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Cite this: Chem. Soc. Rev., 2012, 41, 2256–2282 www.rsc.org/csr

CRITICAL REVIEW

Gold nanoparticles in biomedical applications: recent advances and perspectives Lev Dykmana and Nikolai Khlebtsov*ab Received 19th June 2011 DOI: 10.1039/c1cs15166e Gold nanoparticles (GNPs) with controlled geometrical, optical, and surface chemical properties are the subject of intensive studies and applications in biology and medicine. To date, the ever increasing diversity of published examples has included genomics and biosensorics, immunoassays and clinical chemistry, photothermolysis of cancer cells and tumors, targeted delivery of drugs and antigens, and optical bioimaging of cells and tissues with state-of-the-art nanophotonic detection systems. This critical review is focused on the application of GNP conjugates to biomedical diagnostics and analytics, photothermal and photodynamic therapies, and delivery of target molecules. Distinct from other published reviews, we present a summary of the immunological properties of GNPs. For each of the above topics, the basic principles, recent advances, and current challenges are discussed (508 references).

1. Introduction Gold was one of the first metals discovered by humans, and the history of its study and application is estimated to be a minimum of several thousand years old. The first information a

Institute of Biochemistry and Physiology of Plants and Microorganisms, RAS, 13 Pr. Entuziastov, Saratov 410049, Russian Federation. E-mail: [email protected] b Saratov State University, 83 Ul. Astrakhanskaya, Saratov 410012, Russian Federation

Dr Lev A. Dykman, leading researcher of the Immunochemistry Lab at the Institute of Biochemistry and Physiology of Plants and Microorganisms Russian Academy of Sciences. He has published more than 200 scientific works including one monograph on colloidal gold nanoparticles. His current scientific interests include immunochemistry, fabrication of gold nanoparticles and their applications to biological and medical Lev Dykman studies. In particular, his research is aimed at interaction of nanoparticles and conjugates with immune-responsible cells and at the delivery of engineered particles to target organs, tissues, and cells.

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on colloidal gold can be found in tracts by Chinese, Arabic, and Indian scientists, who obtained colloidal gold as early as in the fifth and fourth centuries B.C. and used it, in particular, for medical purposes (the Chinese ‘‘gold solution’’ and the Indian ‘‘liquid gold’’). In the Middle Ages in Europe, colloidal gold was studied and employed in alchemists’ laboratories. Specifically, Paracelsus wrote about the therapeutic properties of quinta essentia auri, which he prepared by reducing auric chloride with alcohol or oil plant extracts. He used ‘‘potable gold’’ to treat some mental

Professor Nikolai G. Khlebtsov, head of the Nanobiotechnology Lab at the Institute of Biochemistry and Physiology of Plants and Microorganisms Russian Academy of Sciences. He also holds a Biophysics Chair at the Saratov State University. He has published more than 300 scientific works, including two monographs. His current scientific interests include biophotonics and nanobiotechnology of plasmon-resonant particles, Nikolai Khlebtsov biomedical applications of metal nanoparticles, static and dynamic light scattering by small particles and clusters, programming and computer simulation of light scattering and absorption by various metal and dielectric nanostructures. Prof. Khlebtsov also serves as an Associate Editor of the Journal of Quantitative Spectroscopy and Radiative Transfer. This journal is

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disorders and syphilis. Paracelsus once proclaimed that chemistry is for making medicines, not for making gold out of metals. His contemporary Giovanni Andrea applied aurum potabile to the treatment of lepra, ulcer, epilepsy, and diarrhea. In 1583, alchemist David de Planis-Campy, surgeon to the King of France Louis XIII, recommended his ‘‘elixir of longevity’’—an aqueous colloidal gold solution—as a means of life prolongation. The first book on colloidal gold preserved to our days was published by philosopher and doctor of medicine Francisco Antonii in 1618.1 It contains information on the preparation of colloidal gold and on its medical applications, including practical suggestions. In 1880, a method was put forward to treat alcoholism by intravenous injection of a colloidal gold solution (‘‘gold cure’’).2 In 1927, the use of colloidal gold was proposed to ease the suffering of inoperable cancer patients.3 Colloidal gold in color reactions toward spinal-fluid and blood-serum proteins has been taken advantage of since the first half of the twentieth century.4 Colloidal solutions of the 198Au gold isotope (half-life time, 65 h) were therapeutically successful at cancer care facilities.5 More recent examples of colloidal gold applications include catalytic processes and electron transport in biomacromolecules,6 transport of substances into cells by endocytosis,7 investigation of cell motility,8 and improvement of PCR efficiency.9 Despite the centuries-old history, a ‘‘revolution in immunochemistry,’’10 associated with the use of gold particles in biological research, took place in 1971, when British researchers W. P. Faulk and G. M. Taylor published an article titled ‘‘An immunocolloid method for the electron microscope.’’11 In that article, a technique was described to conjugate antibodies with colloidal gold for direct electron microscopic visualization of Salmonella surface antigens, representing the first time that a colloidal gold conjugate served as an immunochemical marker. From this point on, the use of colloidal-gold biospecific conjugates in various fields of biology and medicine became very active. There has been a wealth of reports dealing with the application of functionalized gold nanoparticles (GNPs; conjugates with recognizing biomacromolecules, e.g., antibodies, lectins, enzymes, or aptamers)12–14 to the studies of biochemists, microbiologists, immunologists, cytologists, physiologists, morphologists, and many other specialist researchers. The range of uses of GNPs in current medical and biological research is extremely broad. In particular, it includes genomics; biosensorics; immunoassay; clinical chemistry; detection and photothermolysis of microorganisms and cancer cells; targeted delivery of drugs, peptides, DNA, and antigens; and optical bioimaging and monitoring of cells and tissues with the use of state-of-the-art nanophotonic recording systems. GNPs have been proposed for use in practically all medical applications, including diagnostics, therapy, prophylaxis, and hygiene (e.g., in water purification15). Extensive information on the most important aspects of preparation and use of colloidal gold in biology and medicine can be found elsewhere.16–30 Such a broad range of application is based on the unique physical and chemical properties of GNPs. Specifically, the optical properties of GNPs are determined by their plasmon resonance, which is associated with the collective excitation of conduction electrons and is localized in a wide region (from visible to infrared, This journal is

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Scheme 1 Generalized scheme for the biomedical application of GNPs. Along with basic applications in diagnostics and therapy, this review briefly discusses the immunological properties of GNPs.

depending on particle size, shape, and structure).31 Scheme 1 shows a simplified scheme for the current biomedical applications of GNPs, which reflects the structure of this review. However, since biodistribution and toxicity have been extensively reviewed and discussed in a number of recent publications (see, e.g., ref. 32 and references therein), we restrict ourselves to a short comment in the Conclusions section. Considering the great body of existing information and the high speed of its renewal, we chose in this review to generalize the data that have accumulated during the past few years for the most promising directions in the use of GNPs in current medical and biological research.

2. GNPs in diagnostics 2.1 Visualization and bioimaging methods GNPs have been actively used in various visualization and bioimaging methods to identify chemical and biological agents.33,34 Historically, electron microscopy (mainly its transmission variant, TEM) has for a long time (starting in 197111) been the principal method to detect biospecific interactions with the help of colloidal gold particles (owing to their high electron density). Although GNPs can intensely scatter and emit secondary electrons, they have not received equally wide acceptance in scanning electron microscopy.35 It is no mere chance that the first three-volume book on the use of colloidal gold36 was devoted mostly to the application of GNPs in TEM. A peculiarity of current use of the electron microscopic technique is the application of high-resolution transmission electron microscopes and systems for the digital recording and processing of images.37 The major application of immunoelectron microscopy in present-day medical and biological research is the identification of infectious agents and their surface antigens38–40 (Fig. 1a). The techniques often employed for the same purposes include scanning atomic-force41 (Fig. 1b), scanning electron,42 and fluorescence43 microscopies. Alongside the use of ‘‘classic’’ colloidal gold with quasispherical particles (nanospheres) as labels for microscopic studies, the past few years have seen the application of nonspherical cylindrical particles (nanorods), nanoshells, nanocages, nanostars, and other types of particles, referred to by Chem. Soc. Rev., 2012, 41, 2256–2282

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Fig. 1 TEM image of a Listeria monocytogenes cell labeled with an antibody–colloidal gold conjugate (a) and a scanning atomic-force microscopy image of tobacco mosaic virus labeled with an antibody– colloidal gold conjugate (b). Adapted from Bunin et al.39 (a) and from Drygin et al.41 (b) by permission from Springer.

the broad term ‘‘noble-metal plasmon-resonant particles’’25 (Fig. 2). Table 1 illustrates some plasmonic properties and possible biomedical applications of the gold nanomaterials shown in Fig. 2. This is by no means a detailed description of geometrical or optical parameters (size, shape, structure, absorption and scattering cross sections, their spectra, etc.). In fact, we only provide typical ranges for the major plasmon wavelength and its sensitivity to the dielectric environment in terms of plasmonic shift per refractive index unit (RIU). Accordingly, Fig. 2 and Table 1 should be considered as an attempt to show a cross section of the work in this area, rather than a comprehensive list. Recently, the popularity of visualization methods employing GNPs and optical microscopy,55 in particular confocal laser microscopy, has also been on the rise. Confocal microscopy is a technique for detecting microobjects with the aid of an optical system ensuring that light emission is recorded only when it comes from objects located in the system’s focal point. This allows one to scan samples according to height and, ultimately, to create their 3D images by superposition of scanograms. In this method, the use of GNPs and their antibody conjugates permits real-time detection of gold penetration into living (e.g., cancerous) cells at the level of a single particle and even estimation of their number.56–59 Confocal images can be obtained with, e.g., detection of fluorescence emission (confocal fluorescence microscopy) or resonance elastic or two-photon (multiphoton) light scattering by plasmonic nanoparticles (confocal resonance-scattering or two-photon luminescence microscopy). These techniques are based on detecting microobjects with the optical microscope, in which the luminescence of an object is excited owing to simultaneous absorption of two (or more) photons, the energy of each of which is lower than that needed for fluorescence excitation. The basic advantage of this method is the increase in contrast through a strong reduction in the background signal. Specifically, twophoton luminescence of GNPs enables molecular markers of cancer to be visualized on or inside cells,60–63 Bacillus spores,64 and the like. Fig. 3a shows an example of combined bioimaging of cancer cells with the help of adsorption, fluorescence, and luminescence plasmon resonance labels. Dark-field microscopy remains one of the most popular GNPaided bioimaging methods. It is based on light scattering by 2258

