REVIEW Step by Step towards Understanding Gold ...

c 2007 Institute of Chemistry, Slovak Academy of Sciences DOI: 10.2478/s11696-007-0029-0

REVIEW

Step by Step towards Understanding Gold Glyconanoparticles as Elements of the Nanoworld L. SIHELNÍKOVÁ and I. TVAROŠKA*

Institute of Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, SK-845 38 Bratislava e-mail: [email protected], [email protected] Received 22 January 2007; Revised 11 April 2007; Accepted 16 April 2007

Gold glyconanoparticles as elements of the nanoworld belong to a group of particles with diameters not exceeding 100 nm. This size scale makes them conformable to common biomolecules. A gold glyconanoparticle consists of three different parts: the gold core, the linkers, and saccharide ligands. The glycocalyx-like surface of these particles mimics the presentation of carbohydrate epitopes of cell surface glycoconjugates. As a consequence, gold glyconanoparticles provide inimitable tools for probing and manipulating the mechanisms of biological processes based on carbohydrate interactions. Each component of the gold glyconanoparticle has a profound effect on the nanoparticle’s properties. Therefore, in this review, elucidation of the overall behavior and properties of gold glyconanoparticles is based on a step by step (component by component) description of the system. Keywords: nanoparticles, gold glyconanoparticles, properties, structure

INTRODUCTION Nanoscience is concerned with small clusters or giant molecules; those consisting of fewer than a hundred atoms and with size range around 1 nm, as well as larger particles formed by thousands of atoms with a diameter up to 100 nm. These objects are referred to as nanoparticles [1]. This means that nanoparticles represent an intermediate dimension between small molecules and bulk materials. However, their physical, electronic, and chemical properties are neither those of bulk nor those of molecular compounds, but rather they strongly depend on the particle size, interparticle distance, nature of the protecting organic shell, and shape of nanoparticles [2, 3]. The so-called ‘size effect’ influences the electronic structure and can result in, for example, a unique structural modification [4]. A decrease in size is also accompanied by a dramatic change in the ratio of surface atoms to interior atoms [1]. Due to the tunable nature of their properties, nanoparticles offer the possibility to create a variety of products with novel characteristics, functions, and applications. Since a large number of applications

using nanoparticles is found within biological systems, the term ‘nanobiotechnology’ was created to describe this group of applications [5]. Nanoparticles can be composed of insulating materials, semiconducting materials, or metals, either in their neutral valence state or in other forms such as their oxides, sulfides, phosphines, nitrides, etc. [1]. Nanoparticles that have semiconducting materials as their core, synthesized with II—VI or III—V column elements of the periodic table, are called quantum dots [6]. The ideal optical properties of quantum dots are exploited in their use as biological tags in ultrasensitive biological detection studies [7]. They provide advantages over conventional dye molecules, organic fluorophores, or radioactive labels, in that they have tunable fluorescence signatures, narrow emission spectra, brighter emission, long fluorescence lifetime and high photostability [8, 9]. Their behavior enables multiplex imaging with a single excitation source and thus prevents overheating of cells or tissue during multicolor imaging [6, 10]. Apart from biological applications, semiconductor nanoparticles serve as converters of sunlight into electricity in solar cells [1].

*The author to whom the correspondence should be addressed.

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L. SIHELNÍKOVÁ, I. TVAROŠKA

Magnetic nanoparticles show remarkable new phenomena such as superparamagnetism, high field irreversibility, high saturation field, extra anisotropy contributions, or shifted loops after field cooling [11, 12]. Industrial applications of magnetic nanoparticles include magnetic seals in motors, magnetic inks for bank cheques, magnetic recording media, as well as biomedical applications [12]. Hyperthermia, a therapeutic procedure that is used to kill tumor cells, bacteria, or viruses, is based on the susceptibility of some magnetic nanoparticles, such as Au/Fe-glyconanoparticles, to heating through hysteresis by applying an external alternating magnetic field [13—15]. Site-specific drug delivery by magnetic nanoparticles utilizes an applied magnetic field to retain them at the target sites [16—18]. Commercial iron oxide nanoparticles can be used as contrast agents in nuclear magnetic resonance imaging for location and diagnosis of brain and heart strokes, liver lesions, or tumors, where the magnetic nanoparticles tend to accumulate at higher levels [19]. Neutral metallic nanoparticles are also of great interest to nanotechnology. Nowadays, gold nanoparticles are probably the most intensively studied nanoparticles representing this group and they are the most stable metal nanoparticles [16]. Despite the chemical inertness and resistance to surface oxidation of bulk gold, the dominance of surface atoms of small size particles enhances chemical reactivity. Therefore, interesting catalytic behaviors are observed [20, 21]. Labeling of target molecules with gold nanoparticles revolutionized the visualization of cellular or tissue components by electron microscopy [22]. Gold nanoparticles exhibit a strong surface plasmon resonance band in the visible range, enabling construction of sensitive colorimetric sensors for various analytes [23, 24]. These particles can bind readily to a wide range of biomolecules. This strategy opened the way for utilization of gold nanoparticles in assembling new materials, developing bioassays and in studies of interactions [16]. In order to control the size of nanoparticles, and to prevent their aggregation and precipitation, they have to either be stabilized by molecules attached to their surface or be embedded in a solid matrix [1]. One of the most elegant passivation routes is represented by self-assembly, i.e. spontaneous formation of passivation monolayers of organic molecules [25]. Modifications of the protecting layers provide a tool to obtain the desired characteristics and to widen the areas of nanoparticle applications. As nanoparticles and biomolecules are of similar length scale, their combination results in the appearance of new and interesting tools for mimicking the biomolecules which are present in cellular systems. Such tools can probe the mechanism of biological processes and provide us with the possibility of handling and manipulating biological components [16, 26]. Nanoparticles with carbohydrates as functional lig238

ands are called glyconanoparticles. Globular, watersoluble, and with a chemically well-defined structure, they provide a glycocalyx-like surface that mimics the presentation of carbohydrate epitopes of cell surface glycoconjugates [27]. Therefore, their applications focus mainly on the study and evaluation of carbohydrate interactions. Furthermore, they can also be utilized as biolabels, biosensors, to intervene in carbohydrate mediated processes in biomedicine, or as building blocks in material science [16]. This review is focused on gold glyconanoparticles. Each glyconanoparticle has three potentially variable components – the metal core, the linker, and the saccharide ligand. In the case of gold glyconanoparticles, the metal forming the core is gold that confers useful optical and electronic properties on the whole system. As each gold glyconanoparticle component plays its incommutable role in the system, it is necessary to describe the system step by step (component by component) to elucidate the overall behavior and properties of a gold glyconanoparticle. This approach will be applied in the following chapters. BARE GOLD CLUSTERS Atomic clusters provide a bridge between isolated atoms and bulk material. As a consequence, some of their properties can be expressed as a function of cluster size, evolving towards their bulk limit. On the other hand, some remarkable physical and chemical properties appear only in nanometer scale [28]. In addition, relativistic effects are enormously strong for gold, making the properties of gold clusters unique even in comparison with other coinage metals [29]. For example, gold in nanoscale exhibits surprising mechanical properties by forming stable nanowires and nanobridges with quantized electrical conductivity [30]. Gold particle size has a profound impact on optical absorption, and this property can be used e.g. in labeling applications or in devising precision therapy for selective imaging and destruction of cancer cells [31]. Although totally inert in bulk phase, gold clusters and nanoparticles can be surprisingly active as catalysts in oxidation and hydrogenation reactions [32]. Finally, gold is typified by its cluster structures which are spontaneous and qualitatively different from the ones formed for clusters of the neighboring elements in the periodic table [33]. All aspects of the physical and chemical behavior of clusters are closely related to the cluster size and are largely determined by cluster structure for a given size. Unfortunately, there is, as yet, no direct method for determining the structure of free clusters in molecular beams. Properties dependent upon geometry have to be measured instead. Then, conclusions on the cluster structure can only be drawn on the basis of comparison of experimental results with the predictions of computational methods [34]. However, a de-


