Plasmonic photothermal therapy (PPTT) using gold nanoparticles

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Lasers Med Sci (2008) 23:217–228 DOI 10.1007/s10103-007-0470-x

REVIEW ARTICLE

Plasmonic photothermal therapy (PPTT) using gold nanoparticles Xiaohua Huang & Prashant K. Jain & Ivan H. El-Sayed & Mostafa A. El-Sayed

Received: 26 April 2007 / Accepted: 10 May 2007 / Published online: 3 August 2007 # Springer-Verlag London Limited 2007

Abstract The use of lasers, over the past few decades, has emerged to be highly promising for cancer therapy modalities, most commonly the photothermal therapy method, which employs light absorbing dyes for achieving the photothermal damage of tumors, and the photodynamic therapy, which employs chemical photosensitizers that generate singlet oxygen that is capable of tumor destruction. However, recent advances in the field of nanoscience have seen the emergence of noble metal nanostructures with unique photophysical properties, well suited for applications in cancer phototherapy. Noble metal nanoparticles, on account of the phenomenon of surface plasmon resonance, possess strongly enhanced visible and near-infrared light absorption, several orders of magnitude more intense compared to conventional laser phototherapy agents. The use of plasmonic nanoparticles as highly enhanced photoabsorbing agents has thus introduced a much more selective and efficient cancer therapy strategy,

X. Huang : P. K. Jain : M. A. El-Sayed (*) Laser Dynamics Laboratory, School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA e-mail: [email protected] I. H. El-Sayed Department of Otolaryngology—Head and Neck Surgery, Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143, USA M. A. El-Sayed University of California, Berkeley, CA 94720, USA

viz. plasmonic photothermal therapy (PPTT). The synthetic tunability of the optothermal properties and the biotargeting abilities of the plasmonic gold nanostructures make the PPTT method furthermore promising. In this review, we discuss the development of the PPTT method with special emphasis on the recent in vitro and in vivo success using gold nanospheres coupled with visible lasers and gold nanorods and silica–gold nanoshells coupled with near-infrared lasers. Keywords Surface plasmon resonance (SPR) . Plasmonic photothermal therapy (PPTT) . Cancer . Gold nanospheres . Gold nanorods . Gold nanoshells . Immunotargeting

Introduction The use of heat has become one of the major methods for tumor therapy since its ancient usage in 1700 BC when a glowing tip of a firedrill was used for breast cancer therapy [1]. Later heating sources ranging from radiofrequency [2–5] to microwaves [6–9] as well as ultrasound waves [10–12] were introduced to induce moderate heating in a specific target region, which is termed as hyperthermia. Hyperthermia is commonly defined as heating tissue to a temperature in the range 41–47°C for tens of minutes [13]. Tumors are selectively destroyed in this temperature range because of their reduced heat tolerance compared to normal tissue, which is due to their poor blood supply. Hyperthermia causes irreversible cell damage by loosening cell membranes and denaturing proteins. But the applications of the heating sources conventionally employed for hyperther-