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microscopic objects, including those whose sizes are smaller than the resolution limit for the light microscope (Fig. 3b and c). In dark-field microscopy, the light entering the objective lens is solely that scattered by the object at side lighting (similarly to the Tyndall effect); therefore, the scattering object looks bright against a dark background. Compared with fluorescent labels, GNPs have greater potential to reveal biospecific interactions with the help of dark-field microscopy,65 because the particle scattering cross section is three to five orders of magnitude greater than the fluorescence cross section for a single molecule. This principle was for the first time employed by Mostafa El-Sayed’s group66 for their new method of simple and reliable diagnosis of cancer with the use of GNPs. The method is founded on the preferential binding of GNPs conjugated with tumor-antigen-specific antibodies to the surface of cancerous cells, as compared with binding to healthy cells. With dark-field microscopy, therefore, it is possible to ‘‘map out’’ a tumor with an accuracy of several cells (Fig. 3b and c). Subsequently, gold nanorods,67 nanoshells,68 nanostars,69 and nanocages70 were used for these purposes. The use of self-assembled monolayers or island films, as well as nonspherical and/or composite particles, opens up fresh opportunities for increased sensitivity of detection of biomolecular binding on or near the nanostructure surface. The principle of amplification of a biomolecular binding signal depends on the strong local electromagnetic fields arising near nanoparticles with spiky surface sites or in narrow (on the order of 1 nm or smaller) gaps between two nanoparticles. This determines the increased plasmon-resonance sensitivity to the local dielectric environment71 and the high scattering intensity as compared to the sensitivity and intensity of equivolume spheres. Therefore, such nanostructures show considerable promise for use in biomedical diagnostics assisted by dark-field microscopy.72–74 In dark-field microscopy, GNPs are employed for detection of microbial cells and their metabolites,75 bioimaging of cancerous cells76–78 and revelation of receptors on their surface,79,80 study of endocytosis,81 and other purposes. In most biomedical applications, the effectiveness of conjugate labeling of cells is assessed qualitatively. One of the few exceptions is the work of Khanadeev et al.,82 in which a method was suggested for the quantitative estimation of the effectiveness of GNP labeling of cells and its use was illustrated with the specific example of labeling of pig embryo kidney cells with gold nanoshell conjugates. Another approach was developed by Fu et al.83 Apart from the just mentioned ways to record biospecific interactions with the help of diverse versions of optical microscopy and GNPs, the development of other state-of-the-art detection and bioimaging methods is currently active. These are referred to collectively as biophotonic methods.31,84 Biophotonics combines all studies related to the interaction of light with biological cells and tissues. Existing biophotonic methods include optical coherence tomography,85–87 X-ray and magnetic resonance tomography,88,89 photoacoustic microscopy90 and tomography,91 fluorescence correlation microscopy,92 and other techniques. These methods also successfully use variously sized and shaped GNPs. In our opinion, biophotonic methods employing nonspherical gold particles may hold particular promise for bioimaging in vivo.34,93,94 This journal is

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Fig. 2 Various types of plasmon-resonant nanoparticles: 16 nm nanospheres (a);25 gold nanorods (b);44 gold bipyramids (c);45 gold nanorods surrounded by silver nanoshells (d);25 ‘‘nanorice’’ (gold-coated Fe2O3 nanorods) (e);46 SiO2/Au nanoshells (f)25 (the inset shows a hollow nanoshell47); nanobowls with bottom cores (g);48 spiky SiO2/Au nanoshells (h)49 (the inset shows a gold nanostar50); gold tetrahedra, octahedra, and cubooctahedra (i);51,52 gold nanocubes (j);51 silver nanocubes and gold–silver nanocages obtained from them (in the insets) (k);53 and gold nanocrescents (l).54 Adapted from the data of the cited papers by permission from The Royal Society of Chemistry, Elsevier, IOP Publishing, Springer, Wiley Interscience, and The American Chemical Society.

Table 1

Properties and possible biomedical applications of plasmonic nanoparticles

Particle

Major resonances/nm

Plasmonic shift/RIU/nm

Possible biomedical applications

Colloidal Au nanospheres (3–100 nm) Au nanorods (thickness, 10–20 nm; aspect ratio, 2–10) Au bipyramids Au(core)/Ag(shell) NRs Fe2O3 (core)/Au (shell) nanorice SiO2(core)/Au(shell)

510–570 650–1200 650–1100 550–1000 1100–1300 600–1100

45–90 150–290 150–540 — 790–810 160b 315c 125 — — 240–665 — 83 410–620 240–880

EM, OI, HA, SA, PPT,a DC OI, OA, PPT, HIA, OI, BS OI, SERS SERS, BS

Hollow Au shell Nanobowls Spiky SiO2 nanoshells and Au nanostars Au polyhedralsd Au cubes Au–Ag nanocages Au nanocrescentse

560–1000 600–850, 675–770 550–750 550–700 450–1000 980–2600

OI, SA, PPT OI, PPT SERS OI, SERS EM, OI EM, OI OIA, BS, SERS, PPT BS

Designations: RIU—refractive index unit, EM—electron microscopy, OI—optical imaging, HA—homogeneous assays, SA—solid phase assays, PPT—plasmonic photothermal therapy, DC—drug carriers, OA—optoacoustical applications, BS—biosensing, SERS—surface enhanced Raman scattering. a PPT applications of clusterized Au nanospheres. b Monolayer data. c Suspension data. d Tetrahedra, octahedra, and cubooctahedra. e Nanolithography array.

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Fig. 3 Confocal image of HeLa cells in the presence of GNPs (a). Blue, the nuclei stained with Hoechst 33258; red, the actin cytoskeleton labeled with Alexa Fluor 488 phalloidin; green, unlabeled GNPs. The image was taken by two-photon microscopy.63 Dark-field microscopy of cancerous (b) and healthy (c) cells by using GNPs conjugated with antibodies to epidermal growth factor.66 Adapted from the data of the cited papers by permission from The American Chemical Society.

2.2

Analytical diagnostic methods

2.2.1 Homophase techniques. Beginning in 1980s, colloidal gold conjugated with recognizing biomacromolecules was coming into use in various analytical methods in clinical diagnostics. In 1980, Leuvering et al.95 put forward a new immunoanalysis method that they called sol particle immunoassay (SPIA). A new SPIA version was advanced by Mirkin et al.96 for the colorimetric detection of DNA. Both versions (protein and DNA SPIA) use two principles: (1) The sol color and absorption spectrum change little when biopolymers are adsorbed on individual particles.25 (2) When particles move closer to each other to distances smaller than 0.1 of their diameter, the red color of the sol changes to purple or gray and the absorption spectrum broadens and red-shifts.97 This change in the absorption spectrum can easily be detected spectrophotometrically or visually (Fig. 4a and b98,99). The authors employed an optimized variation of SPIA (by using larger gold particles and monoclonal antibodies to various antigenic sites) to detect human chorionic gonadotropin.100 Subsequently, the assay was used for the immunoanalysis of Shistosoma101 and Rubella102 antigens; estimation of immunoglobulins,103,104 thrombin (by using aptamers),105 and glucose;106 direct detection of cancerous cells;107 detection of Leptospira cells in urine;108 detection of Alzheimer’s disease markers;109 determination of protease activity;110 and other purposes. The simultaneous use of antibody conjugates of gold nanorods and nanospheres for the detection of tumor antigens was described by Liu et al.111 Wang et al.112 provided data on the detection of hepatitis B virus in blood with gold nanorods conjugated to specific antibodies. All SPIA versions proved easy to implement and were highly sensitive and specific. However, investigators came up against the fact that antigen–antibody reactions on sol particles do not necessarily lead to system destabilization (aggregation). Sometimes, despite the obvious complementarity of the pair, changes in solution color (and, correspondingly, in absorption spectra) were either absent or slight. Dykman et al.113 presented a model for the formation of a second protein layer on gold particles without loss of sol aggregative stability. The spectral changes arising from biopolymer adsorption on the surface of metallic particles are comparatively small114 (Fig. 4c and d). However, as 2260

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Fig. 4 Sol particle immunoassay. (a) Scheme for the aggregation of conjugates as a result of binding by target molecules and (b) the corresponding changes in the spectra and in sol color. (c) Scheme for the formation of a secondary layer without conjugate aggregation and (d) the corresponding differential extinction spectra at 600 nm. Adapted from the data of Khlebtsov et al.,97 Wu et al.,98 and Englebienne115 by permission from The American Chemical Society and The Royal Society of Chemistry.

shown by Englebienne,115 even such minor changes in absorption spectra, resulting from a change in the structure of the biopolymer layer (specifically, its average refractive index) near the GNP surface, could be recorded and used for assay in biological applications. For increasing the sensitivity of the analytical reaction, new interaction-recording techniques have been proposed, including photothermal spectroscopy,116 laser-based double beam absorption spectroscopy,117 hyper-Rayleigh scattering,118 differential lightscattering spectroscopy,119 and dynamic light scattering.120 In addition, two vibrational spectroscopy methods—surface enhanced infrared absorption spectroscopy121 and surface enhanced Raman spectroscopy122—have been suggested for use in SPIA. The ability of gold particles interacting with proteins to aggregate with a solution color change served as a basis for the development of a colorimetric method for protein determination.123 A new SPIA version using microplates and an ELISA reader, with colloidal-gold-conjugated trypsin as a specific agent for proteins, was devised by Dykman et al.124 This journal is

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Table 2

Detection of DNA with the use of gold nanoparticles


Particles

Probe

Target

Detection method

Detection limit

Ref.

ssDNA

Cross-linking aggregation, UV–AS, spot test

10 fmol

125, 1997

5 0 -SH–(dT)10-3 0

Biotinylated PCR product

2 fmol (500 copies of PSA cDNA)

126, 2003

5 0 -N15–(CH2)10–SH-3 0 a; 5 0 -SH–(CH2)10–N15-3 0 b 5 0 -N15–C-3 0 –(CH2)3SH; HS(CH2)6–5 0 -N18-3 0 5 0 -HS–N16-3 0

ssDNA

500 zmol (10 copies in 30 mL) 100–250 nM; 1–2 nM 300 nM

127, 2004

1-round PCR product ssDNA

Hybridization of targets with poly-A and streptavidin followed by a strip test with GNSs Bio-bar-code assay, scanometric detection of silver-enhanced spots Non-cross-linking aggregation in 1 M NaCl, VE, spot test Stabilization of nanoprobes by targets in 2M NaCl, VE, UV–AS Aggregation, DLS

128, 2006; 140, 2005 129, 2006

5 pM

130, 2008

ssDNA

SERS

10 zM

136, 2010

ssDNA

Fluorescence quenching/retaining with nontarget/target ssDNA Stabilization/aggregation with nontarget/target ssDNA, UV–AS Aggregation in the case of nontarget molecules, VE, UV–AS

0.5 pM

133, 2004

2 pM

134, 2004

1 pM (DNA); 10 nM (thrombin); 10 mM (cocaine); 50 mM (Hg) 10 pM

144, 2010

1.7 nM

135, 2008

0.1 pM

145, 2010

0

5 -HS–(CH2)6–N13–N15-3

Modified GNSs (GNSs with chemically attached probes)

0

5 0 -N12–C3–SS-3 0 ; 5 0 -SS–C6–N15-3 0 5 0 -SH–(CH2)6–N15-3 0 ; 5 0 -Rox–N15–(CH2)3–SH-3 0 Rhodamine red–5 0 -N15-3 0

Unmodified GNSs

0

5 -N15-3

ssDNA, aptamers + conjugated polyelectrolytec

ssDNA, PCR product ssDNA, thrombin, cocaine, Hg

5 0 -N21-3 0 , 5 0 -N23-3 0

ssDNA

0

ssDNA

Aggregation of positively charged GNSs, UV–AS, DLS Aggregation, UV–LS

5 0 -N30-3 0

ssDNA

Aggregation (optimized), UV–AS

0

5 -N21-3

Unmodified GNRs

0

PCR product

44, 2011

Designations: Nm—m-bases oligonucleotide; GNSs—gold nanospheres (colloidal gold nanoparticles with a roughly spherical shape); UV–AS—UV–vis absorption spectroscopy; VE—visual evaluation; UV–LS—UV–vis light scattering spectroscopy; PSA—prostate-specific antigen; DLS—dynamic light scattering; GNRs—gold nanorods. a Particle probe. b Substrate probe. c Poly [(9,9-bis (60 -N,N,N-trimethylammonium)hexyl)fluorene-alt-1,4-phenylene] bromide.

