumulation of the gold nanomaterials in the tumor and liver. The gold nanorods had significantly higher accumulation in tumor cells than gold nanoshells with approximately 12 times more nanorods observed 24 hours after injection, thus favoring the smaller photothermal agent for higher and more rapid tumor targeting. These results are consistent with the observation that smaller particles can diffuse into tumor cells more easily than larger particles, which would experience higher steric hindrance and slower diffusion in accessing the tumor sites. This is also why larger particles tend to stay longer in tissue and smaller particles have faster clearance from the tumor.

3.2. Magnetic Nanoparticles Magnetic nanoparticles are materials that respond to an external magnetic field and have been extensively used for biomedical applications, such as drug delivery [85-87], MRI [86-88], and hyperthermia [85, 89, 90]. For magnetic fluid hyperthermia (MFH), magnetic particles accumulate at the targeted site of action, such as cancer or bacterial cells, and absorb energy from an external alternating current magnetic field to generate heat to kill the malignant cells [85, 89, 90]. Magnetic nanoparticles used for biomedical applications are typically coated with a protective and biocompatible material, such as dextran and PEG, to prevent agglomeration and enhance stability in physiological environments [88, 90]. In contrast to MFH, there have also been a few studies where magnetic nanoparticles were used in photohyperthermia [55, 91, 92]. IONPs have been one of the most extensively studied magnetic nanomaterials for photothermal and hyperthermia treatment of cancer and bacteria due to their nontoxicity, established biocompatibility, high magnetic susceptibility, and superparamagnetic behavior [53, 85, 89, 90]. A simple and straightforward route to synthesize IONPs is the co-precipitation method, which typically involves adding ferric or ferrous chloride to an aqueous solution [89, 93]. The size and shape of the nanoparticles can be controlled by adjusting the pH, ionic strength, type of salts used, or adding chelating or complexing agents [89]. A major advantage of this synthesis route is that a high yield of nanoparticles can be obtained [89]. Although IONPs have typically been used for MFH, these nanoparticles may also possess photothermal capabilities. Yu et al. [55] was the first to report the use of iron oxide nanoparticles for photohyperthermia and not as a MRI contrast agent, as commonly observed. They utilized iron oxide/alumina core/shell magnetic nanoparticles (alumina-coated IONPs) for magnetic aggregation, targeting, and photothermal destruction of Gram-positive and Gram-negative bacteria (Fig. 6). It has been shown that aluminacoated IONPs have high specificity towards phosphorylated pep-



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Fig. (6). Entire process of iron oxide/alumina core/shell magnetic nanoparticle-based photohyperthermia for the destruction of bacteria (Reproduced from Yu TJ, Li PH, Tseng TW, Chen YC. Multifunctional Fe3O4/alumina core/shell MNPs as photothermal agents for targeted hyperthermia of nosocomial and antibiotic-resistant bacteria. Nanomedicine 2011; Volume 6, Issue 8, pp. 1353-1363 with permission of Future Medicine Ltd).