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mia are limited because of their damage to surrounding healthy tissues. A revolution in cancer therapy has taken place by the emerging use of laser light to achieve controlled and confined thermal damage in the tumor tissue. Laser, the acronym for light amplification by the stimulated emission of radiation [14], is an optical source that emits photons in a coherent and narrow beam. It was proposed in 1959 [14] and first demonstrated in 1960 [15]. Laser usage in surgery was first reported by ophthalmologists in 1963 [16] and then reported for tumor eradication in 1965 [17] followed by wide interest in late 1960s [18–20]. The laser light, usually neodymium–yttrium aluminum garnet (Nd–YAG, 1.06 um) and CO2 laser (10.6 um) [21–25] can either be transmitted from optical fiber tip to exposed tumors in the air or delivered into a confined space by inserting the bare end of the fiber into the center of the target tumor, which is often called interstitial laser hyperthermia [26–30]. Laser light has the characteristics of monochromaticity, coherence, and collimation [31–33]. These properties provide a narrow beam of high intensity, which transmits deep down into the target tissue with minimal power loss and great precision. The biggest disadvantage of laser therapy is its nonselectivity. Both normal and tumor cells in the path of the laser light are damaged. The requirement of the high power density is another problem. High power laser output up to tens to hundreds of watts has to be used to efficiently induce the tumor oblation [23]. Another type of tumor therapy method is the photodynamic therapy (PDT), also known as photochemotherapy [34–41], which involves cell destruction caused by means of toxic singlet oxygen and/or other free radicals that are produced from a sequence of photochemical and photobiological processes. These processes are initiated by the reaction of a photosensitizer with tissue oxygen upon exposure to a specific wavelength of light in the visible or near-infrared (NIR) region. The earliest sensitizer used was acridine, which was reported in 1900 to kill paramecia [42] and followed by eosin for skin cancer treatment in 1903 [43]. Although many chemicals have been later reported for photochemical therapy, porphyrin-based sensitizers [44–49] lead the role in clinical applications because of their preferential retention in cancer tissues and due to the high quantum yields of singlet oxygen produced. The Photofrin® [50], which is a purified hematoporphyrin derivative, has been approved for clinic trials by the US Food and Drug Administration. Porphyrin-based therapy can only be used for tumors on or just under the skin or on the lining of internal organs or cavities because it absorbs light shorter than 640 nm in wavelength. For deep-seated tumors, second generation sensitizers, which have absorbance in the NIR region, such as core-modified porphyrins [51], chlorins [52] phthalocyanine [53], and naphthalocyanine

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[54], have been introduced. A major drawback of PDT is that the photosensitizing drug stays in the body for a long time, rendering the patient to be highly sensitive to light. An alternative to PDT is the photothermal therapy (PTT) in which photothermal agents are employed to achieve the selective heating of the local environment [55–61]. When the PTT agents absorbs light, electrons make transitions from the ground state to the excited state. The electronic excitation energy subsequently relaxes through nonradiative decay channels. This results in the increase in the kinetic energy leading to the overheating of the local environment around the light absorbing species. The heat produced can be employed for local cell or tissue destruction [62–65]. The photoabsorbing agents can be natural chromophores in the tissue [66–71] or externally added dye molecules such as indocyanine green [72, 73], naphthalocyanines [74], and porphyrins coordinated with transition metals [75]. Natural chromophores, however, suffer from very low absorption. The choice of the exogenous photothermal agents is made on the basis of their strong absorption cross sections and highly efficient light-to-heat conversion. This greatly reduces the amount of laser energy required to achieve the local damage of the diseased cells, rendering the therapy method less invasive. But the problem with dye molecules is their photobleaching under laser irradiation. In recent years, the tremendous development of nanotechnology has provided a variety of nanostructures with unique optical properties that are useful in biology and biomedicinal applications [76–83]. From the point of the view of cancer therapeutics, noble metal nanoparticles become very useful as agents for PTT on account of their enhanced absorption cross sections, which are four to five orders of magnitude larger than those offered by conventional photoabsorbing dyes. This strong absorption ensures effective laser therapy at relatively lower energies rendering the therapy method minimally invasive. Additionally, metal nanostructures have higher photostability, and they do not suffer from photobleaching. Currently, gold nanospheres [84–91], gold nanorods [92–95], gold nanoshells [96–99], gold nanocages [100, 101], and carbon nanotubes [102] are the chief nanostructures that have been demonstrated in photothermal therapeutics due to their strongly enhanced absorption in the visible and NIR regions on account of their surface plasmon resonance (SPR) oscillations. Of these structures, the first three nanostructures (see Fig. 1) are especially promising because of their ease of preparation, ready multi-functionalization, and tunable optical properties. In the present review, we discuss the photothermal properties of these plasmonic nanostructures and their application in selective PTT. We propose the name plasmonic photothermal therapy (PPTT) for this treatment to distinguish it from PTT and PDT.