At present, colorimetric DNA detection includes two strategies: (1) The use of GNPs conjugated with thiol-modified ssDNA96,125–130 or aptamers.131 (2) The use of unmodified GNPs132–135 (Table 2). The first strategy is based on the aggregation of conjugates of 10–30 nm GNPs with thiol-modified ssDNA probes after the addition of target polynucleotides to the system. A crosslinking variant of the first strategy uses two types of probes complementary to both terminal target sites. Hybridization of the targets and probes leads to the formation of GNP aggregates, which is accompanied by a change in the absorption spectrum of the solution and can readily be detected visually, photometrically,137 or by dynamic light scattering.130,138 In contrast to the cross-linking aggregation, Maeda and coworkers139,140 developed a non-cross-linking diagnostic system involving GNP conjugates of only one type, with 3 0 or 5 0 thiolmodified probes. The aggregation of GNPs occurred at high ionic strength (1 M NaCl) and only with complementary probes and targets, whereas noncomplementary targets prevented aggregation. Contrary to the observations of the Maeda group,139 Baptista et al.129,141 reported enhanced colloidal stability after the addition of complementary targets to a DNA conjugate solution even at high ionic strength (2 M NaCl), whereas noncomplementary targets did not prevent aggregation at 2 M NaCl. The apparent contradictions between these data were explained by This journal is

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Song et al.142 through the difference in surface functionalization density. Consider now the second DNA-sensing strategy, which utilizes unmodified GNPs. This approach is based on the observation by Li and Rothberg133 that at high ionic strength, ssDNA protects unmodified gold nanoparticles from aggregation, whereas dsDNA does not. This method was employed by Shawky et al.143 to detect hepatitis C virus. Recently, Xia et al.144 described another variant of the second strategy, which uses ssDNA, unmodified GNPs, and a cationic polyelectrolyte. All the above-cited reports on DNA detection used citratestabilized anionic GNPs. He et al.135 described a new version of unmodified-particle assay employing as-prepared positively charged CTAB-coated gold nanorods. After mixing nanorods with the probe and target ssDNA under appropriate hybridization conditions, the authors observed particle aggregation, as determined by absorption and scattering spectra. In contrast, the addition of noncomplementary targets did not cause any spectral changes. According to He et al.,135 the detection limit (DL) of a 21-mer ssDNA was about 0.1 nM, whereas Ma et al.145 reported a 0.1 pM DL for an optimized version of He et al.’s assay135 and 30-mer ssDNA. Quite recently, Pylaev et al.44 applied CTAB-coated positively charged GNPs in combination with spectroscopic and dynamic scattering methods for the detection of DNA targets. Thus, there exists a more than Chem. Soc. Rev., 2012, 41, 2256–2282

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three-order difference in the reported estimations of the detection sensitivity of colorimetric methods (0.1–100 pM). Further work is called for, as the existing aggregation models are inconsistent with the detection limits of about 0.1–1 pM DNA.44 The above-mentioned SPIA formats have served for the detection of the DNA of mycobacteria,129,146,147 staphylococci,148 streptococci,149 and chlamydiae150 in clinical samples. The sensitivity of DNA detection can be increased with optical methods that utilize plasmonic enhancement of the local electromagnetic field near particle-cluster hotspots. For example, Hu et al.136 developed a sensitive DNA biosensor based on multilayer metal–molecule–metal nanojunctions and the SERS technique. With regard to an HIV-1 DNA sequence, the sensor could detect a concentration as low as 1019 M (1023 mol) with the ability of single base mismatch discrimination. Another way to reach PCR-like sensitivity involves a bio-bar-code approach combined with a silver-enhanced spot test.127 2.2.2 Dot immunoassay. At the early stages of immunoassay development, preference was given to liquid-phase techniques, in which bound antibodies were precipitated or unbound antigen was removed by adsorption with dextran-coated activated charcoal. Currently, the most popular techniques are solidphase ones (first used for protein radioimmunoassay), because they permit the analysis to be considerably simplified and the background signal to be reduced. The most widespread solid-phase carriers are polystyrene plates and nitrocellulose membranes. Membrane immunoassays (dot and blot assays) commonly employ radioactive isotopes (125I, 14C, 3H) and enzymes (peroxidase, alkaline phosphatase, etc.) as labels. In 1984, four independent reports were published151–154 in which colloidal gold was proposed as a label in a solid-phase immunoassay. The use of GNP conjugates in solid-phase assays is based on the fact that the intense red coloration of a gold-containing marker allows the results of a reaction run on a solid carrier to be determined visually. Immunogold methods in a dot–blot assay outperform other techniques (e.g., enzyme immunoassay) in terms of sensitivity (Table 3), rapidity, and cost.155,156 After an appropriate immunochemical reaction is run, the sizes of GNPs can be increased by enhancement with salts of silver157 or gold (autometallography),158 considerably expanding the application limits of the method. An optimized solid-phase assay using a densitometry system afforded a dynamic detection range of 1 mM to 1 pM159 with a detection limit of 100 aM, which was lowered to 100 zM by silver enhancement. The use of state-of-the-art instrumental detection methods, such as photothermal deflection of a probing laser beam, caused by heating of the local environment near absorbing particles Table 3 Sensitivity limits for immunodot/blot methods implemented on nitrocellulose filters by using various labels (according to ref. 155) Label

Sensitivity limit (pg of protein per fraction)

125 I Horseradish peroxidase Alkaline phosphatase Colloidal gold Colloidal gold + silver Fluorescein isothiocyanate

5 10 1 1 0.1 1000

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subjected to light pulses from a heating laser (LISNA assay),160 also ensures a very broad detection range (within three orders of magnitude, to the extent of several individual particles on a spot). In specific staining, a membrane with applied material under study is incubated in a solution of antibodies (or other biospecific probes) labeled with colloidal gold.18 As probes, ‘‘gold’’ dot or blot assays use immunoglobulins, Fab and scFv antibody fragments, staphylococcal protein A, lectins, enzymes, avidin, aptamers, and other probes. Sometimes, several labels are used simultaneously (e.g., colloidal gold and peroxidase or alkaline phosphatase) for the detection of multiple antigens on a membrane.161 Colloidal gold in membrane assays has served for the diagnosis of parasitic,162–166 viral,167–170 and fungal171,172 diseases, tuberculosis,173 melioidosis,174 syphilis,175 brucellosis,176 shigellosis,177 E. coli infections,178 salmonellosis,179 and early pregnancy;180 blood group determination;181 dot–blot hybridization;182 detection of antibiotics;183 diagnosis of myocardial infarction184 and hepatitis B;185 and other purposes. The immunodot assay is one of the simplest methods developed to analyze membrane-immobilized antigens. In some cases, it permits quantitative determination of antigens. Most commonly, the immunodot assay is employed to study soluble antigens.186 However, there have been several reports in which corpuscular antigens (whole bacterial cells) served as a research object in dot assays with enzyme labels.187 Bogatyrev et al.188,189 were the first to perform a dot assay of whole bacterial cells, with the reaction products being visualized with immunogold markers (‘‘cell–gold immunoblotting’’). This technique was applied to the serotyping of nitrogen-fixing soil microorganisms of the genus Azospirillum and subsequently to the rapid diagnosis of enteric infections.190 Gas et al.191 used a dot assay with GNPs to detect whole cells of the toxic phytoplankton Alexandrium minutum. Khlebtsov et al.192 first presented experimental results for the use of gold nanoshells as biospecific labels in dot assays. Three types of gold nanoshells were examined that had silica core diameters of 100, 140, and 180 nm and a gold shell thickness of about 15 nm (Fig. 5, data for 140/15 nm nanoshells not shown). The biospecific pair was normal rabbit serum (target molecules) and sheep antirabbit immunoglobulins (target-recognizing molecules). When the authors performed a standard protocol for a nitrocellulose-membrane dot assay, with 15 nm gold nanospheres as labels, the minimum detectable quantity of rabbit IgG was 15 ng. Replacing colloidal gold conjugates with nanoshells increased the assay sensitivity to 0.2 ng for 180/15 nm gold nanoshells and to 0.4 ng for 100/15 and 140/15 nm nanoshells. Such noticeable increases in sensitivity with nanoshells, as against nanospheres, can be explained by the different optical properties of the particles.193 A very promising analytical approach is the use of colloidal gold to analyze large arrays of antigens in micromatrices (immunochips).194,195 These enable an analyte to be detected in 384 samples simultaneously at a concentration of 60–70 ng L1 or, with account taken of the microlitre amounts of sample and detecting immunogold marker, with a detection limit of lower than 1 pg. The sensitivity of protein dot-analysis can be greatly improved with a combination of activated glass slides and a CCD camera196,197 or a flatbed scanner.198 In the case of very dilute This journal is

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Fig. 5 Dot assay of normal rabbit serum (1) by using suspensions of conjugates of 15 nm GNPs and SiO2/Au nanoshells (100 and 180 nm silica core diameters and 15 nm Au shell) with sheep antirabbit antibodies. The amount of IgG in the first square of the top row is 1 mg and decreases from left to right in accordance with twofold dilutions. The lower rows (2) correspond to the application of 10 mg of bovine serum albumin to each square as a negative control. The detected analyte quantity is 15 ng for 15 nm GNPs and 0.4 and 0.2 ng for 100/15 and 180/15 nm nanoshells, respectively. Adapted from ref. 193 by permission from IOP Publishing.

samples, a dot-immunogold filtration assay183 has been suggested. Finally, the sensitivity of a standard ELISA can be enhanced up to the single-molecule detection limit199 by using GNPs in colorimetric analysis of ELISA samples.200,201 2.2.3 Immunochromatographic assays. In 1990, several companies began to manufacture immunochromatographic test systems for hand-held diagnostics. Owing to their high specificity and sensitivity, these strip tests have found a wide utility in the detection of narcotics, toxins, highly dangerous infections, and urogenital diseases.202–208 Methods have been developed for the diagnosis of tuberculosis,209 helicobacteriosis,210 staphylococcal infection,211 hepatitis B,212 prostatitis,213 and early pregnancy,214 for DNA hybridization;215 for the detection of pesticides,216 aflatoxin,217 hexoestrol,218 and cephalexin219 in environmental constituents; and for other purposes. The immunochromatographic assay is based on eluent movement along the membrane (lateral diffusion), giving rise to specific immune complexes at different membrane sites; the complexes are visualized as colored bands.220 As labels, these systems use enzymes, colored lattices, but mostly GNPs.221,222 The sample being examined migrates along the test strip at the cost of capillary forces. If the sample contains the soughtfor substance or immunochemically related compounds, there occurs a reaction with colloidal-gold-labeled specific antibodies as the sample passes through the absorber. The reaction is accompanied by the formation of an antigen–antibody This journal is