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GOLD GLYCONANOPARTICLES

tailed theoretical analysis of experimental results has to begin by determination of cluster structure. Only afterwards, the agreement between theory and experiment on the other cluster properties can serve as evidence in support of the computed structure [35]. From a computational point of view, searching for the lowest energy configuration (global minimum) is a very demanding task, as the potential energy surface is very flat for clusters, i.e. the number of energetically close isomers reaches tremendous values. In addition, the structure of clusters depends on the method of preparation, so that the experimentally analyzed clusters do not necessarily represent their ground state. Preparation and Detection of Bare Gold Clusters

tion for medium sized clusters (around 50 atoms) can be provided by measurements of ionization potentials [36] and photoelectron spectroscopy [43, 44]. Finally, for small clusters with up to 21 atoms, high resolution photoelectron [38] and optical spectroscopy [36] can be applied. Several difficulties accompany these experiments. Firstly, clusters with narrow size distribution have to be obtained. Even for a given particle size a distribution of structural isomers is observed. Next, the experimental resolution is often not sufficient. Finally, if the particles are prepared by evaporation methods, in which kinetics plays a major role, equilibrium structures are not always achieved. This has led to inconsistency regarding the true equilibrium forms [41]. Theoretical Chemistry of Gold

Production and detection techniques for metal clusters in molecular beams provide the possibility of studying clusters in an interaction-free environment. Due to the short lifetime of bare clusters a cluster source is adapted to allow immediate mass selection and detection in all molecular-beam experiments [36]. Laser vaporization [37, 38] and gas aggregation sources [39] are used most frequently to prepare gold clusters. Other sources, such as seeded supersonic nozzle sources, pulsed-arc cluster-ion sources, ion sputtering sources, or liquid-metal ion sources, also enable the preparation of neutral or ionic metal clusters [36]. In most cases, the heart of a cluster source is a region where supersaturated vapor of the material forming the clusters is produced. Hot vapors can be gained by heating up a piece of bulk material in a crucible or by hitting a target with a laser pulse or an ion beam. Supersaturation is then achieved by means of supersonic expansion, which causes an adiabatic cooling, or by mixing the hot vapors with a cold inertgas flow, which acts as a collisional thermostat. In the first approach hot clusters are usually produced at temperatures close to the evaporation limit. In the latter, on the other hand, very cold metallic clusters are grown mainly by the addition of single atoms [40]. During preparation, kinetics plays an important role and equilibrium structures may not be achieved [41]. Bioprecipitation, offering a practical and low-cost method for obtaining gold colloids from water containing gold ions, is based on the ability of Medicago sativa roots and shoots to bind gold(III) ions in aqueous solutions and reduce it to gold(0). In principle, it should be possible to control the size and shape distribution by adjusting chemical parameters [42]. Various experimental techniques have been applied to determine the atomic arrangements in clusters. Each method is restricted to a certain size range of gold clusters [43]. Large particles, consisting of hundreds or thousands of gold atoms, can be studied after deposition by electron microscopy [39, 41] and electron diffraction [41]. Experimental structural informa-

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Gold can be characterized as a noble, but mechanically ductile and malleable, yellow metal. The nobility of bulk gold and its color represent only two unique features of gold. The extraordinary behavior originates from relativistic effects, which are larger for gold than for any other element with an atomic number less than 100 [29]. Therefore, deducing the properties of gold from theoretical calculations requires the relativistic extension of the Schrödinger equation. This is provided by the Dirac equation [45]. Relativistic effects Relativistic effects may be divided into three types, direct and indirect kinematical effects, and effects of spin-orbit coupling [46]. The direct relativistic effects stem from high velocities of the electrons in the vicinity of the nucleus, approaching the velocity of light. As a result, the effective Bohr radius is reduced for inner electrons. The higher shells will suffer a similar contraction to be orthogonal against the lower ones [47]. This contraction is reflected in a decrease of orbital energies and of the total energies in comparison with the non-relativistic. These effects are important for the shells with appreciable amplitude in the vicinity of the nucleus, mainly s and p shells [48]. Electrons of d and f shells, on the other hand, never come close to the nucleus. Therefore, the kinematical effects come to light only indirectly as an expansion of the d and f orbitals due to the shielding of the nucleus charge by the contracted core orbitals [48]. Altogether, kinematical effects result in a much smaller gap, between the full 5d band and the Fermi level of the half-filled 6s band, than the corresponding gap for non-relativistic set of orbitals (Fig. 1) [49]. Finally, strong spin-orbit couplings also play an important role [46]. The relativistic effects on structure and properties increase down the column of the periodic table roughly


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physics of gold in every aspect. Gold clusters do not make an exception in this respect. One important consequence is that small gold clusters favor planar structures. As regards large gold clusters, the relativistic effects confer on them structures different from those of compact ones [50]. Computational methods

nonrelativistic

relativistic

+ spin-orbit interaction

Fig. 1. Energy levels of Au frontier orbitals.

with the fourth power [48], and for the valence electrons with the second power, of the nuclear charge. On the sixth row, they become comparable in size with diverse shell-structure effects. The relativistic effects are amplified by the effect of filling the 4f shell on the subsequent 6s and 6p shells, the so-called lanthanide contraction [29]. Concerning atomic properties of gold, the relativistic valence s-contraction/stabilization results in an increase in both the first ionization potential and the electron affinity [49]. In fact, gold has the highest electron affinity of all metals and is therefore able to form a stable compound in which it acts as an auride anion, Au− . The stabilization of the higher oxidation states +3 and +5 can also be rationalized on the basis of relativistic effects, which cause more pronounced d-participation in bonding through a substantially decreased 5d/6s gap [46]. Molecular properties, as well as properties of bulk gold, can be explained in a like manner. Atomic and ionic radii of gold are strongly reduced. Interestingly, apart from gold—ligand bond distances, which are shortened according to the type of ligand, for bulk gold the relativistic bond contraction is not as significant as for Au2 . Such phenomenon is not demonstrated by silver [46]. The reluctance of Au+ to accept more than two ligands and the aggregation of linearly two-coordinate gold(I) complexes, which is governed by a close approach of the metal atoms (‘aurophilicity’), are inconsistent with the properties of copper and silver congeners. The aurophilic bonding may even overrule substantial repulsive forces between two cations or anions [49]. The spectacular yellow color of bulk gold can be ascribed to a transition from the filled 5d band to the Fermi level. The gap between 4d and 5s for silver is much larger and the analogous absorption occurs in the ultraviolet region [47]. A high oxidation potential makes gold a non-corrosive, noble metal [49]. The relativistic effects influence the chemistry and 240

The most rigorous method for treating relativity in quantum-chemical calculations starts from the four-component Dirac—Coulomb—Breit Hamiltonian, with the Breit operator introducing the next higher order in the electron—electron interaction operator. The charge-conjugated degrees of freedom are in this case treated as dynamical variables and thus require their own basis set in the calculation. This method involves extreme demands on computational resources and time [48]. It can be transformed by integrating out the charge-conjugated degrees of freedom into various two-component equations, such as zero-order regular approximation or Douglas—Kroll approximation. Within these, the two-electron part of the Hamiltonian can also be transformed. Considering only a spin-orbit average leads to a one-component method known as scalar relativistic approach [29]. For a multi electron system, the exchange and correlation parts can be treated by density functional theory or by wave-function-based methods, such as second or fourth Møller—Plesset [29]. The most significant obstacle of the first-principle methods for use in gold cluster calculations is their incapability of optimizing an extremely large number of randomly generated initial structures in a reasonable time interval. This prevents us from determining the true global total energy minimum using these precise methods [51]. Therefore, several empirical approaches have been used to describe larger clusters. The electronic structure of metallic clusters has been treated by invoking empirical potentials or by solving the density functional equations for a jellium background of the cores. In such calculations, both the number of explicitly treated electrons and the number of basis functions needed for each are drastically diminished [47]. Most of the current calculations deal with 11 [52, 53] or 19 [38, 54] outermost electrons. These approximate methods are computationally less demanding, thus allowing for a detailed search in structure space, and the prediction of structures for clusters with well above 100 atoms, in an unbiased way. On the other hand, since they are approximate it is not obvious how reliable they are [51]. The calculations on spherical clusters where only the valence electrons per Au are treated explicitly, whereas all the core electrons are subjected to a uniform jellium background, focus essentially only on electronic-shell effects. In this case, the packing effects are excluded [51]. In contrast with this approach,


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Table 1. Shells of Atoms [58] Structural form Icosahedron Decahedron Truncated decahedron Octahedron Cubooctahedron with triangular faces Cubooctahedron with hexagonal faces Tetrahedron

Total number of atoms 10 K 3 − 5K 2 + 11 K −1 3 3 5 3 1 K + K 6 6 10 K 3 − 5K 2 + 11 K −1 3 3 2 3 K + 13 K 3 10 K 3 − 5K 2 + 11 K −1 3 3 16K 3 − 33K 2 + 24K − 6 1 3 K 6