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Fig. 1 Plasmonic gold nanostructures commonly used for PPTT. a Nanospheres (transmission electron microscopy [TEM] image reproduced with permission from [110]; b nanorods (TEM image

reproduced with permission from [115]); c Nanoshells (TEM image reproduced with permission from [97])

Photothermal properties of plasmonic gold nanoparticles

520 nm due to the transverse electronic oscillation [109, 111, 112, 114–118]. Unlike spherical nanoparticles, the absorption spectrum of the gold nanorods is very sensitive to the aspect ratio (length/width). With an increase in the nanorod aspect ratio, the SPR absorption wavelength maximum of the longitudinal band significantly redshifts (Fig. 2b). Similarly, when the solid gold nanospheres are changed to gold shell structures, the absorption maximum also greatly redshifts. In 1998, Halas and coworkers at Rice University [119] developed the gold nanoshell structure, which is composed of a silica core (100–200 nm in diameter) surrounded by a thin layer of gold shells (5–20 nm). The nanoshells absorb and scatter strongly in the NIR region [120]. The optical resonance of the nanoshells can be tuned by adjusting the ratio of the thickness of the gold shell to the diameter of the silica core (Fig. 2c). It has been shown that the smaller this ratio, the more redshifted is the SPR wavelength [97]. The photothermal properties of gold nanoparticles have been systematically studied using femtosecond transient absorption spectroscopy by Link and El-Sayed [111], who have shown that the photoexcitation of metal nanostructures results in the formation of a heated electron gas that subsequently cools rapidly within ∼1 ps by exchanging energy with the nanoparticle lattice. This is followed by phonon–phonon interactions where the nanoparticle lattice cools rapidly by exchanging energy with the surrounding

In 1857, Faraday [103] made colloidal gold for the first time by reducing gold chloride with phosphors and recognized that the reddish color was due to the small size of the colloidal gold particles. In 1951, Turkevich et al. [104] simplified the method by using sodium citrate as reducing agents. Since then, the interaction between light and gold nanoparticles has been widely studied [105–112]. Gold nanoparticles absorb light strongly in the visible region due to the coherent oscillations of the metal conduction band electrons in strong resonance with visible frequencies of light. This phenomenon is known as the SPR [105–113]. The SPR frequency is dependent on the type of the metal, the size and shape of the metal nanoparticles, as well as the dielectric constant of the surrounding medium, thus imparting a unique optical tunability to the nanostructures. When the size increases, the surface plasmon absorption maximum slightly redshifts (Fig. 2a). When the nanoparticles form assemblies or aggregates, the surface plasmon absorption maximum redshifts to the NIR region. Interestingly, when the shape of the gold nanoparticles is changed from sphere to rod, the SPR spectrum splits into two bands: a stronger long-wavelength band in the NIR region due to the longitudinal oscillation of electrons and a weaker short-wavelength band in the visible region around

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Fig. 2 Size, shape, and composition dependence of the surface plasmon absorption spectrum of plasmonic gold nanostructures. a Nanospheres of different sizes (reproduced with permission from [110]); b nanorods of different aspect ratios (reproduced with permission from [118]); c nanoshells of different shell thicknesses (reproduced with permission from [97])

medium on the timescale of ∼100 ps. This fast energy conversion and dissipation can be readily used for the heating of the local environment by using light radiation with a frequency strongly overlapping with the nanoparticle SPR absorption band. The intense SPR-enhanced absorption of gold nanoparticles makes the photothermal conversion process highly efficient. The absorption cross section of gold nanoparticles [121] is typically four to five orders of magnitude stronger than the strongest absorbing Rhoda-