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complex. The colloidal preparation enters into a competitive binding reaction with the antigen immobilized in the test zone (as a rule, the detection of low-molecular-weight compounds employs conjugates of haptens with protein carriers for immobilization). If the antigen concentration in the sample exceeds the threshold level, the conjugate does not possess free valences for interaction in the test zone and the colored band corresponding to the formation of the complex is not revealed. When the sample does not contain the sought-for substance or when the concentration of that substance is lower than the threshold level, the antigen immobilized in the test zone of the strip reacts with the antibodies on the surface of colloidal gold, causing a colored band to develop. When the liquid front moves on, the gold particles with immobilized antibodies that have not reacted with the antigen in the strip test zone bind to antispecies antibodies in the control zone of the test strip. The appearance of a colored band in the control zone confirms that the test was done correctly and that the system’s components are diagnostically active. Otherwise, the test is invalid. A negative test result—the appearance of two colored bands (in the test zone and in the control zone)—indicates that the antigen is absent from the sample or that its concentration is lower than the threshold level. A positive test result—the appearance of one colored band in the control zone—shows that the antigen concentration exceeds the threshold level (Fig. 6).220 Studies have shown that such assay systems are highly stable, their results are reproducible, and they correlate with alternative methods. Densitometric characterization of the dissimilarity degree for detected bands yields values ranging from 5 to 8%, allowing reliable visual determination of the analysis results. These assays are very simple and convenient to use. Nowadays, GNP-assisted immunochromatographic analysis is used actively in such fields as the rapid diagnostics of pseudorabies,223 tuberculosis,224 and botulism225 and the detection of pesticides,226 antibiotics,227 and toxins,228 in biological liquids and the environment. In summary, being effective diagnostic tools, rapid tests allow qualitative and quantitative determination, in a matter of minutes, of antigens, antibodies, hormones, and other

Fig. 6 Results of an immunochromatographic assay: positive, negative, and invalid determination because of the absent coloration in the control zone. Adapted from ref. 219 by permission from The American Chemical Society.

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diagnostically important substances in humans and animals. Rapid tests are highly sensitive and accurate, as they can detect more than 100 diseases (including tuberculosis, syphilis, gonorrhea, chlamydiosis, various types of viral hepatitis, etc.) and the whole gamut of narcotic substances used, with the reliability of detection being high. An important advantage of these tests is their use in diagnostics in vitro, which does not require a patient’s presence. However, immunochromatographic test strips are not devoid of weak points, related to reliability, sensitivity, and cost-effectiveness. Reliability and sensitivity depend, first, on the quality of monoclonal antibodies used in a test and, second, on the antigen concentration in a biomaterial. The quality of monoclonal antibodies depends on the methods of their preparation, purification, and fixation on a carrier. The antigen concentration depends on the disease state and the biomaterial quantity. For increasing the analysis sensitivity, it has been proposed to employ the silver enhancement procedure229 or gold nanorods as labels.230 In addition, semiquantitative and quantitative instrumental formats of immunochromatographic analysis have been developed that use special readers for recording the intensity of a label’s signal in the test zone of a test strip.220 2.2.4 Plasmonic biosensors. Collective oscillations of conductive electron plasma in metals are called ‘‘plasmons.’’231 Depending on the boundary conditions, these oscillations can be categorized into three types:232 bulk plasmons (3D plasma); propagating surface plasmons (PSP), or surface plasmon polaritons (2D dielectric/metal interfaces); and localized surface plasmons (LSP), excited in nanoparticles (Fig. 7).25 Bulk plasmons cannot be excited by visible light, as their energy is about 10 eV for noble metals.231 The term ‘‘surface plasmon polaritons’’ designates collective charge density oscillations at the metal/dielectric interface, propagating in a waveguide-like fashion along the surface (Fig. 7b). In the normal direction, the exciting electromagnetic field is rapidly falling off with distance. At a given photon energy ho, the wave vector ho/c should be increased to ensure effective coupling for the transformation of incident photons into propagating surface plasmons.232 Therefore, direct excitation of surface plasmon polaritons with freely propagating light is not possible. However, this problem can be solved by two approaches: the grating coupling method and the attenuated reflection method, which use a lattice waveguide structure or total reflection inside a prism, respectively.232 In metal nanoparticles, the electron plasma is restricted in all three dimensions. Accordingly, localized surface plasmons differ from propagating surface plasmons because of the

Fig. 7 Schematic representation of the bulk (a), propagating surface (b), and localized surface (c) plasmons.

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different boundary conditions to the Maxwell electromagnetic equations. In a small metal nanoparticle, the incident optical field exerts a force on conductive electrons and displaces them from their equilibrium positions to create uncompensated charges at the nanoparticle surface (Fig. 7c). As the main effect producing the restoring force is the polarization of the particle surface, the excited nanoparticle behaves like a resonance oscillator possessing a localized plasmon resonance (LSPR). The principal difference between the propagating and localized plasmons is that the former can be directly excited by light waves without any additional coupling set up. On the other hand, in both LSP and PSP cases, the excited plasmons ‘‘feel’’ the dielectric environment. It is the property that is the basis for the LSP and the PSP. The optical response of nanoparticles or their aggregates (especially ordered ones) depends on particle size, shape, and composition71,233 interparticle distance,234,235 and the properties of the particles’ local dielectric environment,236,237 which enables sensor ‘‘tuning’’ to be controlled. The theory behind the creation of LSP biosensors and their use in practice have been considered in ref. 238–254. In general, all sensing strategies are based on the change in the intensity of the LSPR and its spectral shift caused by a change in the local dielectric environment owing to biospecific interactions near the particle surface. A unique local-sensing property of the LSPR is related to the rapid decay of its local field, which only probes a nanoscale volume around the particle. In particular, the local nature of the LSPR allows one to detect single-molecular interactions near the particle surface by using various singleparticle detecting schemes.254 Fig. 8a illustrates a sensitive detection of about 18 streptavidin molecules after their binding to a single biotin-functionalized gold nanorod (74 33 nm).255 Nusz et al.255 also reported a 1 nM low detection limit (Fig. 8b) and discussed several ways to approach single-molecular detection. In recent years, gold and silver nanoparticles and their composites have served widely as effective optical transducers of biospecific interactions.256 In particular, the resonant optical properties of nanometre-sized metallic particles have been successfully used to develop plasmonic biochips and biosensors belonging to a broad family of sensors, viz. colorimetric, refractometric, electrochemical, and piezoelectric.220,257,258 Such devices are of much interest in biology (determination of nucleic acids, proteins, and metabolites), medicine (screening of drugs, analysis of antibodies and antigens, diagnosis of

Fig. 8 (a) Single-gold-nanorod light scattering spectra in water (1), with biotin, and after binding of about 18 streptavidin molecules. (b) LSPR peak shift as a function of the streptavidin concentration. The low detection limit is below 1 nM. Adapted from ref. 255 by permission from The American Chemical Society.

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infections), and chemistry (rapid environmental monitoring, assays of solutions and disperse systems). Of particular significance is the detection of specified nucleic acid (gene) sequences and the construction of new materials that relies on the formation of 3D ordered structures during hybridization in solutions of complementary oligonucleotides attached covalently to metallic nanoparticles.259 For more than 10 years, biospecific interactions have been studied in systems in which GNPs are represented as ordered structures: self-assembled (thin films)260 or as part of polymer matrices.261 Such structures have been actively employed for detection of biomolecules and infectious agents, development of DNA chips, and other purposes. In this case, investigators directly implement the possibility, in principle, of using the strong enhancement of the optical signal from the probe (GNPs conjugated to biospecific macromolecules) resulting from the strengthening of the exciting local field in the aggregate formed from gold nanoclusters. At present, biosensors are built with novel, unique technologies, including monolayer self-assembly of metallic particles,262 fiber-based LSPR sensing,263 and nanolithography.264 The reported types of LPR studies of biospecific interactions include biotin–streptavidin, antigen– antibody, lectin–carbohydrate, toxin–receptor, aptamer–protein, and DNA hybridization.254 For further information about LPR sensing, the readers are referred to a recent excellent review by Mayer and Hafner.254 In experimental work with SPR biosensors, three stages can be singled out:239 (1) one of the reagents (target-recognizing molecules) is covalently attached to the sensor surface. (2) The other reagent (target molecules) is added at a definite concentration to the sensor surface along with the flow of the buffer. The process of complex formation is then recorded. (3) The sensor is regenerated (dissociation of the formed complexes). As this takes place, the following conditions should be met: Reagent immobilization on the substrate should not lead to a critical change in the conformation of native molecules. The relatively small difference between the refractive indices of most biological macromolecules forces one to use a high local concentration of binding sites on the sensor surface (10–100 mM). The reagent being added should be vigorously agitated to achieve effective binding to the immobilized molecules. Unbound reagent should be promptly removed from the sensor surface to avoid nonspecific sorption. Apart from that, the sensitivity, stability, and resolution of a sensor depend directly on the characteristics of the optical system being used for recording. The most popular sensor system of this type is BIAcoret.265,266 The measurement principle in planar, prismatic, or mirror biosensors is similar to the principle of the method of frustrated total internal reflection, traditionally employed to measure the thickness and refractive index of ultrathin organic films on metallic (reflecting) surfaces.257 The excitation of the plasmon resonance in a planar gold layer occurs when polarized light is incident on the surface at a certain angle. The excited electromagnetic waves and charged density waves propagate along the metal/ dielectric interface. These propagating electromagnetic fields are localized near the interface because of the exponential decrease in amplitude perpendicularly to the dielectric with a This journal is

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Fig. 9 Typical setup for analyte detection in a BIAcoret-type SPR biosensor. The instrument detects changes in the local refractive index near a thin gold layer coated by a sensor surface with probing molecules. SPR is observed as a minimum in the reflected light intensity at an angle dependent on the mass of captured analyte. The minimum SPR angle shifts from A to B when the analyte binds to the sensor surface. The sensogram is a plot of resonance angle versus time that allows for real-time monitoring of an association/dissociation cycle. Adapted from ref. 267 by permission from Springer.