tides and proteins, which are present in the cell wall of bacteria, through Al-phosphate chelation. Thus, alumina-coated IONPs should have high affinity for most bacteria. In addition to their magnetic properties, alumina-coated IONPs are also able to absorb light in the NIR region. Photothermal capabilities of the aluminacoated IONPs was demonstrated by NIR irradiation (808 nm, 640 mW/cm2) of a 1.33 g/L nanoparticle suspension, which increased the temperature of the suspension by 20°C over 5 min. Finally, photothermal killing of bacteria was investigated by incubating the nanoparticles with various bacteria, such as E. coli and Streptococcus pyogenes, aggregating the nanoparticle-attached bacteria with a magnet, then irradiating the solution with a NIR laser (808 nm, ~640 mW/cm2) for 3, 5, and 10 min. Nearly complete destruction of bacteria was observed at a concentration of 1.33 g/L aluminacoated IONPs under NIR irradiation for 10 min. Photothermal killing of bacteria was significantly reduced at lower nanoparticle concentrations and shorter illumination times. The alumina-coated IONPs were incubated with carcinomic human alveolar basal epithelial cell A549 and cell viability was shown to be approximately 80%, demonstrating biocompatibility of the nanoparticles. Liao et al. [91] synthesized mesoporous silica-coated iron oxide nanostructures for NIR photothermal therapy and as a possible MRI contrast agent. Tumor cells exhibited good cell viability (over 99%) in the presence of the nanocomposites. Upon NIR irradiation at 808 nm for 15 min, cell viability dropped to 55% and 15% for laser power densities of 1.4 W/cm2 and 2 W/cm2, respectively. For tumor-bearing mice that were injected with the nanocomposites, NIR irradiation induced an increase in the body temperature of the mouse from ~34°C to ~47°C. This resulted in tumor regression one day after irradiation and complete tumor resorption 4 days after injection of the nanocomposites. Finally, in vivo monitoring of the tumor site injected with the iron oxide nanocomposites and photothermal therapy of the tumor was achieved with MRI. Vardarajan et al. [92] used magnetic carbon nanoparticles (MCNPs) for photothermal therapy of human prostate cancer cells and human fibroblast sarcoma cells. Fe-doped MCNPs had an average particle size of approximately 5 nm, were ferromagnetic, and had high optical absorption in the NIR region. They were also able to induce aggregation of nanoparticles with an external magnetic

field, which is useful for targeting nanoparticles at a tumor site for in vivo applications. Cancer cells without MCNPs were irradiated with a NIR laser (720 nm, 92 mW) for up to 2 min, which did not harm the cells. However, NIR irradiation of cells incubated with MCNPs led to photothermal destruction of the cells, even at lower laser exposure. 3.3. Carbon Nanotubes Carbon nanotubes (CNTs) are cylindrical tubules composed of graphitic sheets and were discovered over two decades ago by Iijima [94]. Synthesis methods for CNTs are electric arc discharge, laser ablation, and chemical vapor deposition, which is the most popular method for producing large quantities of the material [95]. Its unique structure and interesting properties has led to applications in electronics, energy storage, as a reinforcement material in composites, nanoprobes, and template materials [95]. More recently, CNTs have been used in the biomedical field for bioconjugation, biosensing, drug delivery, and therapeutic applications [96, 97]. CNTs, single-walled carbon nanotubes (SWNTs) [98] and multiwalled carbon nanotubes (MWNTs) [99, 100], have been shown to strongly absorb NIR light and efficiently convert it into thermal energy, which makes them excellent photothermal agents for photohyperthermia. In addition, CNTs can be transported across the cellular membrane into the cell via endocytosis [98]. Bioconjugation of recognition molecules and PEG on to CNTs have been used for selective cancer cell targeting, enhanced biocompatibility, and long blood circulation lifetimes [97, 101-103]. Both SWNTs and MWNTs have been used for in vitro and in vivo photothermal therapy on cancer cells [56, 98-106]. Researchers have used SWNTs [56] and MWNTs [99, 100] for in vivo photothermal therapy of tumors in mice. For example, Moon et al. [56] investigated the use of SWNTs for in vivo photothermal therapy on mice bearing human epidermoid mouth carcinoma KB tumor cells on their backs. SWNTs were PEGylated and had average lengths and diameters ranging from 50 – 300 nm and 2 – 5 nm, respectively. Tumors in mice were completely destroyed 20 days after the initial treatment with PEG-SWNTs and NIR irradiation with no recurrence of tumors. In addition, rapid disappearance of solid tumors shortly after treatment was frequently observed. Con-