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mine 6G dye molecules [122]. Hot electron temperatures of several thousand kelvins are easily reached in the nanoparticles even with laser excitation powers as low as 100 nJ and the lattice temperature on the order of a few tens of degrees can be achieved [111]. This highly efficient production of heat energy from the absorbed light energy by gold nanoparticles make them greatly promising in the PPTT of cancers and other diseases. Further, in the case of gold nanorods and gold nanoshells, this strong absorption can be tuned to the NIR region (Fig. 2b,c), a region where light penetration is optimal due to minimal absorption from tissue chromophores and water [123]. This makes NIR-resonant gold nanostructures very useful for clinical therapy applications involving tumors located deep within bodily tissue. In addition to the local heating of the surrounding environment, which leads to irreversible cell destruction through protein denaturation and coagulation as well as cell membrane destruction, bubble formation around gold nanoparticles is also involved in the case of short pulse laser irradiation, which imposes mechanical stress leading to cell damage. Irradiation with short laser pulses has been shown to lead to the rapid heating of the particles and vaporization of a thin layer of fluid surrounding each particle, producing a microscopic version of underwater explosion and cavitation bubble formation [84–86, 88, 124, 125]. Zharov et al. [88] also found that nanoclusters formed by the assembly of gold nanoparticles on human breast cancer cells significantly enhance the bubble formation causing more efficient cancer cell killing. Very recently Khlebtsov et al. theoretically simulated the photothermal conversion efficiency of the different nanostructures including gold nanospheres, gold nanorods, gold nanoshells, linear chains, 2D arrays, and 3D clusters [91] by calculating their SPR absorption spectra. It was found that gold spheres with diameters of about 30–40 nm are most preferable, as their normalized absorption is maximal in the visible spectrum region. The nanorods with length between 15 and 70 nm were predicted to be most efficient. Of course, it would also be required that the longitudinal absorption maximum be matched to the wavelength of the NIR laser to get optimal photothermal efficiency. Gold nanoshells with external diameters of about 50–100 nm and gold shell thicknesses of about 4–8 nm are estimated to be the most effective due to the strong absorption and low scattering near 800 nm.

Bioconjugation and targeting Most laser-based therapeutic methods rely on the use of endoscopes and fiber optic catheters to deliver light specifically to the tumor region and intravenously admin-

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istered photosensitizers/absorbers to achieve selectivity. However, the use of immunotargeting strategies to deliver the photodynamic or photothermal agents selectively to the diseased cells and tissue offers an efficient route to achieving selectivity and reducing nonspecific injury to healthy cells. Metal, especially gold, nanoparticles allow easy biofunctionalization, thus making them promising for integration with immunotargeting strategies. The selectivity of gold nanostructures for photothermal cancer therapy has been demonstrated by their functionalization with specific tumor-targeting molecules. Two targeting strategies are commonly used. One involves nanoparticles passivated by poly (ethylene) glycol (PEG), and the other employs nanoparticles conjugated to antibodies specific to biomarkers on the diseased cells. PEG is used to increase the biocompatibility and biostability of nanoparticles and impart them an increased blood retention time. Citrate-capped gold nanospheres, cetyl trimethylammonium bromide (CTAB)-capped gold nanorods, as well as gold nanoshells have poor stability when they are dispersed in buffer solution due to the aggregating effect of salt ions. By capping the nanoparticles with PEG, the biocompatibility is greatly improved, and nanoparticle aggregation is prevented. PEGylated nanospheres and nanorods can be readily made by the conjugation of thiol-functionalized PEG with the gold nanoparticles [126, 127]. In case of in vivo applications, PEGylated nanoparticles are preferentially accumulated into tumor tissues due to the enhanced permeability and retention effect, known as the “golden standard” for drug design [128–135]. Compared to normal tissue, the blood vessels in tumor tissue are more leaky, and thus, macromolecular or polymeric molecules preferentially extravasate into tumor tissue. Due to the decreased lymphatics, the tumor tissue retains large molecules for a longer time, whereas normal tissue quickly clears out the external particles. This tumor targeting method is called passive targeting as against the antibody-targeting method [128–135]. The antibody based targeting is more active, specific and efficient. The antibodies are selected to target a specific tumor marker. For instance, anti-epidermal growth factor receptor (EGFR) antibodies can be employed to target overexpressed EGFR on oral cancer cells [89, 90, 92] and cervical cancer cells [136, 137], anti-Her2 for overexpressed Her2 on breast cancer cells [99] and seprase on breast cancer cells [88]. The binding of antibodies to gold nanospheres was first reported in the 1950s when antibodies were used for the staining of cellular components by electron microscopy [138]. The antibodies are generally bound to negatively charged citrate-capped gold nanospheres by nonspecific interactions by adjusting the pH of the colloidal solution to be just above the isoelectric point (pI, zero net charge of the protein) of the antibody such that