typical attenuation length of up to 200 nm (the effect of total internal reflection, Fig. 9). The reflection coefficient at a certain angle and light wavelength depends on the dielectric properties of the thin layer at the interface, which are ultimately determined by the mass of the captured target molecules at the sensing surface. Various types of GNP-aided biosensors have been developed for the immunodiagnostics of tick-borne encephalitis,268 the papilloma269 and HIV270 viruses, and Alzheimer’s disease;271,272 the detection of organophosphorus substances and pesticides,273 antibiotics,274 allergens,275 cytokines,276 carbohydrates,277 and immunoglobulins;278 the detection of tumor279 and bacterial280 cells; the detection of brain cell activity;281 and other purposes. GNP-based biosensors are used not only in immunoassay281–284 but also for the supersensitive detection of nucleotide sequences.96,259,285 In their pioneering works, Raschke et al.286 and McFarland et al.287 obtained record-high sensitivity of such sensors in the zeptomolar range, and they showed the possibility of detecting spectra of resonance scattering from individual particles as an analytical tool. This opens up the way to the recording of intermolecular interactions at the level of individual molecules.288,299 To make the response stronger, investigators often use avidin–biotin, barnase–barstar, and other systems.290 In addition, GNPs are applied in other analytical methods (diverse versions of chromatography, electrophoresis, and mass spectrometry).291 SPR and LSPR biosensors were compared in side-by-side experiments by Yonzon et al.292 for concanavilin A binding to monosaccharides and by Svedendahl et al.293 for biotin–streptavidin binding. It was found that both techniques demonstrate similar performance. As the bulk refractive index sensitivity is known to be higher for SPR, the above similarity was attributed to the long decay length of propagating plasmons, as compared to localized ones. The overall comparison of SPR and LSPR sensors can be found in ref. 251 and 254. Future development of low-cost SPR and LSPR biomedical sensors needs increasing the detection sensitivity and creating substrates that can operate in biological fluids and can be easy to functionalize with probing molecules, to clean, and to reuse. Chem. Soc. Rev., 2012, 41, 2256–2282

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3. GNPs in therapy


3.1

Plasmonic photothermal therapy

Photothermal damage to cells is currently one of the most promising research avenues in the treatment of cancer and infectious diseases.294 The essence of this phenomenon is as follows: GNPs have an absorption maximum in the visible or near-IR region and get very hot when irradiated with corresponding light. If, in this case, they are located inside or around the target cells (which can be achieved by conjugating gold particles to antibodies or other molecules), these cells die. The thermal treatment of cancerous cells has been known in tumor therapy since the 18th century, employing both local heating (with microwave, ultrasonic, and radio radiation) and general hyperthermia (heating to 41–47 1C for 1 h).295 For local heating to 70 1C, the heating time may be reduced to 3–4 min. Local and general hyperthermia leads to irreversible damage to the cells, caused by disruption of cell membrane permeability and protein denaturation. Naturally, the process also injures healthy tissues, which imposes serious limitations on the use of this method. The revolution in thermal cancer therapy is associated with laser radiation, which enabled controlled and limited injury to tumor tissues to be achieved.296 Combining laser radiation with fiber-optic waveguides produced excellent results and was named interstitial laser hyperthermia.297 The weak point of laser therapy is its low selectivity, related to the need for highpowered lasers for effective stimulation of tumor cell death.298 A variant of photothermal therapy was also proposed in which photothermal agents help to achieve selective heating of the local environment.299 Selective photothermal therapy relies on the principle of selective photothermolysis of a biological tissue containing a chromophore—a natural or artificial substance with a high coefficient of light absorption.

GNPs were first used in photothermal therapy in 2003.300,301 Subsequently, it was suggested to call this method plasmonic photothermal therapy (PPTT).295 Pitsillides et al.302 first described a new technique for selective damage to target cells that is founded on the use of 20 and 30 nm gold nanospheres irradiated with 20 ns laser pulses (532 nm) to create local heating. For pulse photothermia in a model experiment, those authors were the first to employ a sandwich technology for labeling T-lymphocytes with GNP conjugates. In a particularly promising method, GNPs have found application in the photothermal therapy of chemotherapy-resistant cancers.303 Unlike photosensitizers (see below), GNPs are unique in being able to keep their optical properties in cells for a long time under certain conditions. Successive irradiation with several laser pulses allows control of cell inactivation by a nontraumatic means. The simultaneous use of the scattering and absorbing properties of GNPs permits PPTT to be controlled by optical tomography.68 Fig. 10 shows an example of successful therapy of an implanted tumor in a model experiment with mice.304 The further development of PPTT and its acceptance in actual clinical practice305 depends on success in solving many problems, the most important ones being (1) the choice of nanoparticles with optimal optical properties, (2) the enhancement of nanoparticle accumulation in tumors and the lowering of total potential toxicity, and (3) the development of methods for the delivery of optical radiation to the targets and the search for alternative radiation sources combining high permeability with a possibility of heating GNPs. The first requirement is determined by the concordance of the spectral position of the absorption plasmon resonance peak with the spectral window for biological tissues in the 700–900 nm nearIR region.306 Khlebtsov et al.234 made a resumptive theoretical analysis of the photothermal effectiveness of GNPs, depending on their size, shape, structure, and aggregation extent. They showed that although gold nanospheres themselves are

Fig. 10 Scheme and the results of an experiment on the photothermal destruction of an implanted tumor in a mouse (2–3 weeks after injection of MDA-MB-435 human cancer cells). Laser irradiation (a, b; 810 nm, 2 W cm2, 5 min) was performed at 72 h after injection of gold nanorods functionalized with poly(ethylene glycol) (PEG) (a, c; 20 mg Au per kg) or of buffer (b, d). It can be seen that the tumor continued developing after particle-free irradiation (control b), as it did after particle or buffer administration without irradiation (controls a and d), and that complete destruction was obtained only in the experiment (a). Designations: NIR, near-IR region; NRs, nanorods. Adapted in part from ref. 304 by permission from The American Association for Cancer Research.

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ineffective in the near-IR region, aggregates formed from them can be very effective at sufficiently short interparticle distances (shorter than 0.1 of the particle diameter). Such clusters can be formed both on the surface of and inside cells.307 Experimental data indicating an enhancement of PPTT through clusterization have been presented in ref. 308–310. Specifically, Huang et al.308 demonstrated that small aggregates composed of 30 nm particles enable cancerous cells to be destroyed at a radiation power 20-fold lower than that in the particle-free control. The gold nanoshell and nanorod parameters optimal for PPTT have also been defined.234,311 By now, there have been quite a few publications dealing with the application in PPTT of gold nanorods;67,312–314 nanoshells;301,315–320 and a comparatively new particle class, gold–silver nanocages.93,321,322 Experimental data comparing the heating efficiencies of nanorods, nanoshells, and nanocages have been reported in ref. 53, 323 and 324. Regarding the optimization of particle parameters, one should be aware of three matters of principle. First, the absorption cross section is not the sole parameter determining the effectiveness of PPTT.325 Rapid heating of nanoparticles or aggregates gives rise to vapor bubbles,326 which can cause cavitation damage to cells irradiated with visible309 or near-IR327 light. The effectiveness of vapor bubble formation increases substantially when nanoparticle aggregates are formed.301,307 Possibly, it is this effect, and not enhanced absorption, that bears responsibility for greater damage to cells, with all other factors being the same.325 Finally, particle irradiation with high-power resonant nanosecond IR pulses can lead to particle destruction as early as after the first pulse (see, e.g., ref. 328 and 329 and references therein to earlier publications). In a series of recent investigations, Lapotko et al.325,330 (see also references therein) paid their attention to the fact that the heating of GNPs and their destruction can sharply reduce the photothermal effectiveness of ‘‘cold’’ particles, which have been tuned to the laser wavelength. The use of femtosecond pulses offers no solution to this problem because of the low energy supplied, and for this reason, it is necessary to exert close control over the preservation of nanoparticles’ properties for the chosen irradiation mode. Furthermore, bubble formation strongly depends on the media as well as on laser intensity, thus making cellular damage poorly controlled. We now shift to consider the second question, associated with targeted nanoparticle delivery to a tumor. This question has two important aspects: increasing the particle concentration in the target and lowering the side effects caused by GNP accumulation in other organs, primarily in the liver and spleen (see below). Usually, there are two delivery strategies. One is based on the conjugation of GNPs to PEG; the other, on the conjugation with antibodies developed to specific marker proteins of tumor cells. PEG acts to enhance the bioavailability and stability of nanoparticles, ultimately prolonging the time of their circulation in the blood stream. Citrate-coated gold nanospheres, CTAB-coated nanorods, and nanoshells are less stable in saline solutions. When nanoparticles are conjugated to PEG, their stability is improved considerably and salt aggregation is prevented. In vivo PEGylated nanoparticles preferentially accumulate in tumor tissue owing to the increased permeability of the tumor vessels331 and are retained in it owing to the decreased lymph outflow. In addition, PEGylated nanoparticles are less This journal is

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Fig. 11 Scheme for a PPTT employing active delivery of GNPs to cancer cells.

accessible to the immune system (stealth technologies). This delivery method is called passive, as distinct from the active version, which uses antibodies332,333 (Fig. 11). The active method of delivery is more reliable and effective, employing antibodies to specific tumor markers, most often to epidermal growth factor receptor (EGFR) and its varieties (e.g., Her2),315,334,335 as well as to tumor necrosis factor (TNF).336 Particular promise is offered by the simultaneous use of GNP–antibody conjugates for both diagnosis and PPTT (methods of what is known as theranostics).337–339 In addition to antibodies, active delivery may also use folic acid, which serves as a ligand for the numerous folate receptors of tumor cells,313,340,341 and hormones.342 In the very recent past, the effectiveness of targeted nanoparticle delivery to tumors has again become a subject for detailed study and discussion.343 In experiments with liposomes labeled with anti-Her2344 and GNPs labeled with transferrin,345 it was shown that functionalization improves nanoparticle penetration into cells but produces no appreciable increase in particle accumulation in tumors. Huang et al.343 examined the biodistribution and localization of gold nanorods labeled with three types of probing molecules, including (1) an scFv peptide that recognizes EGFR; (2) an amino terminal fragment peptide that recognizes the urokinase plasminogen activator receptor; and (3) a cyclic RGD peptide that recognizes the avb3 integrin receptor. The authors showed that when injected intravenously, all three ligands induce insignificant increases in nanoparticle accumulation in cell models and in tumors but greatly affect extracellular distribution and intracellular localization. They concluded that for PPTT, direct administration of particles to the tumor can be more effective than intravenous injection. The final important question in current PPTT concerns effective delivery of radiation to a biological target. Because the absorption of biological tissue chromophores in the visible region is lower than that in the near-IR region by two orders of magnitude,294 the use of IR radiation radically decreases the nontarget heat load and enhances the penetration of radiation into the tissue interior. Nevertheless, the depth of penetration usually does not exceed 5–10 mm,84,311 so it is necessary to look for alternative solutions. One approach consists in using pulse (nanoseconds) irradiation modes in preference to continuous ones, which enables irradiation power to be enhanced without Chem. Soc. Rev., 2012, 41, 2256–2282