+ 12 K 2 + 13 K

Values for K = 1—5 1, 13, 55, 147, 309 1, 7, 23, 54, 105 1, 13, 55, 147, 309 1, 6, 19, 44, 85 1, 13, 55, 147, 309 1, 38, 201, 586, 1289 1, 4, 10, 20, 35

K denotes the number of shells.

metallic potentials developed under different names (effective medium, embedded atom, glue model) [55] include electronic effects only approximately and put emphasis on packing effects. For clusters both geometric packing effects and electronic-shell effects may be responsible for the occurrence of particularly stable clusters with a certain number of gold atoms, the so-called magic numbers [51]. Generally, the simple potentials that do not directly include effects due to electronic orbitals, i.e. due to direct chemical bonds, tend to prefer closed packed structures. When taking into account the electronic orbitals, the structures get less symmetric, and when increasing the accuracy of the treatment of the electronic orbitals, the geometric arrangement of the atoms becomes less and less closed packed [51]. Despite the utilization of empirical potentials for a simplified description of the interatomic interactions, searching the global minimum of gold clusters continues to be a very time-consuming task. The increase in the number of minima might be even proportional to an exponential function of the number of atoms. The global minimum searches [40] are based upon the ‘basin-hopping’ algorithm [34], genetic algorithm [56], simulated annealing [57], quantum annealing, etc. Although these algorithms are very helpful, they cannot guarantee that the lowest minimum is reached. The only way to reach the global minimum for certain is to sample all minima, compare them, and choose the lowest one. This cannot be done routinely due to extreme time demands [40]. Structures of Bare Gold Clusters Magic numbers The optimal structure of a metal nanocluster is a delicate balance between several factors whose relative importance depends on the size of the cluster. Size-dependent variations in the energetic stability can be found, resulting either from an arrangement of the delocalized valence electrons into a collective shell structure or from an arrangement of atoms into special structures of atomically closed-shell configurations. Filling of a major angular momentum shell leads

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to extra stability and corresponds to electronic magic cluster sizes [53]. The growth of clusters by accretion of a layer of atoms is responsible for the extra stability of a cluster when a new complete layer of a structure of certain symmetry is built up. The total number of atoms in such clusters agrees with the geometric magic numbers [58]. Nanometer-size particles frequently exhibit structures prohibited in the crystallographic translationalsymmetry regulations, such as icosahedral and decahedral morphologies with five-fold symmetry axes [59]. The total number of atoms in highly symmetric polyhedral morphologies is given by a corresponding equation [58], as listed for some of them in Table 1, where K is the number of shells. However, not all of these structures are likely to be exhibited by real clusters. Decahedron and octahedron have very large surface area in addition to internal strain and therefore truncated forms are expected to be energetically preferred at any cluster size. Marks decahedron presents another form of truncation which exposes reentrant (111) faces in addition to (100) faces [58]. There are two ways to detect magic numbers in the size distribution of clusters. The first one is based on the momentary hesitation of the evaporation process on heating clusters, for example by laser, to the temperature at which they evaporate atoms. The other method capitalizes on the fact that the ionization threshold of geometrically perfect clusters is higher in energy than that of imperfect clusters. For this reason, stable clusters will show up as minima in the mass spectra [58]. Theoreticians, on the other hand, employ the clusters in ground-state structures to find the rules of cluster growth by calculating the maximum of nearest neighbors of atoms in the clusters [60]. However, for real clusters the energetic competition between structural types is likely to be important in determining the morphology. Examination of this competition requires comparing the growth sequences of different structural types for a specific potential, rather than just counting nearest neighbors [61]. The basin-hopping algorithm, with Sutton—Chen potential employed for gold clusters of up to 80 atoms, revealed the 38-atom truncated octahedron and the


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75-atom Marks decahedron to be particularly stable. For silver and copper the stability was also revealed for the 55-atom Mackay icosahedra [34]. However, through more profound studies these magic number gold clusters were detected to be amorphous [55]. The electronic shell structure can be theoretically predicted using the jellium model developed to a high degree of sophistication. Experimental verification is derived from the electronic response properties, such as ionization potentials, electron affinities, or collective excitations [36]. Experiments revealed that for clusters of gold the most significant dips in electron affinities are that of 8-, 14-, 20-, 34-, and 58-atom clusters [37, 44]. However, in contrast to silver and to the well-known ligand-stabilized Au55 complexes, no particular strong signal is found for the Au55 bare cluster [37]. In addition, a poor correspondence between the electron affinities and the shell model for very small gold clusters was detected. This result is not surprising due to the preference of many small metallic clusters, especially gold clusters, to support planar geometries. Another recognized feature of small gold clusters is presented by large odd-even oscillations in the electron affinities as a result of a wider spacing of the energy levels in the HOMO—LUMO energy region. The odd-even oscillations diminish with increasing cluster size until they are completely washed out [44].

Fig. 2. Geometries of neutral gold clusters [28] (reprinted figure with permission from Fernández, M., Soler, M., Garzon, L., Balbas, C., Phys. Rev. B 70, 165403, 2004; copyright (2006) by the American Physical Society).

Planar structures of small gold clusters Relativistic effects are performed in the geometry of even very small gold clusters. While the different behavior of neutral and charged coinage metal clusters with respect to alkali clusters is understood through the relative contribution of d electrons to the bonding, the explanation of the especially pronounced deviations in the case of gold is based on the strong relativistic effects in gold systems. A major feature that distinguishes Au clusters from Ag and Cu ones is the different onset for the transition from one-dimensional to two-dimensional and from two-dimensional to threedimensional geometry as the cluster size increases [28]. DFT calculations on small gold clusters revealed, among many close-lying isomers, the preference of global minima for planar structures. Namely, this preference is pronounced for neutral gold clusters consisting of up to 11 [28], 13 [62, 63], or 14 [64] atoms, for cationic gold clusters with up to 7 [28] atoms and for anionic gold clusters with up to 12 [28, 62] atoms. In contrast, the maximum number of atoms forming planar structures of silver is 6, 5, and 5, and for copper 6, 4, and 5, for neutral, cationic, and anionic clusters, respectively. The gain of cohesive energy by forming three-dimensional Ag and Cu structures was demonstrated to be two times larger than for gold [28]. An analysis of different contributions to the binding energy revealed 242

Fig. 3. Geometries of cationic gold clusters [28] (reprinted figure with permission from Fernández, M., Soler, M., Garzon, L., Balbas, C., Phys. Rev. B 70, 165403, 2004; copyright (2006) by the American Physical Society).

that it is a substantial d—d overlap that makes planar structures energetically competitive for small Au clusters, driven by a sizeable gain in kinetic energy [65]. The favorable geometries of global minima were suggested and the example for gold clusters as presented in reference [28] is depicted in Figs. 2— 4. The nearest-neighbor distance decreases progressively by 7 % (8 %) for two-dimensional (onedimensional) gold geometry in comparison with the three-dimensional (two-dimensional) case. The interatomic distance is 2.88 ˚ A for bulk gold and only 2.47 ˚ A for Au2 [52]. The corresponding decline for both


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Fig. 4. Geometries of anionic gold clusters [28] (reprinted figure with permission from Fernández, M., Soler, M., Garzon, L., Balbas, C., Phys. Rev. B 70, 165403, 2004; copyright (2006) by the American Physical Society).

silver and copper is only 4 % (two-dimensional vs. three-dimensional) and 5 % (one-dimensional vs. twodimensional), respectively, which is connected with completely different geometrical structures of these clusters [28]. The results for the planarity of gold clusters agree with the expectations from ion mobility measurements, calculations for cationic and anionic gold clusters, and with photoelectron spectra [28, 62, 66, 67]. The above-mentioned calculations, allowing for full relaxation without any symmetry constraints, considered scalar relativistic effects only. The spin-orbit coupling was shown to increase the binding energy for all the clusters within the same magnitude, and therefore did not change the relative stability among different isomers predicted from the DFT calculations without spin-orbit coupling. The spin-orbit coupling also results in a decrease of the HOMO—LUMO energy gap, but has no effect on the magnetic moment [64]. The choice of approximation to the exchange-correlation functional may change the isomer ordering of small metal clusters. Generally, inclusion of gradient corrections stabilizes open structures with respect to the local density approximation [65]. Modeling of the clusters by the Sutton—Chen family of potentials [34] or Murrell—Mottram potential [68] predicted a three-dimensional structure for gold tetramer. This is not surprising since the parameters in the Sutton—Chen potential for Au clusters were obtained by fitting the properties of bulk Au [63, 69]. Structures of magic number gold clusters Gold clusters consisting of 38, 55, and 75 atoms correspond to the magic number clusters and their lowest energy structures are therefore expected to be highly symmetrical. The pair-potential structures