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the antibody has an small net negative charge. The antibodies are thus nonspecifically adsorbed onto gold nanoparticles while still keeping the nanoparticles negatively charged, providing stability in colloidal solution. In recent years, Sokolov et al. [136, 137] used this method to bind anti-EGFR to gold nanospheres, which were then used as optical labels to detect the overexpressed EGFR on ovarian cancer cells by light scattering imaging using a single wavelength laser. El-Sayed et al. [139] used the same method to bind anti-EGFR to gold nanospheres and realized both diagnostics using dark field microscopy and therapy of oral cancer cells using a 514 nm argon ion laser [89]. Gold nanorods are capped with CTAB molecules, which are positively charged [140]. As antibodies are slightly negatively charged at pH=7.4, antibodies can be adsorbed onto gold nanorods by electrostatic interactions. However, this causes particle aggregation in solution due to the neutralization of the surface charge. For the binding of antibodies to gold nanorods solution, the surface charge is reversed by adsorption of a PSS− layer [141, 142]. Then, the antibodies are adsorbed onto the PSS− layer probably by hydrophobic interactions while still stabilizing the nanorods by the negative charge on the antibodies [141, 142]. Figure 3a shows the scheme of the antibody binding to gold nanorods through a PSS bridging layer. Another method is the use of chemical binding between a functional group on the antibodies and the metal surface of the nanoparticles [143]. The covalent binding of the thiol group to gold is used very commonly for nanoparticle surface bioconjugation. In the work by Liao et al. [126] the antibodies were bound to nanorods with a long chain succinimidyl 6-[3′-[2-pyridyldithio]-propionamido] (LCSPDP) cross-linker hexanoate (see Fig. 3b). LC-SPDP consists of a pyridildithio group that binds to the gold nanorod surface, and an N-hydroxysuccinimide (NHS) ester, which binds to the primary amines in the antibodies. For nanoshell bioconjugation [99], antibody molecules are first bound to a PEG linker orthopyridyl-disulfide (OPSS)–PEG–NHS through an amidohydroxysuccinimide group (NHS). The antibody-PEG linker complex is then attached to the nanoshell surface through the sulfur-containing OPSS group located at the distal end of the PEG linker. In addition to antibodies, folic acid can also be used for active tumor targeting because cancer cells require excessive folic acid, which is a ligand for folate receptors [95, 102, 144, 145]. Wei and coworkers [95] have conjugated folate ligands with oligoethyleneglycol spacers to gold nanorods by in situ dithiocarbamate formation. The folateconjugated gold nanorods were found to specifically bound to the surface of KB cancer cells. Thus, there exist a variety of surface chemistry techniques that can be utilized for designing biofunctionalized nanoparticles targeted to the disease biomarker of choice.