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increasing side effects. Another approach involves fiber-optic devices for endoscopic or intratissue delivery of radiation. The strong and weak points of such an approach are evident. Finally, for hyperthermia, it is possible to use radiations with greater depths of penetration, e.g., radiofrequency346–349 or nonthermal air plasma.350 GNPs conjugated to antibiotics and antibodies have also served as photothermal agents for selective damage to protozoa and bacteria.351–354 Information on certain issues in the use of PPTT can be found in several books and reviews.295,355–359 Of particular note is the most recent comprehensive review by Kennedy et al.294 In summary, gold nanostructures with a plasmon resonance offer considerable promise for selective PPTT of cancer and other diseases. Without doubt, several questions await further study, including the stability and biocompatibility of nanoparticle bioconjugates, their chemical interaction in physiological environments, the period of circulation in blood, penetration into the tumor, interaction with the immune system, and nanoparticle excretion. We expect that the success of the initial stages of nanoparticle use for selective PPTT can be effectively enhanced at the clinical stage, provided that further studies are made on the optimal procedural parameters. In particular, one can mention the efforts of J. Feldmann’s group360 related to thermoplasmonics—a field that is not well understood yet and that is nowadays is a trend for hyperthermia and delivery upon light-to-heat conversion. 3.2

Photodynamic therapy with GNPs

The photodynamic method of treating oncological diseases and certain skin or infectious diseases is based on the application of light-sensitizing agents called photosensitizers (including dyes) and, as a rule, of visible light at a specific wavelength.361 Most often, sensitizers are introduced intravenously, but contact and oral administration is also possible. The substances used in photodynamic therapy (PDT) can selectively accumulate in tumors or other target tissues (cells). The affected tissues are irradiated with laser light at a wavelength corresponding to the peak of dye absorption. In this case, apart from the usual heat emission through absorption,21 an essential role is played by another mechanism, related to the photochemical generation of singlet oxygen and the formation of highly active radicals, which induce necrosis and apoptosis in tumor cells. PDT also disrupts the nutrition of the tumor and leads to its death by damaging its microvessels. The major shortcoming of PDT is that the photosensitizer remains in the organism for a long time, leaving patient tissues highly sensitive to light. On the other hand, the effectiveness of dye use for selective tissue heating21 is low because of the small cross section of chromophore absorption. It is well known362 that metallic nanoparticles are effective fluorescence quenchers. However, it has been shown recently363,364 that fluorescence intensity can be enhanced by a plasmonic particle if the molecules are placed at an optimal distance from the metal. In principle, this idea can improve the effectiveness of PDT. Several investigators have proposed methods for the delivery of drugs as part of polyelectrolyte capsules on GNPs 2268

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(which decompose when acted upon by laser radiation and deliver the drug to the targets365,366) or by using nanoparticles surrounded by a layer of polymeric nanogel.367,368 Apart from that, the composition of nanoconjugates includes photoactive substances,369peptides (e.g., CALLNN), and proteins (e.g., transferrin), which facilitate intracellular penetration.345,370,371 Recently, Bardhan et al.372 suggested the use of composite nanoparticles, including, in addition to gold nanoshells, magnetic particles, a photodynamic dye, PEG, and antibodies. Finally, according to the data of Kuo et al.,373,374 nanoparticles conjugated with photodynamic dyes can demonstrate a synergetic antimicrobial effect, though the absence of such an effect has also been reported.375 3.3 GNPs as a therapeutic agent In addition to being used in diagnostics and cell photothermolysis, GNPs have been increasingly applied directly for therapeutic purposes.29 In 1997, Abraham and Himmel376 reported success in colloidal gold treatment of rheumatoid arthritis in humans. In 2008, Abraham published a great body of data from a decade of clinical trials of Aurasols—an oral preparation for the treatment of severe rheumatoid arthritis.377 Tsai et al.378 described positive results obtained when rats with collageninduced arthritis were intraarticularly injected with colloidal gold. The authors explain the positive effect by an enhancement of antiangiogenic activity resulting from the binding of GNPs to vascular endothelium growth factor, which brought about a decrease in macrophage infiltration and in inflammation. Similar results were obtained by Brown et al.,379,380 who subcutaneously injected GNPs into rats with collagen- and pristane-induced arthritis. A series of papers by a research team from Maryland University have described the application of a colloidal gold vector to the delivery of TNF to solid tumors in rats.381–384 When injected intravenously, GNPs conjugated to TNF accumulated rapidly in tumor cells and could not be detected in cells of the liver, spleen, and other healthy animal organs. The accumulation of GNPs in the tumor was proven by a recordable change in its color, because it became bright red-purple (characteristic of colloidal gold and its aggregates), which was coincident with the peak of the tumor-specific activity of TNF (Fig. 12). The colloidal gold–TNF vector was less toxic and more effective in tumor reduction than was native TNF, because the maximal antitumor reaction was attained at lower drug doses. A medicinal preparation based on the GNP–TNF conjugate, which is called AurImmunet and intended for intravenous injection, is already in the third stage of clinical trials. In experiments in vitro and in vivo, Bhattacharya et al.385 and Mukherjee et al.386 demonstrated the antiangiogenic properties of GNPs. The particles were found to interact with heparin-binding glycoproteins, including vascular permeability factor/vascular endothelial growth factor and basic fibroblast growth factor. These substances mediate angiogenesis, including that in tumor tissues, and inhibit tumor activity by changing the conformation of the molecules.387 Because intense angiogenesis (the formation of new vessels in organs or tissues) is a major factor in the pathogenesis of tumor growth, the presence This journal is

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4. GNPs as drug carriers


4.1 Targeted delivery of anticancer drugs

Fig. 12 Accumulation of the GNP–TNF conjugate in the tumor after 1–5 h. Diseased mice were intravenously injected with 15 mg of the GNP–TNF vector. The belly images were obtained at the indicated times and show changes in tumor color within 5 h. The red arrow shows vector accumulation in the tumor, and the blue arrows mark the accumulation in the tissues around the tumor. Adapted from ref. 382 by permisson from Wiley Interscience.

of antiangiogenic properties in GNPs makes them potentially promising in oncotherapy.388,389 The same research team has shown that GNPs enhance the apoptosis of chronic lymphocytic leukemia cells resistant to programmed death390 and inhibit the proliferation of multiple myeloma cells.391 Quite recently, Wang et al.392 revealed that PEG-coated gold nanorods have an unusual property: they can induce tumor cell death by accumulating in mitochondria and subsequently damaging them. Unexpectedly, for normal and stem cells, such an effect is either absent or less pronounced.

Table 4

One of the most promising aspects of GNP use in medicine, currently under intense investigation, is targeted drug delivery.393–395 The most popular objects for targeted delivery are antitumor preparations396 and antibiotics. GNPs have been conjugated to a variety of antitumor substances382–411 listed in Table 4. Conjugation is done both by simple physical adsorption of preparations on GNPs and by using alkanethiol linkers. The action of the conjugates is evaluated both in vitro (primarily), with tumor cell cultures, and in vivo, with mice bearing implanted tumors of various nature and localizations (Lewis lung carcinoma, pancreatic adenocarcinoma, etc.). For creation of a delivery system, target molecules (e.g., cetuximab) are applied along with the active substance so as to ensure better anchoring and penetration of the complex into the target cells.399 It was also suggested that multimodal delivery systems be used,412 in which GNPs are loaded with several drugs (both hydrophilic and hydrophobic) and with auxiliary substances (target molecules, PDT dyes, etc.;413,414 Fig. 13). Most researchers have noted the high effectiveness of GNP-conjugated antitumor preparations.415 4.2 Delivery of other substances and genes Besides antitumor substances, other objects employed to deliver GNPs are antibiotics and other antibacterial agents. Gu et al.416 prepared a stable vancomycin–colloidal gold

Antitumor substances conjugated with GNPs

Drugs

Particles

Methods of functionalization

Auxiliary substances

Cell lines or animals

Paclitaxel

GNSs, 26 nm

Paclitaxel–SH

PEG–SH, TNF

Methotrexate

GNSs, 13 nm

Physical adsorption

—

Daunorubicin

GNSs, 5 nm, 16 nm GNSs, 5 nm

3-Mercaptopropionic acid as a linker Physical adsorption

—

MC-38; C57/BL6 mice implanted 382, 2006 with B16/F10; melanoma cells LL2, ML-1, MBT-2, TSGH 8301, 397, 2007 TCC-SUP, J82, PC-3, HeLa K562/ADM 398, 2007

Gemcitabine

Ref.

GNSs, 5 nm GNSs, 3–6 nm 5-Fluorouracil GNSs, 2 nm c,c,t-[Pt(NH3)2Cl2(OH) GNSs, 13 nm (O2CCH2CH2CO2H)] Cisplatin GNSs, 5 nm

Physical adsorption Physical adsorption

Cetuximab (monoclonal antibodies) — —

Thiol ligand Amide linkages

— DNA

MCF-7 HeLa, U2OS, PC3

402, 2009 403, 2009

PEG–SH as a linker

Folic acid, PEG–SH

404, 2010

Oxaliplatin

GNSs, 30 nm

PEG–SH as a linker

PEG–SH

Kahalalide F

—

406, 2009

PEG–SH —

MDA-MB-231, MCF-7, HSC-3 BT474, SKBR3, MCF-7

407, 2009 408, 2009

b-Lapachon

GNSs, 20, Physical adsorption 40 nm GNSs, 25 nm PEG–SH as a linker GNRs, lmax=760 nm 11-Mercaptoundecanoic acid as a linker GNSs, 25 nm Physical adsorption

OV-167, OVCAR-5, HUVEC, OSE A549, HCT116, HCT15, HT29, RKO HeLa

Doxorubicin Prospidin

GNSs, 12 nm GNSs, 50 nm

6-Mercaptopurine Dodecylcysteine

Tamoxifen Herceptin

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PANC-1, AsPC-1, MIA Paca2

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K-562 EAC

400, 2008 401, 2008

Cyclodextrin as a drug MCF-7 pocket, anti-EGFR, PEG–SH Folate-modified PEG KB — HeLa

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409, 2009 410, 2010 411, 2010

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Fig. 13 Schemes for different versions of drug delivery systems. Adapted from ref. 412.

complex and showed its effectiveness toward various (including vancomycin-resistant) enteropathogenic strains of Escherichia coli, Enterococcus faecium, and Enterococcus faecalis. Similar results were presented by Rosemary et al.:417 a complex formed between ciprofloxacin and gold nanoshells had high antibacterial activity against E. coli. Selvaraj and Alagar418 reported that a colloidal gold conjugate of the antileukemic drug 5-fluorouracil exhibited noticeable antibacterial and antifungal activities against Micrococcus luteus, Staphylococcus aureus, Pseudomonas aeruginosa, E. coli, Aspergillus fumigatus, and A. niger. Noteworthy is the fact that in all those cases, the drug–GNP complexes were stable, which could be judged by the optical spectra of the conjugates. By contrast, Saha et al.419 (antibiotics: ampicillin, streptomycin, and kanamycin; bacteria: E. coli, M. luteus, and S. aureus) and Grace and Pandian420,421 (aminoglycoside antibiotics: gentamicin, neomycin, and streptomycin; quinolone antibiotics: ciprofloxacin, gatifloxacin, and norfloxacin; bacteria: E. coli, M. luteus, S. aureus, and P. aeruginosa) failed to make stable complexes with GNPs. Nevertheless, those authors showed that depending on the antibiotic used, the increase in the activity of an antibiotic–colloidal gold mixture, as compared to that of the native drug, ranged from 12 to 40%. From these data, it was concluded that the antibacterial activity of the antibiotics is enhanced at the cost of GNPs. However, the question as to the mechanisms involved in such possible enhancement remained unclarified, which was noted by the authors themselves. Burygin et al.422 experimentally proved that free gentamicin and its mixture with GNPs do not significantly differ in antimicrobial activity in assays on solid and in liquid nutrient media. They proposed that a necessary condition for enhancement of antibacterial activity is the 2270