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found for these sizes are the truncated octahedron, Mackay icosahedron, and Marks decahedron, respectively [70]. However, several theoretical studies [43, 53, 55, 57, 71, 72] as well as experiments [43] pointed out that the global minima at these magic cluster sizes owe the amorphous structures. The structures of Au55 and Au75 , as obtained by unconstrained global optimizations with the Gupta potential, have a central atom surrounded by 14 atoms. In the amorphous structure of Au38 , one of the atoms of the central octahedron is transferred to the surface shell, leaving a 5-atom core with a triangular bipyramid structure [71]. There are many close-lying isomers for each cluster size, the energy of which is only slightly larger than that of the global minimum. For Au75 the energy difference between Marks decahedron and the global minimum amorphous structure is so small that some less accurate calculations indicated the Marks decahedron to be the global minimum [55, 73]. Although the disordered and ordered gold cluster isomers are very close in energy, their calculated electronic properties are different. Such an effect could lead to different cluster optical responses according to their size and symmetry [57]. The above-mentioned peculiarities of the structural properties of gold clusters do not result from kinetic or temperature effects but are caused by special bonding mechanisms involving gold atoms, such as strong non-additivity in the many-body forces, shortrange interaction, relativistic effects, and d-electron contribution [72]. The key factor that favors the amorphisation of gold nanoclusters is the tendency of metallic bonds to contract at the cluster surface due to reduced coordination [55]. In contrast to gold clusters, the potential parameters of silver generate longer range interactions which give rise to a reverse behavior. The symmetric structures of the ground states are preferred and the lowestlying isomers of higher energy are separated by a finite energy gap from the ground state [57]. Ordered structure of Au20 The trend of higher energetic stability for disordered or low-symmetry isomers in gold clusters in the size range 13—75 is interrupted by the 20-atom gold cluster. Photoelectron spectroscopy experiments and relativistic DFT calculations revealed that Au20 has the lowest-energy tetrahedral structure. While for Ag20 and Cu20 an amorphous-like structure was found to be more stable than the tetrahedral one, for Au20 the tetrahedral structure is 0.033 eV per atom more stable than the first amorphous-like structure [28]. Tetrahedral Au20 has a very large surface area, as all atoms are on the cluster surface, and a large fraction of corner sites with low coordination. Neutral


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Au20 is a closed-shell molecule with a large HOMO— LUMO gap, largest among all known coinage-metal clusters. This suggests that Au20 is a highly inert and stable molecule and may possess novel chemical and physical properties [38]. Kinetic and thermodynamic effects in gold cluster structures When comparing the growth sequences obtained from theoretical calculations with the experimental ones, it must be remembered that the structures exhibited by clusters in experiments depend on factors such as the method of production, the time scale of the experiment, and the growth kinetics. Therefore, the thermodynamic equilibrium is not always reached. In addition, theoretical methods for structure optimization which minimize the energy, not the free energy, only look for the zero temperature equilibrium structure [61]. These effects were demonstrated on gold nanoparticles in a size range of 3—18 nm produced by cooling gold vapor. The kinetics of nucleation and growth determined the structure of the clusters to be icosahedral. However, when annealing at temperatures just below the melting points these particles undergo a solid-solid transformation into the decahedral morphology. Conversely, no solidsolid transition from the noncrystalline to the crystalline structure was observed up to the melting points. The size- and temperature-dependent structural transitions are strongly ruled by the free-energy barriers between the different structural types [41, 59]. Gold clusters consisting of 32 atoms were predicted, using relativistic quantum-chemical calculations, to possess a highly stable cage structure with the same icosahedral symmetry as C60 [74]. This ‘golden fullerene’, the first all-gold fullerenic species, was anticipated to possess some fascinating physical and chemical properties. However, this isomer was not obtained experimentally. Although the Ih cage is the most stable structure at zero temperature, the relative stability of the C1 isomer increases rapidly with temperature, due to the contribution of vibrational entropy, and becomes the most stable cluster above approximately 300 K [54]. Instability of bare gold clusters Unprotected nanoclusters are unstable by nature and tend to coalesce with other nanoclusters. To prevent aggregation, the surface of clusters needs to be passivated with ligands such as thiols, long-chain fatty acids, amines or polymers [75]. However, an understanding of the properties of isolated clusters of welldefined size in the gas phase is an essential first step 244

towards the description of surface-passivated clusters [36]. PASSIVATED GOLD NANOPARTICLES Preparation of stable gold particles of nanometer dimensions requires passivation of the individual particles to protect them from sintering and modifications of their properties by their environment. Such passivation can be achieved in various ways. Bare surfaces of metals adsorb organic molecules readily because these adsorbates lower the free energy of the interface between the metal and the ambient environment. The spontaneous absorption of passivating agents results in the formation of self-assembled monolayers [76]. A self-assembling molecule consists of three parts. The first part is the headgroup, a chemical functionality with a high affinity for the surface. The headgroup is connected to a specific site on the gold surface through a chemical bond. The second molecular part is formed by an organic moiety, in the simplest case an alkyl chain, which is terminated by the last part, an air-monolayer interface group. The interplay between interchain forces and the interaction with the surface, combined with entropic effects, determines both conformation of the individual chains within the assembly and their packing and ordering with respect to each other [77]. The steric bulk of the self-assembling molecules provides a physical barrier that prevents the metal surfaces from contacting each other directly. This can also change the surface charge of a cluster and thus change its stability towards aggregation. The combination of the energetic stabilization of the metal surface by the molecules, the consequences of charge—charge interactions, and the steric repulsion between particles prevent the system from forming aggregates [76]. There is a number of headgroups that bind to specific metals [76]. Anchor sulfur organic groups, such as thiols (RSH) and disulfides (RSSR), R refers to an alkyl, become a standard component of supramolecular systems using self-assembled monolayers for the functionalization of extended gold surfaces and for the preparation of monolayer-protected gold clusters [78, 79]. The thiol-capped gold nanoparticles represent a strong interaction between the gold nanoparticle and a capping agent [80], where the compact ordered monolayer structure does not substantially disrupt the geometric or electronic structure of the metal surface. On the other hand, approaches based on halide- or oxygen-cluster surface chemical bonds ‘deaden’ the surface gold layer and otherwise limit handling and measurements [73, 81]. Despite a large variety of possible capping agents, this chapter is focused on sulfur-organic-group-passivated gold clusters which are the most common. Due to the fact that these self-assembled monolayers provide a convenient platform for attaching a wide range of functional groups


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to the surface [82], including biomolecules, they also have the closest relation to gold glyconanoparticles. Preparation and Characterization of Passivated Gold Clusters The Brust—Schiffrin method [83] allows a facile synthesis of gold nanoparticles stabilized with alkylthiols. A gold salt (AuCl− 4 ) is transferred to toluene using tetraoctylammonium bromide as the phasetransfer reagent and reduced by NaBH4 in the presence of alkylthiol. The technique of synthesis results in gold nanoparticles of controlled size, with a diameter ranging from 1 nm to 3 nm and with a maximum in the particle size distribution at about 2.0 nm. Smaller average core sizes are obtained by using larger molar ratios of thiol to gold or by the rapid addition of reducing agent. These nanoparticles can be repeatedly isolated and redissolved in common organic solvents without irreversible aggregation or decomposition. Brust et al. extended this synthesis into a single phase system [84], opening a way to the synthesis of gold nanoparticles stabilized by a variety of functional thiol ligands [2]. The second most important method of synthesis of stabilized gold nanoparticles is that of Turkevich et al. [85], which uses a citrate reduction of a gold salt in water. This leads to gold nanoparticles of approximately 20 nm in diameter. Such a method is used when a rather loose shell of ligands is required around the gold core in order to prepare precursors to valuable gold nanoparticle-based materials [2]. Size of the prepared passivated nanoparticles, of the corresponding gold core and its coverage by the passivating molecules can be determined quite easily. However, the chemical processes accompanying the formation of the adsorbed species are not sufficiently elucidated [78, 86, 87]. The identification of the preferred absorption geometries and binding energies [88], and the form of the adsorbed organic-sulfur chains (existence of disulfides vs. thiolates) is necessary, but has not yet been satisfactorily characterized by either experimental or theoretical studies [79]. The most common characterization technique [2] is high-resolution transmission electron microscopy [73, 89]. It directly provides a photograph of the gold core of the passivated nanoparticles. The core dimensions can also be determined using scanning tunneling microscopy, atomic force microscopy, small-angle Xray scattering [90], a laser desorption-ionization mass spectrometry [91], and X-ray diffraction [73]. The dispersity of the sample can be deduced from transmission electron microscopy pictures [83, 84]. The mean diameter of the cores allows determination of the mean number of gold atoms in the cores. Then, the calculation of the average number of ligands starts from the ratio of gold to sulfur atoms determined by the elemental analysis. This number can also be deduced from X-ray photoelectron spectroscopy or thermo-