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PPTT by visible lasers In 1999, Lin et al. [125] first reported the selective PTT based on the use of light-absorbing microparticles that absorb light in the visible region. In 2003, they demonstrated selective PPTT using gold nanoparticle immunoconjugates [84]. Lymphocytes incubated with gold nanoparticles conjugated to antibodies and then exposed to short laser pulses (565 nm wavelength, 20 ns duration) showed cell death with 100 laser pulses at an energy of 0.5 J/cm2. The cell death is attributed mainly to the cavitation bubble formation around the nanoparticles. By adjusting the particle number, size, and laser energy, the researchers were able to selectively induce cell death or transiently modify cellular functions without causing cell destruction. In the same year, Zharov et al. [85] studied the threshold and the dynamics of thermal events around the particles incorporated into K562 cancer cells using nanosecond Nd–YAG laser at 532 nm and a photothermal contrast technique. They found that, at an energy level of 2–3 J/cm2, only one or three laser pulses are sufficient to damage a cell containing 10–15 particles of 20 nm size, whereas at a lower fluence rate of 0.5 J/cm2, at least 50 pulses and approximately 100 particles are required to produce the same harmful effects on the cells. Recently, El-Sayed and coworkers [89, 90] demonstrated selective PPTT by using gold nanoparticles with a visible continuous wave (CW) laser. In these studies, 40 nm gold nanoparticle were conjugated to anti-EGFR antibodies and then incubated with both human oral cancer cells and nonmalignant skin cells for 30 min. By using dark field light scattering imaging and surface plasmon absorption Fig. 3 Antibody conjugation of gold nanorods. a Gold nanorods are coated with PSS polyelectrolytes and antibodies are adsorbed onto PSS by nonspecific interactions; b antibodies are covalently bound to the rod surface by LC-SPDP crosslinker (reproduced with permission from [126])

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spectroscopy, it was found that gold nanoparticles were preferentially and specifically bound to the cancer cells, while only a heterogeneous nonspecific distribution of the nanoparticles was seen over the healthy cells [139]. The nanoparticle-labeled cells were then exposed to a CW argon ion laser at 514 nm [89]. It was found that the malignant cells required less than half the laser energy to be killed as compared to the benign cells (see Fig. 4, [89]). No photothermal destruction was observed for any of the cell types without nanoparticle labeling, even at four times the energy required to kill the malignant cells labeled with antiEGFR/gold nanoparticle conjugates. This selective photodamage of the cancer cells is clearly attributed to the higher gold nanoparticle loading on cancer cells due to the overexpressed EGFR on the cancer cell surface. Higher gold nanoparticle labeling results in a consequently higher optical density. Thus, a lower laser energy is required to raise the temperature above the threshold for destruction, as estimated to be in the range of 70–80°C [90]. This method can be extended to other types of cancers as well because most types of cancer cells have an overexpression of EGFR receptors. However, the use of visible light absorbing nanospheres is restricted to skin or near-surface type cancers due to the inability of visible light to penetrate through skin and tissue.

PPTT by NIR lasers For in vivo therapy for tumors under skin and deeply seated within tissue, NIR light is required because of its deep penetration due to minimal absorption of the hemoglobin

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Fig. 4 Selective PPTT for cancer cells by using anti-EGFR conjugated gold nanospheres (reproduced with permission from [89]). After incubation with anti-EGFR conjugated gold nanoparticles, HaCat normal cells are destroyed at a laser power threshold of 57 W/cm2, while HSC and HOC cancer cells are destroyed at much lower thresholds of 25 and 19 W/cm2, respectively. The difference reflects the much larger density of anti-EGFR conjugated gold nanospheres on the surface of the cancer cells compared to that on the normal cells due to the selective targeting of EGFR overexpressed on cancer cells