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trol treatments, such as no treatment, only PEG-SWNT injection, or only NIR irradiation, had no effect on the tumors. In addition, the biodistribution of the PEG-SWNTs in various tissues and organs were monitored. Initially, PEG-SWNTs circulated in the blood and accumulated in the spleen and liver. Injected SWNTs primarily remained in the muscle and skin but gradually diffused into blood over time. RES uptake is common among nanotubes and other nanomaterials but since the levels of PEG-SWNTs decreased over time, it seems that most of the nanotubes were excreted from the body. Large nanotubes (over 100 nm in length) are excreted through the biliary pathway while shorter, smaller nanotubes are excreted through the urinary pathway, which was the case for most of the PEG-SWNTs. MWNTs are expected to be able to absorb more light than SWNTs due to MWNTs having more electrons for light absorption and more metallic tubes than SWNTs per molecule [99]. Burke et al. [99] investigated the use of MWNTs for in vitro and in vivo photothermal treatment of kidney tumor cells. MWNTs were shown to be more photothermally efficient than SWNTs. Upon exposure to a NIR laser (1,064 nm, 3 W/cm2) for 30 s, SWNT suspensions needed a concentration 20 times higher than that of MWNT suspensions to induce the same temperature increase. Thus, shorter laser exposure times are possible with MWNTs for effective photothermal therapy. For in vivo experiments, mice were injected with solutions containing 0.2, 1, and 2 g/L of MWNTs. For mice treated with 10 g (0.2 g/L) and 50 g (1 g/L) of MWNTs and NIR light, tumor growth was suppressed for about two weeks before the tumors started growing. After 30 days, tumors treated with 1 g/L MWNTs were approximately half the size of those treated with 0.2 g/L MWNTs. However, photohyperthermia with 100 g (2 g/L) of MWNTs was able to induce complete tumor regression without recurrence in 80% of the mice for over 3 months. Therefore, the long-term effectiveness of photothermal therapy was dependent on the amount of nanotubes with higher MWNT concentrations having more success. Tumors that were untreated and treated with only MWNTs or NIR laser grew rapidly. For over 6 months after treatment, carbon nanotubes showed no major toxicities with only local skin injury being observed. In addition, no organ damage was observed but additional studies are still needed to determine their nontoxicity. Ghosh et al. [100] encased DNA in MWNTs for photothermal treatment of human prostate cancer cells in mice. The hydrophilicity of DNA imparts aqueous solubility to the MWNTs that is necessary for in vivo use. In addition, DNA-encased MWNTs exhibited higher photothermal efficiency than unmodified MWNTs. DNAencased MWNTs were obtained by sonicating MWNTs with an aqueous solution of single-stranded DNA. These modified MWNTs had an average diameter of 49 nm, length of 571 nm, aspect ratio of 13, and produced two to three times more heat than unencased MWNTs. For example, when irradiated with a NIR laser (1,064 nm, 3 W) for 25 s, an aqueous solution of MWNTs required 30 g/mL of MWNTs to induce a temperature increase of 5°C in the solution. Consequently, only 15 g/mL of DNA-encased MWNTs in solution was needed to cause the same elevation in temperature. To induce a 10°C temperature increase with the same NIR irradiation (1,064 nm, 3 W) for 70 s, 24 g/mL of MWNTs was required while only 8 g/mL of DNA-encased MWNTs was needed to achieve the same effect. The lower concentrations of carbon nanotubes are more suitable for in vivo therapy due to reduced toxicity. Figure 7 shows the changes in tumor volume for four groups of mice that underwent various treatments and pictures of two mice with different treatments on their left and right flanks. Tumors in all 8 mice that were treated with both MWNTs and laser irradiation were completely eradicated in 6 days while mice that had control treatments (only MWNTs, laser, or neither) did not have tumor regression.

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Right Flank: MWNT-only Left Flank: No Treatment Fig. (7). (a) Changes in tumor volume over time for four groups of mice that underwent different treatments. Complete tumor destruction in mice was observed 6 days after treatment with MWNTs and laser. (b) Pictures of a mouse treated with only laser on the left flank and both MWNT and laser on the right flank (top row) at one day, one week, and four weeks posttreatment; pictures of another mouse with an untreated left flank and treated with only MWNTs on the right flank (bottom row) at the same time intervals post-treatment. Tumor regression was only observed for the mouse with both MWNT and laser treatment on its right flank (Reprinted with permission from Ghosh S, Dutta S, Gomes E, et al. Increased heating efficiency and selective thermal ablation of malignant tissue with DNA-encased multiwalled carbon nanotubes. ACS Nano 2009; 3: 2667-2673. Copyright 2009 American Chemical Society).