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gravimetric analysis [90]. The global shape can be determined by mobility measurements, and useful information on the geometry can be provided by photoabsorption and photodetachment spectra, when combined with reliable calculations [92]. For an understanding of cluster chemisorption, identification of size effects and especially of the most probable chemisorption sites, photoelectron detachment spectroscopy was found to be a very useful technique [93]. The most commonly used organic structural tool, nuclear magnetic resonance spectroscopy, can be utilized to understand, on a molecular level, the bonding between the organic substrate and the gold nanoparticle [94]. The electronic behavior of the capped gold nanoparticles can be monitored by X-ray absorption near-edge structure, a technique that is very sensitive to the d-charge redistribution of transition metals induced by a change of local environments [95]. The role of the extended X-ray absorption fine-structure analysis is also very relevant as it allows determination of the microstructure that produces the higher d-hole density in thiol-functionalized gold nanoparticles [96]. Due to the complexity and newness of nanomaterials, combinations of different experimental techniques are usually required. In addition, these must be combined with computational methods to get a deeper insight into the nature of the problem. In theoretical calculations, the interactions of gold cluster-sulfur headgroup and chain—chain interactions have to be considered apart from all the requirements on the gold cluster itself. Influence of Capping Agents on Gold Nanoparticle Properties A large fraction of atoms located at the surface is a characteristic feature of bare gold clusters. Capping the clusters with different chemical species results in the modification of the surface, and these capping agents can significantly alter the properties of the nanoparticles as a whole [80]. Although properties of the passivated clusters will be discussed in this chapter in comparison with bare gold clusters, it should be remembered that bare gold clusters are not stable particles and can only be produced with a very limited life-time. Therefore, most of their properties cannot be assessed experimentally unless embedded in a solid matrix or passivated. Thus, theoretical calculations are the only source of information. For this reason, the properties of bare gold clusters were not mentioned in the chapter devoted to them and will only be discussed here. Structural properties Detailed knowledge of the lattice structure, shape, morphology, surface structure and bonding of pas-


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sivated gold clusters, and the contribution of the passivating shell to these characteristics, is fundamental in predicting and understanding their electronic, optical, and other physical and chemical properties [97, 98]. In self-assembled monolayers, the packing and ordering are determined by the interplay of chemisorption and intra- and interchain nonbonded (e.g. van der Waals, steric, repulsive, electrostatic) interactions [77]. However, the question as to exactly how thiols and disulfides bind to gold surfaces to form self-assembled monolayers has not been clarified yet [99]. Many computer simulations aimed at revealing the mechanism of thiol, thiolate or disulfide absorption relied on a slab as a model of gold cluster surfaces. On Au(111), formation of thiolates was found to be favored over methylthiol absorption, with sulfur in fcc threefold hollow site forming three bonds with the surface [99, 100] or at the bridge site slightly off-centered towards the fcc hollow site [101]. Modifications induced on the slab surface were particularly important at the fcc site around which Au—Au distances elongate by 16—20 % upon absorption of methylthiolate to a length of 3.45 ˚ A [99]. Longer alkyl chains were shown not to change the absorption energies and the Au—S bonding geometry [101]. However, comparative studies on the slab model and the smaller clusters found differences in the structural characteristics, in the energetics, and also in the nature of the chemisorptive bonds of the thiolates, thus showing that smaller aggregates can by no means capture the chemical picture of the (111) surface [99, 102]. The quantum-mechanical calculations on structural properties of the smallest gold passivated clusters, Aun S for n = 1—5 and Aun S2 , for n = 1—4 led to the appearance of the three-dimensional structures already at n = 4, in contrast to bare gold clusters. Another important aspect provided by the calculations is a high preference of the S atom to bind to two, three, and four Au atoms [103]. For completely thiolated small gold clusters, gold complexes of the homoleptic type (RSAu)x , R being an alkyl, for x = 2—12, the metal—metal cohesion is smaller or in the same range as the CH3 SAu—CH3 SAu cohesion in the thiolated clusters. This suggests that small thiolated gold clusters should prefer open cyclical structures instead of a compact metal core structure capped by a protecting thiolate layer. For (CH3 SAu)2 to (CH3 SAu)4 , the Au—S frameworks are close to planar. For the larger sizes, the directionality in the S bonds develops a zigzag motif. For (RSAu)4 , for example, the bond lengths Au—S, Au—Au and S—C are 2.35 ˚ A, 3.31 ˚ A and 1.84 ˚ A, respectively. The structural and energetic changes for (RSAu)4 upon ligand exchange are minor. However, the electronic structure is clearly dependent on the ligand [102]. Interestingly, there is growing evidence for the relevance of (RSAu)x in the area of larger gold nano246

particles. An example of the passivated 38-atom gold cluster will be discussed later [104]. The energetically most favorable structure for the Au38 cluster, according to recent molecular dynamics investigations using the embedded atom potential, is face-centered-cubic with a truncated octahedral morphology [91, 105]. In this structure, there is a regular six-atom octahedron centered about the origin, with an interatomic distance of 2.82 ˚ A. The distance from these inner atoms to the surface atoms is 2.67 ˚ A, and the interatomic distance between nearestneighbor surface atoms is 2.72 ˚ A. The surface consists of six (100) facets and eight (111) facets. The unconstrained optimization of this structure within the local-density approximation introduces only minor changes to the structure. The eight atoms in the middle of the (111) facets displace slightly outwards to make the cluster more spherical, and as a result all of the interatomic distances become more uniform, falling in the range of 2.74—2.78 ˚ A. These two structures are used as a starting point in studies on passivation effects [106]. An energetical comparison of absorption of intact thiols, thiolates and disulfides on Au38 revealed that dissociation of the disulfide with formation of strongly bound thiolates is favored, in agreement with experimental evidence [77]. Thiolates resulting from S—H bond cleavage of thiols can coexist with the adsorbed intact species and become favored if accompanied by the formation of molecular hydrogen [99]. The preferred absorption site for a thiolate is the bridge site [99]. The passivated crystal, after the outward relaxation of the six-atom inner octahedron and the 24 corner surface gold atoms, was found to have interatomic distances increased to 2.95—2.97 ˚ A, which mean less significant elongation than on the extended surface [99, 106]. The eight atoms in the middle of the (111) facets are for this structure relaxed inwards with respect to the facet edges, and the Au—S, S—C, and C—H distances are 2.52 ˚ A, 1.87 ˚ A, and 1.10 ˚ A, respectively [106]. The conclusion that the effect of the passivating monolayer is strong enough to distort the bare cluster geometry, either changing an achiral cluster into a chiral one or increasing the index of chirality in an already chiral structure, was drawn based on structural analysis of passivated Au28 (SCH3 )16 and Au38 (SCH3 )24 clusters, respectively [97]. In very recent large-scale density functional theory calculations [104] of Au38 (SCH3 )24 , optimizations of the passivated particle with a gold core of both, compact truncated octahedral (suggested in early DFT calculations using the local density approximation [106]) and disordered structures [107] have been carried out. Whereas the re-optimization of the structure with the disordered gold core resulted only in a minor relaxation of interatomic distances (Fig. 5), dramatic changes were observed for the truncated oc-


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Fig. 5. Structure of Au38 (SCH3 )24 [104] (reprinted from J. Phys. Chem. B 110, Hakkinen, H., Walter, M., Gronbeck, H., Divide and protect: Capping gold nanoclusters with molecular gold-thiolate rings, 9927—9931 (2006); copyright (2006) American Chemical Society).