and water molecules in tissues in this spectral region. Carbon nanotubes have optical absorbance in the NIR window [146] and, thus, have potential for NIR PTT. Dai and coworkers [102] achieved selective cancer cell destruction by the functionalization of single-walled carbon nanotubes with a folate moiety that selectively targets the folate receptors on tumor cells, while the receptor-free normal cells are unaffected. Gold nanorods and nanoshells have been demonstrated for selective PPTT using CW NIR lasers mainly by the ElSayed [92] and Halas groups [96, 99], respectively. By using dark-field light scattering imaging, El-Sayed and coworkers found that gold nanorods conjugated to antiEGFR antibodies were well organized on the surface of cancer cells with relatively higher binding affinity, while they were randomly distributed nonspecifically on and around the normal cells, similar to the case of the gold nanospheres [92, 139]. A CW Ti:Sapphire laser with a wavelength at 800 nm, overlapping with the SPR absorption wavelength maximum of gold nanorods at 800 nm, was used for the photoirradiation of the cells labeled with the nanorods. It was found that the cancer cells required half the laser energy (10 W/cm2) to be photothermally

damaged as compared to the normal cells (20 W/cm2), as attributed to the selective targeting of the overexpressed EGFR on the cancer cell surface by the anti-EGFRconjugated gold nanorods (Fig. 5). Later, Takahashi et al. [93] in Japan achieved cell death using phosphatidylcholine-passivated gold nanorods and a pulsed Nd–YAG laser at 1,064 nm. Recently, Wei and coworkers at Purdue University [95] demonstrated that gold nanorods conjugated to folate ligands can be used for hyperthermic therapy of KB oral cancer cells with a CW Ti:Sapphire laser. Severe blebbing of cell membranes was observed at laser irradiation with power density as low as 30 J/cm2. The work by Halas and coworkers has shown that gold nanoshells can be used for PPTT in the NIR region by both passive cancer targeting using PEG-conjugated nanoshells [96–98] and active targeting using antibody-conjugated nanoshells [99]. In the antibody case [99], gold nanoshells conjugated through PEG linkers to anti-Her2 antibodies were employed for targeting breast cancer cells. A diode laser at 820 nm was used for photothermal heating (7 min) of the labeled cells (Fig. 6). Only the cancer cells incubated with the antibody conjugated gold nanoshells were dam-

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Fig. 5 Selective PPTT for cancer cells in the NIR region by using anti-EGFR conjugated gold nanorods (reproduced with permission from [92]). After incubation with anti-EGFR conjugated gold nanorods, HaCat normal cells are destroyed at a laser power threshold of 20 W/ cm2, while HSC and HOC cancerous cells are destroyed at a much lower threshold of 10 W/ cm2. The difference reflects the much larger density of gold nanorods on the surface of the cancer cells compared to that on the normal cells

aged under the laser irradiation. In the PEG case [96], the researchers demonstrated successful PTT both in vitro and Fig. 6 Selective PPTT for cancer cells by using anti-Her2 antibody conjugated gold nanoshells (reproduced with permission from [99]). Only the cells incubated with anti-Her2 antibody conjugated gold nanoshells are damaged under NIR irradiation

in vivo. For in vivo therapy, the researchers achieved successful targeting using the PEGylated gold nanoshells

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injected directly into the tumor region [96] or delivered intravenously [98]. It was shown that NIR light of 820 nm at 4 W/cm2 caused irreversible tumor tissue damage. Most notably, these studies show that laser dosages required to induce tissue damage using the plasmonic gold nanostructures are 10- to 25-fold lower than those used in studies employing photoabsorbing dyes such as indocyanine green dye.

Summary Plasmonic gold nanostructures thus show great promise for the selective PTT for cancer as well as other diseases. We propose the name PPTT for this treatment. It is realized that a number of variables need to be further addressed, e.g., stability, biocompatibility, and chemical reactions of nanoparticle bioconjugates in physiological environments, blood retention time, tumor extravasation, the fate of the nanoparticles following therapy, etc. We anticipate that the success and promise of the initial use of plasmonic nanoparticles for selective PPTT could be efficiently extended to clinical stage once the optimal parameters of these variables are identified, as is being done through current research studies.

Acknowledgment We thank the financial support of NCI Center of Cancer Nanotechnology Excellence (CCNE) Award (U54CA119338).

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