Researchers have also attached biomarkers and antibodies to CNTs for photothermal therapy of cancer cells. For example, Wang et al. [96] conjugated SWNTs with antibodies specific to CD133, a transmembrane glycoprotein and a biomarker for brain tumorinitiating cells, to selectively target these cells. The absorption peak of antibody-conjugated SWNTs (anti-CD133-SWNTs) was around 808 nm. 105 tumor-initiating cells were treated with 10 g of antiCD133-SWNTs for 6 h and then subcutaneously injected into mice. After two days, the SWNT-injected cells were exposed to a NIR laser (808 nm, 2 W/cm2) for 5 min. Tumor growth and progression in mice were significantly inhibited for several weeks. Finally, Zhou et al. [105] conjugated SWNTs with glycated chitosan (GC) for in vitro and in vivo photothermal therapy of mouse mammary tumor cells. GC, the result of galactose attaching to chitosan, was chosen as the bioconjugate due to chitosan’s ability to stimulate immunological responses while the sugar imparts water solubility with good biocompatibility [107]. GC-conjugated SWNTs (SWNT-GC) had a strong absorption peak at around 980 nm. After 100 days, all mice with SWNT-GC and laser treatment survived while mice treated with PEG-attached SWNTs and laser had 43.75% survival, those treated with GC and laser had 25% survival, and those treated with only laser had 12.5% survival. These results show that the combination of SWNT-GC and laser


irradiation provided a synergistic photothermal and immunological effect for enhanced cancer treatment. 3.4. Other Nanomaterials Besides the nanomaterials that have already been discussed, other nanomaterials have also been investigated as photothermal agents, such as copper sulfide [108], copper selenide [109], titania nanotubes (TiO2 NTs) [110], and polymeric composites [111, 112]. Young et al. [113] has discussed these other nanomaterials in a review of photothermal agents. Copper-based semiconductors have been gaining interest as a biocompatible alternative [108, 109] to Cd-containing contrast agents for in vivo cancer imaging due to cytotoxicity concerns with Cd-containing semiconductor quantum dots [114]. In addition, copper-containing nanoparticles have been explored for their photothermal potential due to their ability to strongly absorb light in the NIR region [108, 109]. Li et al. [108] demonstrated the first reported use of semiconductor nanoparticles for photothermal therapy. They synthesized 3 nm copper sulfide nanoparticles with a maximum absorbance at 900 nm. At a concentration of 384 M copper sulfide nanoparticles, 5 min irradiation with an 808 nm laser at 24 W/cm2 and 40 W/cm2 yielded an average cell viability of 55.6% and 21.2%, respectively. For 3 min irradiation at 64 W/cm2, average cell viability was 12.2%. Hessel et al. [109] synthesized spherical copper selenide nanocrystals and coated them with an amphiphilic polymer, poly(maleic anhydride), for hydrophilicity and biocompatibility. The nanocrystals had a diameter of 39 nm and a broad absorbance peak centered at 970 nm. 800 nm light irradiation at 2 W/cm2 on an aqueous dispersion of copper selenide nanocrystals for 5 min raised the temperature of the solution by 22°C. The photothermal transduction efficiency of the nanocrystals was 22%, similar to that of gold nanorods and higher than that of gold nanoshells. The nanocrystals were biocompatible with human colorectal carcinoma HCT-116 cancer cells for up to 6 h. NIR irradiation (800 nm, 30 W/cm2) on cancer cells for 5 min destroyed all cells with nanocrystals. In contrast to carbon nanotubes, Lee et al. [110] synthesized TiO2 NTs for photothermal therapy of cancer cells. TiO2 NTs are known to be biocompatible and easily prepared by simple electrochemical anodization of titanium. The inner diameter of the TiO2 NTs was ~100 nm and the thickness of the nanotube layers was ~160 m. Suspensions of TiO2 NTs, SWNTs, and gold nanoparticles were irradiated with NIR light to compare their photothermal performance. Under NIR irradiation (808 nm, 300 mW/cm2) for 20 min, TiO2 NTs induced higher increases in temperature than that from SWNTs (diameter of 1 - 1.2 nm, length of 5 - 20 m) and 50 nm gold nanoparticles. This higher photothermal effect could be due to TiO2 NTs having a higher optical absorbance than that of both SWNTs and gold nanoparticles. In vitro experiments were also done where murine colon cancer cells (CT-26) were incubated with TiO2 NTs and irradiated with the NIR laser. When exposed to the same NIR laser conditions, the cell viability of cancer cells treated with TiO2 NTs were as low as 1.35%. Treatment without TiO2 NTs yielded a cell viability of 96.4% while treatment with TiO2 NTs but no laser irradiation had a cell viability of 98.2%. Finally, Yang et al. [111] synthesized composite polymer gold nanoshells for both photothermal and drug delivery therapy. PLGA nanoparticles were synthesized via a nanoemulsion method and loaded with doxorubicin (DOX), a chemotherapeutic agent. The DOX-loaded PLGA nanoparticles (80 ± 10 nm) were coated with a gold nanoshell layer for photothermal purposes. EGFR-abundant A431 (human epidermoid carcinoma) cells treated with just antibody-conjugated polymer gold nanoshells (no laser irradiation) had relatively high cell viabilities (at least 60%) while cells treated with both nanoshells and laser irradiation (820 nm, 15 W/cm2) for 10 min had significantly lower cell viability (below 30%). In addition, cells photothermally treated with DOX-loaded PLGA nanoparticles had an average viability of 15%, which was approximately 40%