These ring-like units are bound to the central Au14 core with weak metallic bonds (binding energy of 1.1 eV) between the Au atoms in the units and the vertex atoms of the Au14 core. The two optimized structures of the passivated Au38 cluster are very close in energy, Au14 [(AuSR)4 ]6 being preferred for longer or bulkier thiolate ligands [104]. For larger clusters with a diameter up to 4 nm Xray absorption spectroscopy detected a size-dependent nearest neighbor gold atom contraction, attaining 2— 4 % for particles up to 2 nm in diameter, significantly lowering with increasing size, and being less than 1 % for 4-nm particles [4]. The X-ray diffraction and high resolution electron microscopy evidence on gold nanocrystals passivated by alkylthiol monolayers shows that the transition from decahedral type to face-centered-cubic type of gold core takes place at cores not greater than 1.8 nm (180 ± 30 atoms) [91]. With increasing size the absorption geometry, expressing the absorption sites of headgroups of passivating molecules in reference to the cluster structure, and arrangements of self-assembled monolayers on finite crystalline gold nanocrystallites, exposing adjacent (111) and (100) facets, becomes very complicated. The arrangements of the molecules on such nanocrystallites, tested up to the size of 1289 gold atoms, are different from those found on extended gold surfaces and depend on the size of the nanocrystallite [25]. Electronic, optical, and magnetic properties

Fig. 6. Structure of Au14 ((AuSCH3 )4 )6 [104] (reprinted from J. Phys. Chem. B 110, Hakkinen, H., Walter, M., Gronbeck, H., Divide and protect: Capping gold nanoclusters with molecular gold-thiolate rings, 9927—9931 (2006); copyright (2006) American Chemical Society).

tahedral core structure which spontaneously opened up forming an octahedral gold core of 14 atoms and six planar, ring-like gold-thiolate tetraunits (Fig. 6). Thus, the formula of the latter structure can be written as Au14 [(AuSCH3 )4 ]6 . Consequently, bonding in thiolate-protected gold clusters can be viewed as a competition between maximizing the gold—gold cohesion and forming molecular ring-like gold-thiolate units on the surface of the cluster, in the expense of reducing the number of gold-gold bonds in the core.

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Physical properties of passivated gold nanoparticles are neither those of bulk metal nor those of molecular compounds, but they strongly depend on the particle size and shape, interparticle distance and nature of the protecting organic shell [2]. Controlling the surface environments of gold nanoparticles through capping agents enables modifications of their electronic behavior, which exercise decisive influence especially on the optical and magnetic properties [80, 95, 108]. The weak interacting dipolar molecules, such as tetraalkylammonium salts, dendrimers [95] or phosphines [104] reduce gold and therefore increase the charge on the gold core surface. The strongly interacting thiols [80, 95, 104, 108], on the other hand, oxidize the gold core. This means that d electrons are removed from the gold site and the density of holes at the 5d Au level is increased. Therefore, in thiol-capped gold nanoparticles the ligand effect overcomes the size effect [108]. The addition or removal of extra charge takes place almost exclusively within the molecular layer [106]. Charge analysis of the Au14 [(AuSCH3 )4 ]6 structure indicated gold atoms in two distinct charge states: the 14 inner “core” atoms are essentially neutral, whereas the 24 gold atoms within the gold-thiolate units are positively charged. The analysis yielded an electron deficiency of 0.19 e per atom, resulting in a


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total charge transfer of about 4.5 electrons to the thiolates [104]. Optical spectra of metallic nanoparticles are dominated by the surface plasmon band, a broad absorption band in the visible region around 520 nm. It is caused by collective oscillations of the electron gas at the surface of nanoparticles that is correlated with the electromagnetic field of the incoming light [2]. The excess charge produced at the surface because of electron movement acts as a restoring force, while the electron movement is damped mainly because of the electron interaction with atomic cores and the nanoparticle surface. As thiols induce an increase of the hole density at the 5d Au level, thiol-capped gold nanoparticles exhibit a wider surface plasmon band than bare nanoparticles. In some cases, thiol capping can even result in the absence of a surface plasmon absorption band in the spectrum [109]. Since magnetic behavior is also determined by the d electrons, different capping can even tune the magnetic properties, the observed magnetization being an intrinsic effect of the gold core [110]. Very small thiolcapped gold nanoparticles exhibit a localized permanent magnetism in contrast to the metallic diamagnetism characteristic of bulk gold or tetraalkylammonium-protected gold nanoparticles [108]. Place-Exchange Reactions Exchange of thiols at the monolayer protected gold cluster surface is a direct and widely exploited way to introduce novel functionalities on the nanoparticles. This approach provides a direct route to mixed monolayer protected clusters without introducing drastic alterations of the experimental synthetic conditions. This functional diversity makes mixed monolayer protected clusters central in the creation of numerous nanoparticle-based materials and devices [111, 112]. A place-exchange reaction, during which a new thiolate ligand is incorporated into a cluster monolayer, is initialized by mixing the corresponding thiol and monolayer protected gold cluster in solution. The most straightforward explanation of the process is that the new thiol enters the monolayer and protonates the bound thiolate ligand in an associative ratedetermining step. The rates of ligand exchange depend on the concentrations of entering and exiting ligand and are lowered by an increase in the size of the entering ligand and the chain length of the protecting monolayer. Some sites on the gold surface are significantly more willing to exchange the ligand, while others are nearly nonexchangeable sites. Fast placeexchange reaction can be expected at edge and vertex thiolate sites on the cluster core, whereas slower exchange occurs at near-edge and interior terrace sites [86]. The easy-to-exchange sites are not a static population. Surface migration of thiolate ligands is enabled 248

[86]. This is of very high importance in biomolecular recognition. The mobility of thiolate ligands on nanoparticles can be exploited to create templated multivalent receptors [111]. The phosphine—thiolate ligand-exchange reactions were demonstrated on a 38-atom gold cluster. As the binding energies of phosphines and (AuSCH3 )4 units to core are similar, PH3 could be exchanged with (AuSCH3 )4 resulting in a natural change in the number of gold atoms in this process as Au39 (PH3 )14 Cl6 is transformed into Au14 [(AuSC6 H13 )4 ]6 [104]. Biomedical Applications of Passivated Gold Nanoparticles The tunable shape- and size-dependent properties of gold nanoparticles can be exploited in various biomedical applications. They are biocompatible, nontoxic [113], and depending on the linked structure they can bind readily to a large range of biomolecules such as amino acids [114], proteins [115], and DNA [116]. Gold nanoparticles possess distinctive attributes that make them promising as drug carriers. The ability to formulate mixed monolayers provides direct access to systems. For instance, the surface of nanoparticles can be tailored to realize tumor specificity and cell membrane penetration. The surface monolayer is stable under most physiological conditions, thus providing a reservoir of hydrophobic drugs. Their release is mediated through place-exchange reactions of thiols on gold nanoparticle surfaces with glutathione. Utilizing the glutathione-mediated release of drugs is based on the difference in intracellular and extracellular glutathione concentrations which is substantially higher in the intracellular case [117, 118]. A perspective application of gold nanoparticles has been found for insulin delivery [119]. In normal human beings, the pancreatic human insulin response is described as an early burst of insulin release, followed by a gradual increasing phase of insulin secretion lasting for several hours. In postprandial hyperglycemia, there is a loss of this first phase of insulin secretion, which may contribute to a reduced suppression of hepatic glucose production leading to higher glucose appearance in the blood [120]. Insulin can be bound via hydrogen bonds with amino acid-modified gold nanoparticles and this approach is promising for the development of a nonparenteral delivery system for insulin and for alleviating the pain and trauma associated with the subcutaneous administration of insulin [119]. GOLD GLYCONANOPARTICLES Gold glyconanoparticles were designed with the intent to find means for basic studies in carbohydrate— carbohydrate and carbohydrate—protein interactions and for intervention in cell—cell adhesion processes