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preparation of stable conjugates of nanoparticles coated with antibiotic molecules. Specifically, Rai et al.423 suggested the use of the antibiotic cefaclor directly in the synthesis of GNPs. As a result, they obtained a stable conjugate that had high antibacterial activity against E. coli and S. aureus. Other drugs conjugated to GNPs are referred to much more rarely in the literature. However, some of those works deserve mention. Nie et al.424 demonstrated high antioxidant activity of GNPs complexed with tocoferol and suggested potential applications of the complex. Bowman et al.425 provided data to show that a conjugate of GNPs with the preparation TAK779 exhibits more pronounced activity against HIV than the native preparation at the cost of the high local concentration. Joshi et al.426 described a procedure for oral and intranasal administration of colloidal-gold-conjugated insulin to diabetic rats, and they reported a significant decrease in blood sugar, which was comparable with that obtained by subcutaneous insulin injection, Finally, Chamberland et al.427 reported a therapeutic effect of the antirheumatism drug etanercept conjugated to gold nanorods. In conclusion, it is necessary to mention gene therapy, which can be seen as an ideal strategy for the treatment of genetic and acquired diseases.428 The term ‘‘gene therapy’’ is used in reference to a medical approach based on the administration, for therapeutic purposes, of gene constructs to cells and the organism.429 The desired effect is achieved either as a result of expression of the introduced gene or through partial or complete suppression of the function of a damaged or overexpressing gene. There have also been recent attempts at correcting the structure and function of an improperly functioning (‘‘sick’’) gene. In such a case, too, GNPs can serve as an effective means of delivery of genetic material to the cytoplasm and the cell nucleus.430–433 Furthermore, gold glyconanoparticles have been proposed for use as a carrier of tumor-associated antigens in the development of anticancer vaccines.434

5. Immunological properties of GNPs 5.1 Production of antibodies by using GNPs Since the 1920s, the immunological properties of colloidal metals (in particular, gold) have been attracting much research interest. This interest was mainly due to the physicochemical (nonspecific) theory of immunity proposed by J. Bordet, who had postulated that immunogenicity, along with antigenic specificity, depends predominantly on the physicochemical properties of antigens, first of all on their colloidal state. In 1929, Zilber and Friese successfully obtained agglutinating sera to colloidal gold.435 (Curiously, another attempt to prepare antisera to colloidal gold was made almost 80 years later, in 2006.436) Yet, several authors have shown that the introduction of a complete antigen together with colloidal metals promotes the production of antibodies.437 Moreover, some haptens may cause antibody production when adsorbed to colloidal particles.438 Numerous data pertaining to the influence of colloidal gold on nonspecific immune responses are given in one of the best early reviews.439 Specifically, it was noted (with reference to the 1911 work of Gross and O’Connor) that at 2 h after an This journal is

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intravenous injection of 5 mL of colloidal gold into rabbits, there occurs a sizable increase in total leukocytes in 1 mL of blood (from 10 000 to 19 800) against a slight decline in mononuclear cells (from 5200 to 4900) and a considerable increase in polynuclear cells (from 4700 to 14 900). On injection of other colloidal metals, no such phenomena are observed. Unfortunately, with advances in immunology and denial of many postulates of Bordet’s theory, the interest in the immunological properties of colloids decreased. There is no doubt, though, that the data obtained on the enhancement of immune response to antigens adsorbed on colloidal particles were utilized to develop various adjuvants.440 It is known that antibody biosynthesis is induced by substances possessing sufficiently developed structures (immunogenicity). These include proteins, polysaccharides, and some synthetic polymers. However, many biologically active substances (vitamins, hormones, antibiotics, narcotics, etc.) have relatively small molecular masses and, as a rule, do not elicit a pronounced immune response. In standard methods of antibody preparation in vivo, this limitation is overcome by chemically attaching such substances (haptens) to high-molecular-weight carriers (most often proteins), which makes it possible to obtain specific antisera. However, such antisera usually contain attendant antibodies to the carrier’s antigenic structures.441 In 1986, Japanese researchers442 first reported success in generating antibodies against glutamate by using colloidal gold particles as a carrier. Subsequently, a number of papers were published whose authors applied and further developed this technique to obtain antibodies to the following haptens and complete antigens: amino acids;443,444 platelet-activating factor;445,446 quinolinic acid;447 biotin;448 recombinant peptides;449,450 lysophosphatide acid;451 endostatin;452 the capsid peptides of the hepatitis C,453 influenza,454 and foot-and-mouth disease455 viruses; a-amidated peptides;456 actin;457 antibiotics;458 azobenzene;459 Ab-peptide;460 clenbuterol;461 Yersinia surface antigens;462 transmissible gastroenteritis virus;463 tuberculin;464 and the peptides of the malaria (Plasmodium) surface protein.465 In all these studies, the haptens were directly conjugated to colloidal gold particles, mixed with complete Freund’s adjuvant or alum, and used for animal immunization. As a result, hightiter antisera were obtained that did not need further purification from contaminant antibodies (Fig. 14). In 1993, Pow and Crook466 suggested attaching a hapten (g-aminobutyric acid) to a carrier protein before conjugating this complex to colloidal gold. This suggestion was supported in articles devoted to the raising of antibodies to some peptides,467–471 amino acids,472–475 phenyl-b-D-thioglucoronide,476 and diminazene.477 The antibodies obtained in this way possessed high specificities to the antigens under study and higher (as Pow and Crook466 put it, ‘‘extremely high’’) titers—from 1 : 250 000 to 1 : 1 000 000, as compared with the antibodies produced routinely. In 1996, Demenev et al.478 showed for the first time the possibility of using colloidal gold particles included in the composition of an antiviral vaccine as carriers for the protein antigen of the tick-borne encephalitis virus capsid. According to the authors’ data, the offered experimental vaccine had higher protective properties than its commercial analogs, despite the fact that the vaccine did not contain adjuvants. This journal is

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Fig. 14 Schematic representation of immunogen localization on the surface of keyhole limpet hemocyanin (KLH) and GNPs, used as antigen carriers. (A) Antibodies toward the peptide–KLH conjugate are produced to the epitopes of both peptide and KLH. (B) Antibodies toward the peptide–GNP conjugate are produced only to the epitopes of the peptide. Adapted from ref. 455 by permission from IOP Publishing.

In 2011, Wang et al.479 suggested a new therapeutic vaccine based on the combination of myelin-associated inhibitors and GNPs for the treatment of rat medullispinal traumas. Also, for GNP-assisted antigens, two groups reported new administration ways: through the skin and mucous coats.480,481 Scheme 2 summarizes the literature data on antigens and haptens that have been conjugated with GNP carriers and then used for immunization of animals. The titers of the antibodies have been increased owing to GNPs. A considerable number of papers devoted to the use of GNPs for creating DNA vaccines have emerged as well. The principle of DNA immunization is as follows: gene constructs coding for the proteins to which one needs to obtain antibodies are introduced into the organism being treated. If the gene expression is effective, these proteins serve as antigens for the development of an immune response. Among the nanoparticles used as DNA carriers, colloidal gold particles are especially popular with researchers.482,483 5.2 Adjuvant properties of GNPs Dykman et al.458,464 proposed a technology for the preparation of antibodies to various antigens, which uses colloidal gold as a carrier and as an adjuvant. In their method, antigens are adsorbed directly on the GNP surface, with no cross-linking reagents added. It was found that animal immunization with colloidal gold–antigen conjugates (with or without Freund’s complete adjuvant) yielded specific, high-titer antibodies to a variety of antigens, with no concomitant antibodies. GNPs can stimulate antibody synthesis in rabbits, rats, and mice, and the required amount of antigen is reduced, as compared to that needed with some conventional adjuvants (Table 5). It was demonstrated that GNPs used as an antigen carrier activate the phagocytic activity of macrophages and influence the functioning of lymphocytes, which apparently may be responsible for their immunomodulating effect. It was also revealed that GNPs and their conjugates with low- and highmolecular weight antigens stimulate the respiratory activity of cells of the reticuloendothelial system and the activity of macrophage mitochondrial enzymes.484 This stimulation is possibly one of the causative factors determining the adjuvant properties of colloidal gold. That GNPs act as both an adjuvant and a carrier (i.e., they present haptens to T cells) Chem. Soc. Rev., 2012, 41, 2256–2282

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Scheme 2

Conjugates of antigens and haptens used for immunization of animals.

seems the most interesting aspect of immunogenic properties exhibited by colloidal gold. In particular, GNPs conjugated to antigens were found to influence the activation of T cells, inducing a tenfold increase in proliferation, as compared with that observed on the addition of the native antigen. This fact indicates that there is a fundamental possibility of targeted activation of T cells followed by macrophage activation and pathogen killing. However, not a single paper available to us has reported data on the mechanism of such properties of gold particles. In our opinion, the reasoning given by Pow and Crook466 on the preferable macrophage response to corpuscular antigens, as opposed to soluble ones, is certainly valid. This fact has also been confirmed by researchers studying the mechanism of action of DNA vaccines and using gold particles to deliver genetic material to cells.485,486 The role of Kupffer and Langerhans cells in the development of immune response was shown in those investigations. The influence of dendritic cells on the development of immune response upon injection of a GNPconjugated antigen was discussed by Vallhov et al.487 In addition, those authors noted that when using nanoparticles in medical practice, one has to ensure that there are no lipopolysaccharides on their surface. The interaction of cells of the immune system with GNPs was examined recently by Villiers et al.488 and by Zolnik et al.489 Table 5

The penetration of GNPs complexed with peptides into the cytoplasm of macrophages, causing their activation, was shown electron microscopically by Bastu´s et al.490,491 They established that after the conjugates have interacted with the TLR-4 receptors of macrophages, the nanoparticles penetrate into the cells, this being accompanied by secretion of the proinflammatory cytokines TNF-a, IL-1b, and IL-6 and by suppression of macrophage proliferation. Dobrovolskaia and McNeil492 do not exclude the possibility of another (noninflammatory) way of GNP penetration into macrophages, namely by means of interaction with scavenger receptors. França et al.493 showed that irrespective of size, GNPs are internalized by macrophages via multiple routes, including both phagocytosis and pinocytosis. If either route is blocked, the particles enter the cells via the other route. GNPs with hydrodynamic sizes below 100 nm can be phagocytozed. Phagocytosis of anionic gold colloids by RAW264.7 cells is mediated by macrophage scavenger receptor A. Ma et al.494 investigated the inhibitory effect of PEG-coated GNPs on NO production and its molecular mechanism in lipopolysaccharidestimulated macrophages. It was found that GNPs inhibited lipopolysaccharide-induced NO production and inducible nitric synthase expression in macrophages. Yen et al.495 noted that on the administration of GNPs, the number of macrophages decreases and their size increases, this being accompanied by