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lower than that for cells treated with nanoparticles and laser without drug. This reduced cell viability was due to the combination of NIR light melting part of the polymeric substrate to release a large amount of DOX for additional cytotoxic activity against cancer cells and potential hyperthermia from NIR irradiation of the gold nanoshell. Cheng et al. [112] also loaded a chemotherapeutic drug, in this case Taxol, in composite PLGA nanoparticles, conjugated with gold nanorods, iron oxide, and quantum dots, for in vitro and in vivo destruction of HeLa cervical cancer cells through photothermal and drug therapy. For in vivo studies, tumors were transplanted into mice, injected with the Taxol-loaded hybrid nanoparticles (100 g/kg), and then irradiated with a NIR laser (808 nm, 3 W/cm2) for 7 min. One week after NIR irradiation (laser beam spot of 12 mm2), tumors in mice treated with drug-loaded nanoparticles were at most half the size as those treated under the same conditions without drug. Mice that had combined chemotherapy and photothermal treatment survived for two months with complete tumor suppression and no sign of regrowth. These studies demonstrate that NIR photohyperthermia combined with drug delivery exhibited a synergistic photothermal and chemotherapeutic effect for enhanced treatment of cancer. 4. DISCUSSION Photohyperthermia has recently emerged as an alternative and promising therapeutic method for the treatment of cancer and even bacteria, as evidenced by the active research in this area and the many successful in vitro and in vivo studies performed on various diseased cells. Theranostics was demonstrated where nanomaterials were implemented for both imaging and photothermal destruction of cancer cells. In addition, researchers also combined photohyperthermia with chemotherapy where light radiation on drug-loaded polymeric nanoparticles initiated release of chemotherapeutic agents for enhanced cancer treatment. Translating this therapy to the clinical setting is still preliminary as many different factors still need to be considered before taking this next step. However, clinical studies are in progress, such as the clinical trials involving AuroLase™ Therapy for the treatment of head and neck tumors where patients are given doses of gold nanoshells and irradiated with an 808 nm laser [115]. In these trials, patients will be monitored for 6 months after treatment to observe if there are any adverse side effects. One concern is the light radiation and whether or not the light can penetrate skin deep enough to reach the tumor without harming other tissues or organs. NIR lasers, especially those that operate at around 800 nm, seem to be one of the most popular energy sources for photohyperthermia due to NIR light being transparent through tissues and water. However, NIR irradiation for photothermal treatment seems to be limited to superficial tumors, especially subcutaneous ones, and may be unsuitable for more deep-seated tumors in the body that cannot be safely reached by NIR light. For the treatment of more deeply embedded tumors, radiofrequency ablation and magnetic fluid hyperthermia have been used where microwaves and external magnetic fields, respectively, were able to penetrate deeper into the body to reach these tumors. Another issue is whether or not the laser energy and power are safe for medical use. Low laser energy would be safer but may require long irradiation times to reach a therapeutic effect, which may cause undesired side effects in the patient. This obstacle can be overcome by multiple irradiation therapy. These types of concerns are heavily influenced by the choice of the photothermal agent, essentially the nanomaterial. The photothermal agent has a significant influence on the clinical application of photohyperthermia. Properties of nanomaterials for clinical photohyperthermia should include ease of synthesis, biocompatibility, long blood circulation times, long-term nontoxicity in patients, cell targeting capabilities, be relatively inexpensive, and have high photothermal transduction efficiency to allow for use of low power, safe energy sources while still maintaining a therapeutic effect. Despite all the advantages nanomaterials possess for