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[27]. They were verified to be adequate tools for these purposes and the newly integrated approach was named the glyconanotechnology strategy [16, 121]. The important role of carbohydrates in a broad spectrum of physiological and pathological processes, including metastasis, inflammation, and infection, is well established nowadays. All of these processes involve protein—carbohydrate, as well as carbohydrate— carbohydrate, interactions [27]. The most remarkable characteristic of these interactions is their extremely low affinity, which is compensated in nature by polyvalent presentation of the ligands and receptors at cell surfaces. This hallmark makes the study of such interactions a real challenge [122, 123]. It can only be enabled through models with multivalent presentation of the carbohydrate ligands. Although multivalent model systems based on peptides, proteins, liposomes, dendrimers, or polymers, have been widely prepared [124—127], the glyconanoparticles are more advantageous as they provide strict control of ligand numbers and nanoparticles size, a higher degree of multivalence and easy chemical characterization, high storage stability, and high biological stability against enzyme degradation [27]. Different strategies for preparing gold nanoparticles, with important naturally occurring carbohydrate epitopes attached to their surfaces in the form of selfassembled monolayers, were developed and they have been tested for various applications. Biological Interactions of Carbohydrates Carbohydrates are, together with nucleic acids, proteins and lipids, important molecules for life. Relatively few monosaccharide components can confer vast amounts of information on carbohydrate structures through variations in sugar composition, and modifications to those sugars, as well as different linkage types and branching patterns. Further layers of complexity are added when carbohydrates are attached, as it is frequently the case, to proteins or lipids. In addition, for multiple glycoconjugate molecules (glycoproteins, glycolipids or proteoglycans) displayed on the cell surface; their density, distribution, and relative orientations may contribute to even greater specificity [128]. A dense coat of glycoconjugates, the so-called glycocalyx, covers the surface of most types of cells. In some cell configurations, attractive forces outweigh the repulsive ones enabling the formation of cell— cell contacts. Cell-surface oligosaccharides contribute to the cell recognition and adhesion by protein— carbohydrate and carbohydrate—carbohydrate interactions [129]. Characteristic features of these interactions are their high specificity and low affinity. For carbohydrate—carbohydrate interaction, strong dependency on divalent cations is crucial as well [16]. Nature overcomes the low affinity by the clustering

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of ligands and receptors at cell surfaces. Glycosyl epitopes, carried by glycosphingolipids or glycoproteins, are clustered to form microdomains, in which specific signal transducers, adhesion receptors, or growth factor receptors are organized. Microdomains involved in carbohydrate-dependent adhesion, coupled with signal transduction, were termed glycosynapses. Through this organization, carbohydrate-dependent adhesion creates signals that are transmitted to the nucleus, leading to changes in cellular phenotype associated with cell adhesion, such as differentiation, oncogenic transformation, metastasis, etc. Various disease processes can be elucidated through the study of glycosynapse structure and function [130]. For example, the Lewis X (Lex ) antigen, the terminal trisaccharide moiety of numerous cell surface glycolipids and glycoproteins, is involved in both protein—carbohydrate binding and direct carbohydrate—carbohydrate interactions. Selectin-mediated cell—cell adhesion and recognition processes, i.e. the processes in which a family of cell adhesion molecules (having the character of single-chain transmembrane glycoproteins) called selectins are involved, represent the former group of such interactions [131]. Homotypic Lex —Lex interactions play a crucial role in the morula compaction process in mice [132] and aggregation of F9 teratocarcinoma cells [133]. A heterotopic carbohydrate—carbohydrate interaction of the Lex antigen seems to be responsible for metastasis of melanoma cells in mice [134]. Lactosylceramide is involved in melanoma lung metastasis in mice [135]. In addition, lactose is the primer disaccharide in the biosynthesis of all glycosphingolipids [136]. A sulfated disaccharide and a pyruvated trisaccharide were identified to be responsible for the speciesspecific cell aggregation of marine sponges, providing an example of carbohydrate—carbohydrate interactions from outside the eukaryotic world [121, 137, 138]. Another glycosphingolipid interaction is involved in the binding of sperm to egg membrane in rainbow trout fertilization [139]. Preparation and Properties of Gold Glyconanoparticles The first synthesis of water-soluble gold glyconanoparticles evolves from the method described by Brust et al. [83], which is the most popular synthetic scheme for the production of colloidal gold nanoparticles. In the Brust two-phase synthesis, a gold salt (AuCl− 4 ) is transferred from a water solution to toluene, using tetraoctylammonium bromide as the phase-transfer reagent, and then reduced by NaBH4 in the presence of a thiol [83]. The method was also found to be feasible in a methanol—water solution [84, 140]. Derived from here, the synthesis of gold glyconanoparticles was carried out by adding a methanolic


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Fig. 7. Preparation of gold glyconanoparticles [16] (Reprinted from Biochim. Biophys. Acta, 1760, De la Fuente, J. M., Penades, S., Glyconanoparticles: Types, synthesis and applications in glycoscience, biomedicine and material science, 636–651; copyright (2006), with permission from Elsevier).

solution of a neoglycoconjugate, functionalized with a thiol group or in the form of disulfide, to an aqueous solution of tetrachloroauric acid (HAuCl4 ) and subsequent reduction with NaBH4 (Fig. 7) [122]. Utilizing this method, the syntheses of different glyconanoparticles functionalized with the tetrasaccharide Ley [141], the trisaccharide Lex [122], the disaccharides lactose and maltose or the monosaccharide glucose [142] were reported [16]. Manipulation of the ratio of gold salt to organic ligand permits the control of the nanoparticle’s size and polyvalence [27]. Variations in the number and the nature of neoglycoconjugates, and the inclusion of different spacers without carbohydrate termination, provide a great structural diversity of nanoparticles [142]. The length and nature of the linker between the reducing end of the saccharide and the mercapto group not only affects the ligand density but may also play a role in the organization of the monolayer and affect the solubility and biocompatibility of the resulting nanoparticles [128]. Such tuning of self-assembled monolayers leads to surface structures that resemble oligosaccharide groups in glycoproteins [142] and provide an under-control model for investigating the influence of density and carbohydrate presentation on molecular recognition events [121]. Hybrid glycoclusters made up of carbohydrates and other molecules (fluorescent probes, peptides, biotin, DNA, RNA, etc.) can also be prepared using this technology [116, 122]. The introduction of a fluorescein molecule into the lacto- and Lex -nanoparticles confers on them the possibility of establishing additional aromatic interactions. The two-dimensional, hexagonal structure obtained by transmission electron microscopy may be attributed to hydrophobic and π— π interaction of the fluorescein with the carbon grid [142]. The gluco-, malto-, lacto-, and Lex -glyconanoparticles prepared by this methodology, purified and 250

characterized by NMR, UV-, and FT-infrared spectroscopy, transmission electron microscopy and elemental analysis, were found to be endowed with an exceptionally small core, to be highly soluble in water, and to be stable for months under physiological conditions without flocculation [121, 122]. So-prepared lacto- and Lex -gold nanoparticles had a narrow size distribution and an average diameter for the metallic core of 1.8 nm [121, 122, 142] or 2 nm [143]. This particle size corresponds to an average number of 201 gold atoms per particle. The gluconanocluster showed an average core diameter of 2 nm [142]. A gold core mean diameter of 1.0 nm, correlating with an average number of gold atoms less than 79, classified the malto-nanoparticles as the smallest soluble protected gold nanoclusters [142]. While all of the above-mentioned gold glyconanoparticles are highly soluble in water, their solubility differs from that of the respective neoglycoconjugates. The thiol-derivatised neoglycoconjugate of lactose is soluble in methanol but poorly soluble in water whereas the Lex derivative is soluble in methanol as well as in water. The glyconanoparticles produced from them are, on the other hand, insoluble in methanol but have good solubility in water. Both the maltose neoglycoconjugates and corresponding nanoparticles are highly water-soluble. The differences in solubility can be used to purify the glyconanoparticles from the unreacted disulfides by washing them with methanol [142]. The stability of these models to enzymatic degradation is a critical condition for their use in investigations of the in vivo cell-adhesion processes. The enzymatic hydrolysis of the lacto-glyconanoparticles by β-galactosidase of Escherichia coli resulted in a barely detectable hydrolysis. This is in contrast to the neolactoconjugates for which the hydrolysis was at a level comparable to that of lactose itself [122]. However, the lowered density of the neolactoconjugates on the gold surface influences the ability of a protein to bind it and makes the enzyme hydrolysis possible, though to