The antibody titers obtained during immunization of rabbits with Yersinia antigen

Preparation

1st immunization

2nd immunization

Boosting

Colloidal gold + antigen (1 mg) Complete Freund’s adjuvant + antigen (100 mg) Physiological saline + antigen (100 mg)

1 : 32 1 : 32 1:2

1 : 256 1 : 256 1 : 16

1 : 10 240 1 : 10 240 1 : 512

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elevated production of IL-1, IL-6, and TNF. The influence of colloidal gold on immunocompetent cells was examined in vivo also by Tian et al.496 and by Lou et al.497 They showed that injection of nonconjugated GNPs into mice enhances the proliferation of lymphocytes and normal killers, as well as an increase in IL-2 production. Recently, many articles have appeared (see above) discussing problems in GNP use for targeted drug delivery. In our opinion, this question should be dealt with very carefully, with account taken of the possibility of production in animals or humans of antibodies specific to the administered drug adsorbed on gold particles. We believe that the discovery of adjuvant properties in GNPs has created favorable conditions for designing next-generation vaccines. Alongside GNPs, other nonmetallic nanoparticles also can serve as antigen carriers. The published examples include liposomes, proteosomes, microcapsules, fullerenes, carbon nanotubes, dendrimers, and paramagnetic particles.464 In our view, especially promising carriers are synthetic and natural polymeric biodegradable nanomaterials [polymethyl methacrylate, poly(lactid-co-glycolid acid), chitosan, gelatin]. With the use of such nanoparticles, the immunogenicity of a loaded substance and its representation in a host immune system will be changed. A nanoparticle conjugate with an absorbed or a capsulated antigen can serve as an adjuvant for the optimization of immune response after vaccination. The evident advantages of biodegradable nanoparticles are their utilization in the vaccinated organism, high loading efficiency for the target substance, enhanced ability to cross various physiological barriers, and low systemic side effects. In all likelihood, the immune actions of biodegradable nanoparticles and GNPs as corpuscular carriers are similar. Keeping in mind the recent data for the low toxicity of GNPs and their efficient excretion by the hepatobiliary system, we expect that both nanoparticle classes—GNPs and biodegradable nanoparticles—will compete on equal footing for being used in the development of next–generation vaccines.

6. Conclusions Owing to the success of the rapid development of technologies for the chemical synthesis of GNPs during the past decade, investigators currently have at their disposal an enormous diversity of available particles with required parameters in respect of size, shape, structure, and optical properties. Moreover, the question that is now on the agenda is the primary modeling of a nanoparticle with desired properties and the subsequent development of a procedure for the synthesis of a theoretically predicted nanostructure. From the standpoint of medical applications, much significance was held by the development of effective technologies for the functionalization of GNPs with molecules belonging to various classes, which ensure nanoparticle stabilization in vivo and targeted interaction with biological targets. At this juncture, the best stabilizers are thiolated derivatives of PEG and other molecules. Specifically, PEG-coated particles can circulate in the blood stream for longer times and are less susceptible to the attack of the cellular components of the immune system. However, the creation of ‘‘stealth’’ conjugates, able to bind to This journal is

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biological targets in an effective and target-oriented way, remains an unresolved problem. It is now generally recognized that GNP conjugates are excellent labels to use in bioimaging, which can be realized by various biophotonic technologies, including dark-field resonance scattering microscopy, confocal laser microscopy, diverse versions of two-photon scattering and own luminescence of GNPs, optical coherence and acoustic tomography, and so on. GNP conjugates have found numerous applications in analytical research based on both state-of-the-art instrumental methods (SERS, SEIRA, LISNA, etc.) and simple solid-phase or homophase techniques (dot assay, immunochromatography, etc.). The following two examples are illustrative: (1) by using GNP–antibody conjugates, it is possible to detect a prostate-specific antigen with a sensitivity that is millionfold greater than that in the ELISA.498 (2) The sharp dependence of the system’s color on interparticle distances enables mutant DNAs to be detected visually in a test known as the Northwestern spot test.125 Along with the literature examples of clinical diagnostics of cancer, Alzheimer’s disease, AIDS, hepatitis, tuberculosis, diabetes, and other diseases, new diagnostic applications of GNPs should be expected. Progress in this direction will be determined by success achieved in improving the sensitivity of analytical tests with retention of the simplicity of detection. The limitations of homophasic methods with visual detection are due to the need to use a large number [approximately 1010 (ref. 21)] of nanoparticles. Even at the minimal ratio between target molecules and particles (1 : 1), the detection limit will be ca. 0.01 pM—considerably (millionfold) higher than the quantity of target molecules to be detected, e.g., in typical biopsy samples.21 Thus, sensitivity can be improved either by enhancing the signal (PCR, autometallography, etc.) or by using sensitive instrumental methods. For instance, single-particle instrumental methods289 have a single-molecule detection limit that is attainable in principle. Specifically, the SERS is a trend technique to detect very low concentrations of solutes (see, e.g., the recent review and reports by Liz-Marzań and coworkers499–501 regarding SERS detection of biological molecules). However, the topical problem is to create multiplex sensitive tests that do not require equipment and can be performed by the end user under nonlaboratory conditions. A prototype of such tests is Pro Strips,TM which can simultaneously detect five threads: antrax, ricin toxin, botulinum toxin, Y. pestis (plague), and staphylococcal enterotoxin B. The physical basis of the new tests may be associated with the dependence of the plasmon resonance wavelength on the local dielectric environment or on the interparticle distance. GNP-assisted PPTT of cancer, first described in 2003, is now in the stage of clinical trials.305 The actual clinical success of this technology will depend on how quickly it will be possible to solve several topical problems: (1) development of effective methods for the delivery of radiation to tumors inside the organism by using fiber-optic technologies or nonoptical heating methods, (2) improvement of the methods of conjugate delivery to tumors and enhancement of the contrast and accumulation uniformity, and (3) development of methods for controlling the process of photothermolysis in situ. GNP-aided targeted delivery of DNA, antigens, and drugs is one of the most promising directions in biomedicine. Chem. Soc. Rev., 2012, 41, 2256–2282

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Specifically, research conducted by Warren Chan’s teams at Toronto University502 has shown the size-dependent possibility of delivery of GNPs complexed with herceptin to cancer cells with much greater effectiveness than that obtained with a pure preparation. The recent critical reexamination of the PPTT concept, based on the intravenous targeted delivery of GNPs conjugated with molecular probes to the molecular receptors of cancer,343 indicates that there is a pressing need to continue research in this direction. The discovery of adjuvant properties in GNPs has created favorable conditions for the development of next-generation vaccines. Finally, there is need to continue and expand work in the area of GNP biodistribution and toxicity. Although the past five years have seen significant research activity22,32,503–505 several important aspects remain to be studied. It is commonly recognized now that the final conclusions concerning biodistribution and toxicity can be affected by many factors, including particle size and shape, functionalization methods, animal types, particle administration doses and methods, and so on. For instance, Alkilany and Murphy504 addressed the important question of the origin of toxicity of GNP suspensions. The well-known example of CTAB-coated gold nanorods clearly shows that one should discriminate between the toxicity of GNPs themselves and that of a dispersion medium in which the GNPs are dispersed (‘‘supernatant control’’).504 Although bulk gold is known to be chemically inert, the nanotoxicity of GNPs with sizes smaller than 3–5 nm may be different from that of both organogold complexes and larger GNPs. In particular, GNPs with diameters of 1–2 nm have potentially higher toxicity because of the possibility of irreversible binding to cell biopolymers. For example, Tsoli et al.506 and Pan et al.507 reported that 1.4 nm GNPs were toxic to various cell lines, whereas no toxicity was found for 15 nm GNPs. Yet, numerous experiments with cell cultures did not reveal noticeable toxicity of 3 to 100 nm colloidal particles, provided that the limiting dose did not exceed a value of approximately 1012 particles per mL. The available data on the toxicity of GNPs in vivo are rare and somewhat controversial. One can only speculate that noticeable toxicity does not occur during short-period (approximately weeklong) administration of GNPs at a daily dose not greater than 0.5 mg kg1. Perhaps this estimate may sound too strong if we compare it with the data reported by von Maltzahn et al.304 Those authors used gold nanorods at a total dose of 20 mg kg1 and did not observe any toxicity in either tumor-bearing or tumor-free mice. Whereas there are more than 40 reports on GNP toxicity in vitro, those studies cannot be used as good predictors of possible toxicity in vivo. For example, Chen et al.454 observed that the toxicity of the same GNPs was contradictory for models in vivo and in vitro. As pointed out by Alkilany and Murphy,504 one should introduce standards for GNP characterization not only prior to administration to a biological model but also after mixing with biological media. Otherwise, there may be a change in GNP charge, desorption of stabilizing molecules, and, eventually, GNP aggregation. It should be emphasized that GNPs are not biodegradable. Therefore, the biodistribution and excretion kinetics have to 2274

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be studied comprehensively for different animal models. The organs of the reticuloendothelial system are the basic primary target for the accumulation of GNPs within the size range 10–100 nm, and the uniformity of biodistribution increases with a decrease in particle size. As the excretion of accumulated particles from the liver and spleen can take up to 3–4 months, the question as to the injected doses and possible inflammation processes is still of great importance. Bioaccumulated GNPs can interfere with different diagnostic techniques, or accumulated GNPs can exhibit catalytic properties. All these concerns, together with potential toxicity, are big limitations of GNPs on a successfully clinical translation. Nowadays, despite the huge numbers of studies regarding the synthesis and functionalization of GNPs (different shapes, coatings, sizes, charges, etc.), there are very few nanomaterial-based pharmaceuticals on the market (see Rivera Gil et al.508). In summary, there should be a coordinated research program to establish correlations between the particle parameters (size, shape, and functionalization with various molecular probes), the experimental parameters (model; doses; method and time schedule of administration; observation time; organs, cells and subcellular structures examined; etc.), and the observed biological effects.

Acronyms CTAB EGFR GNP(s) PEG PDT PPTT SPIA SPR TEM TNF

cetyltrimethylammonium bromide epidermal growth factor receptor gold nanoparticle(s) poly(ethylene glycol) photodynamic therapy plasmonic photothermal therapy sol particle immunoassay surface plasmon resonance transmission electron microscopy tumor necrosis factor

Acknowledgements We acknowledge support from the Russian Foundation for Basic Research and from the Presidium of the Russian Academy of Sciences within the program ‘‘Basic Sciences for Medicine.’’ We also acknowledge support by grants from the Ministry of Education and Science of the Russian Federation (no. MK-1057.2011.2, 2.1.1/ 2950, 14.740.11.260, and 02.740.11.0484) and by a grant from the Government of the Russian Federation designed to support research projects supervised by leading scientists at Russian institutions of higher education. We thank D. N. Tychinin (IBPPM RAS) for his help in preparation of the manuscript.

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