photohyperthermia, there are drawbacks for these materials when considering clinical use. Although gold nanospheres are the simplest gold nanostructures to synthesize, their peak optical absorption is in the visible region and not in the NIR. Visible light has shallow penetration depths through tissues that are insufficient to reach tumors. This is probably why in vivo photothermal experiments with gold nanomaterials utilized gold nanorods and gold nanoshells as the photothermal agents. However, aggregated gold nanoclusters are a viable alternative since they have been shown to strongly absorb NIR light for effective photothermolysis of cancer cells, although the large sizes of these nanoclusters need to be considered for clinical use. In addition, gold nanoparticles, iron oxide nanoparticles, and carbon nanotubes all have concerns over potential in vivo toxicity, especially due to particle size, unless they are biofunctionalized or modified. This requires additional processing and further investigation into the in vivo behavior of these modified nanomaterials to ensure their safety and efficacy for clinical photohyperthermia. Besides the common photothermal agents discussed, semiconductor nanoparticles have shown some promising preliminary results but further, extensive research is needed to explore their photothermal potential and possible toxicities. Costs of the various nanomaterials are also a factor, especially the use of antibody-conjugated nanoparticles for cell targeting since it can be quite expensive to produce antibodies. Targeted photohyperthermia has been achieved with nanoparticles that have been conjugated with relatively inexpensive, non-antibody biorecognition molecules with high specificity for cancer and bacterial cells, such as folate and vancomycin, respectively. However, certain cases might require a level of specificity beyond what can be achieved with these other biomolecules, which then necessitates the use of antibodyconjugated nanoparticles. In addition, localized photohyperthermia has been demonstrated with unmodified and composite magnetic nanoparticles. Additional studies on biodistribution, pharmacokinetics, long-term toxicity, optimization of material properties for photothermal efficiency, and physiological fate of these nanomaterials are still needed to evaluate their suitability for clinical applications.

Fang and Chen

ACKNOWLEDGEMENTS We thank the National Science Council of Taiwan for financial support of this research. REFERENCES [1]

[2] [3]

[4] [5]

[6] [7] [8]

[9] [10] [11] [12] [13] [14]

5. CONCLUSION The last few decades have seen a rise in the research dedicated to nanomaterials and its applications to health care, such as in photothermal therapy for effective cancer treatment. The most common photothermal agents are gold nanomaterials and carbon nanotubes, with other materials, such as magnetic nanoparticles and polymer nanocomposites, also being used. These nanomaterials also possess the capability for dual functionality, such as combined imaging and therapy or photohyperthermia with drug delivery. Currently, gold nanomaterials are the most prevalent and promising photothermal agents due to their established biocompatibility, photothermal effectiveness, ease of bioconjugation, and flexibility in synthesizing various structures (e.g. spheres, rods, shells) and sizes, which enables optimization of optical and physical properties of the gold nanomaterial for use in clinical photohyperthermia. The prospect of using magnetic nanoparticles for targeted photohyperthermia of cancer is an attractive one due to the ability to manipulate the nanoparticles with a magnet to localize treatment without the need for antibodies. However, research in this area is at a preliminary stage and requires extensive investigation for future clinical use. In vitro and in vivo photothermal destruction of various cancers and bacteria has been demonstrated with the various materials that have been discussed. Researchers are continually improving and testing these nanomaterials for greater efficacy and safety, which bodes well for the employment of photohyperthermia in the clinical setting. CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest.

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Received: January 31, 2013

Accepted: April 22, 2013

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