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a lesser extent than the neoglycoconjugate itself. It follows that the density of a ligand designates the biological properties of the gold glyconanoparticles [142]. Cytotoxicity is another aspect which has to be taken into account before an application of the glyconanoparticles to biological models. Gold maltonanoparticles were demonstrated to have deleterious effects on cellular viability, whereas lacto- and gluconanoparticles can be considered as nontoxic model systems [27]. Despite the good stability of the gold glyconanoparticles in aqueous solutions [142], in calcium solution aggregation of the gold Lex -nanoparticles takes place. Lex -antigen aggregates arise from selfrecognition between Lex molecules in the presence of Ca2+ ions and do not result from nonspecific interactions with the salt [122]. The Lex self-aggregation in water is a selective, stabilizing, multivalent, and Ca2+ -dependent event and supports the assumption that carbohydrate trans-associations may be a mechanism for membrane to membrane interactions [121]. To prepare gold glyconanoparticles, the original method of Brust and coworkers [83] can be used with further modifications providing for surface functionality and water-solubility applied afterwards. The placeexchange reaction [90, 144], conventional organic protocol [145] (for nanoparticle with surface featuring chemically reactive groups) and the incorporation of hydrophobic nanoparticles into the hydrophobic interiors of surfactant micelles [146] are the conceivable modification methods [147]. In the three-step procedure of Kataoka et al. [148], gold nanoparticles protected with a poly(ethylene glycol) derivative, containing both mercapto and acetal groups, were prepared at first by the Brust’s method. This was followed by the conversion of the α-acetal groups to aldehyde by acid treatment and a reductive amination with p-aminophenyl glycosides in the presence of (CH3 )2 NHBH3 . Likewise, Turkevich’s process [85] for the preparation of gold nanoparticles, which uses citrate as both a reductant and a capping agent, can be implemented in the gold glyconanoparticle synthesis [149]. The introduction of thiol-linked saccharides is subsequently performed by ligand displacement. One advantage of this method is that gold glyconanoparticles having identical gold cores but displaying different carbohydrates can be easily prepared, a task that is difficult with the Brust reaction due to the influence of the carbohydrate ligand nature on particle growth [128, 150]. Chitosan-capped gold nanoparticles were prepared using a modified Turkevich process in which trisodium citrate was replaced by monosodium glutamate [151]. Another approach for the preparation of gold glyconanoparticles utilizes free oligosaccharides [152]. The introduction of a thiol-spacer into the free oligosaccharides occurs in the two-step reaction sequence by a reductive amination of the saccharides

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with trityl-protected cysteamine and further detritylation. The glyconanoparticles prepared from these thiol-spacer-extended oligosaccharides show complete colloidal stability, even in buffers with high salt concentrations. Gold glyconanoparticles prepared from isolated glycans, which were released from proteins and lipids or obtained via hydrolysis of polysaccharides, by using the presented method can find applications in ligand-identification processes and interaction studies with carbohydrate-binding proteins and, ultimately, help to elucidate their role in biological processes [152]. Polysaccharides, such as heparin, chitosan or dextran [153—155], can be used simultaneously as reducing and stabilizing agents. In both cases the metal nanoparticles are stabilized by electrostatic interactions between the surface of the nanoparticle and the polysaccharides. This so-called green method provides a simple and environmentally friendly strategy for preparing glyconanoparticles without any additional chemical reducing agent in the aqueous solution [16]. Applications of Gold Glyconanoparticles Gold glyconanoparticles with their globular shape, size range similar to many common biomolecules, and their chemically well-defined structure, provide a glycocalyx-like surface that mimics carbohydrate presentation in glycoproteins or in glycosphingolipid patches at the cell surface. Therefore, glyconanoparticles are adequate tools for basic studies in carbohydrate interactions and for intervention in cell—cell adhesion processes. The interactions of cell—surface glycoproteins and glycolipids play important roles in cell—cell communication, proliferation, and differentiation. Thus, studies of carbohydrate-related interactions might provide new insights into their biological roles and reveal new possibilities for drug development. Glyconanoparticles demonstrate the potential to be used as metastasis inhibitors and antiadhesion agents. Metastasis is the origin of the bad prognosis of most cancers. In metastasis, tumoral cells detach from the primary tumor and travel through the lymphoid and blood vessels until they arrive at a specific target location. One of the critical steps in metastasis is the adhesion of tumor cells to the vascular endothelium [27, 156]. In addition to interactions between tumor-associated antigens and epithelial cell adhesion molecules selectins, carbohydrate—carbohydrate interactions between glycosphingolipids expressed on the tumor and endothelial cell surfaces are involved in the critical adhesion step [157]. Lactosylceramide and lactoneotetraosylceramide were proposed to be involved in the first adhesion step of tumor cells to endothelium before transmigration [135, 158], evoking a desire to investigate whether gold lacto-nanoparticles


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can provide effective antiadhesion therapy and thus negatively influence tumor progression. These particles were found to induce specific tumor inhibition up to 70 % [121]. A study of cell aggregation in the red-beard marine sponge, mediated by proteoglycan-like macromolecular aggregation factor, using gold glyconanoparticles coated with the α- or the β-anomer of fucose, indicated that the α-anomeric form exhibits stronger selfrecognition. This result identified α-L-fucose to be the anomeric form of fucose found in the macromolecular aggregation factor [137]. Carbohydrate-encapsulated gold nanoparticles were verified to be efficient affinity probes for separation and enrichment of target proteins from a mixture at the femtomole level, and subsequent protein identification and mapping of the binding-epitopecontaining peptides by MALDI-TOF MS with minimum sample handling [159]. Gold lacto-nanoparticles reversibly aggregate upon the exposure to the lectin RCA120 . The degree of aggregation is proportional to lectin concentration. A visible color change from pinkish-red to purple accompanying the aggregation gives a tool for detection of the interactions between the lectin and the gold glyconanoparticles and evaluation of the ligand-density effects [148, 160]. The visualization of cellular or tissue components by electron microscopy was revolutionized by the labeling of target molecules with nanoparticles [22]. Mannose gold nanoparticles have been used to observe the specific binding to FimH adhesion of bacterial type 1 pili by TEM [161]. A new method to quantify glucose utilizes dextrancoated gold nanoparticles [153, 162]. The method is based on the aggregation of the gold nanoparticles with Concanavalin A (Con A), which results in a significant shift and broadening of the gold plasmon absorption. The addition of glucose competitively binds to Con A, reducing gold nanoparticles aggregation and therefore decreasing the plasmon absorption when monitored at a near-red arbitrary wavelength [16, 162]. Monitoring of glucose concentrations is one of the major challenges in the management of diabetes, a disease causing long-term health disorders including cardiovascular disease and blindness [153]. A strategy for the detection of heavy metal ions in water was developed employing 20 nm gold particles capped with a biopolymer called chitosan [151]. Chitosan has free amines in some of its repeat units, which get protonated in dilute acidic media. These protonated amines form the multiple bonding sites that are useful in chelating heavy metals like Cu2+ and Zn2+ . On the other hand, the optical properties of gold nanoparticles warrant a relatively simple characterization of the concentration levels of the analyte by, for example, UV-visible absorption spectroscopy [151]. 252

CONCLUSION Gold glyconanoparticles are unique systems of nanometer size and globular shape, providing a multivalent carbohydrate presentation on a threedimensional gold surface. Therefore, they represent adequate tools for basic studies of carbohydrate— carbohydrate and carbohydrate—protein interactions and for intervention in carbohydrate-mediated cell— cell adhesion processes. As carbohydrates are involved in a vast number of physiological and pathological processes, it is of high importance to have available gold glyconanoparticles with different properties and which meet a variety of different requirements. The design of these desired gold glyconanoparticles requires profound understanding of all effects influencing their properties. Due to the fact that gold glyconanoparticles are complex systems, consisting of three components (gold core, passivating monolayer, and carbohydrate ligands), knowledge of the properties and potentials of each separate component is a fundamental prerequisite to insure a complete understanding of the particle as a whole. Therefore, a step by step (component by component) approach was applied in this review. Current knowledge of bare gold clusters, passivated gold clusters, and gold glyconanoparticles was summarized. There remain many unanswered questions about these systems, thus providing ample possibilities for new research. Acknowledgements. This work was supported by the grants from EC under Contract No: MRTN-CT-2004-005645.

LIST OF ABBREVIATIONS Con A C1 symmetry DFT DNA FT-infrared spectroscopy HOMO Ih Lex antigen LUMO MALDI

Concanavalin A No symmetry Density functional theory Deoxyribonucleic acid Fourier transform infrared spectroscopy Highest occupied molecular orbital Icosahedral Lewis X antigen Lowest unoccupied molecular orbital Matrix-assisted laser desorption/ ionization MS Mass spectroscopy NMR Nuclear magnetic resonance RNA Ribonucleic acid TEM Transmission electron microscopy TOF MS Time of flight mass spectroscopy UV spectroscopy Ultraviolet spectroscopy

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