Synthesis and Theoretical Analysis of Samarium Nanoparticles

The Journal of Physical Chemistry B .... The use of lanthanides as radionuclides in nuclear medicine is well-known, because they can be used for ... l...
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J. Phys. Chem. B 2005, 109, 8806-8812

Synthesis and Theoretical Analysis of Samarium Nanoparticles: Perspectives in Nuclear Medicine Jorge A. Ascencio,*,†,‡ Ana C. Rincon,‡ and Gerardo Canizal§ Instituto Mexicano del Petroleo, Eje Central La´ zaro Ca´ rdenas 152, Col. San Bartolo Atepehuacan, C.P. 07730, Me´ xico D.F., Mexico, Facultad de Quimica, UniVersidad Autonoma del Estado de Mexico, Paseo Colon esq. Paseo Tollocan, C.P. 50110, Toluca, Me´ xico, and Instituto Polite´ cnico Nacional, Centro de Educacio´ n Continu´ a y a Distancia (Unidad Allende), Allende No. 38, Centro, Me´ xico D.F. 06010, Me´ xico ReceiVed: September 4, 2004; In Final Form: January 18, 2005

The use of lanthanides as radionuclides in nuclear medicine is well-known, because they can be used for detecting and treating cancerous tumors. Due to the fact that the doses are directly related to the number of unstable atoms involved, the possibility of obtaining controlled-size lanthanide nanoparticles opens a wide scope for their application in nuclear medicine. In this work, we report the synthesis of anew samarium nanoparticle by using the bioreduction method, where the pH conditions play an important role in the size control of the produced clusters. The nanoparticles were characterized by using an transmission electron microscope, in addition to the use of a quantum mechanical method to relate the atomic and electronic structures to the chemical selectivity, which allows us to predict a direct coordination between the DTPA-bis-biotin molecules with the samarium nanoparticles larger than 55 atoms. This work involves experimental and theoretical methods to propose a totally new application for nanotechnology in nuclear medicine.

1. Introduction Multiple efforts are actually focused on the detection and treatment of cancer tumors from the first stages. Development of new materials and molecular manipulation are strongly involved in the goal of improving health. In the nuclear medicine field, the discovery and development of molecules characterized by their high avidity for both avidin and streptavidin allows the localization of tumors. Particularly, the use of DTPA-bisbiotin, which has been demonstrated to exist in low concentrations in the blood, has been labeled with 153SmIII to produce a contrast in the region where there is a tumor.1 For the purpose of radionuclide labeling, the use of selective molecules appears to be a promising method for radiation, showing that most tumors act as peptide collectors. Somatostatin is considered as the universal inhibitor of hormone release from several organs, this peptide being a 14 amino acid hormone. The pharmacological properties of somatostatin have been replicated by ocreotide, which is an 8 amino acid peptide. This peptide has been labeled with 99mTc, 123I, 111Inm and 90Y, and it has proven to be useful for tumor detection and therapy.2-7 Besides, it was reported that the 90Y- and 111In-radiolabeled DOTA-lanreotide has been used for treatment of somatostatin-receptor-expressing tumors.8-10 Also, the labeling of β-naphthyl-peptide with 188Re to study its biodistribution in normal and tumor-bearing nude mice has been reported.11 Besides, human studies have also identified the use of 188Re-β-naphthyl-peptide and a similar complex as potential therapeutic agents.11 However, the doses produced for these complex pharmaceutical products depend directly on the number * Author to whom correspondence should be addressed. Phone: 52 55 91758055. Fax: 52 55 91756429. E-mail: [email protected]; jascencio@ yahoo.com. † Instituto Mexicano del Petroleo. ‡ Facultad de Quimica, Universidad Autonoma del Estado de Mexico. § Instituto Polite ´ cnico Nacional, Centro de Educacio´n Continu´a y a Distancia (Unidad Allende).

of radionuclide atoms fixed to selective peptides, which seek out the cancer tumors. At the same time, the accelerated development of nanometric clusters of different elements, structures, and sizes,12 where the control of these variables has become greater, and the use of different theoretical13,14 and experimental15-17 methods allows a better knowledge of the small particles and their use in the design of new materials and pharmaceuticals. This way, nanoparticles have become quite important in medicine during the past few years, since small metal clusters for producing contrast and other applications in disease evaluation and treatment18-21 started to be used. Besides, the use of quicker calculations allows a faster and more carefully controlled dosage with less damage to nearby healthy tissues.22 These tools have become important to evaluate the doses with high precision, which involves the necessity for a well-controlled number of radionuclide atoms. To achieve this goal, it is indispensable to produce small nanoparticles of a wellcontrolled size, which directly implies having control over the number of atoms and the controlled radiation delivery. This entails the additional difficulty of reducing the possible physical stimulation of the materials to avoid risks when the atoms are unstable, so the synthesis method must also be an eco-friendly method to produce samarium nanoparticles without toxic chemicals. Samarium has five different stable isotopes and several unstable isotopes. The most used radionuclide among them is 153Sm, which is well-known for nuclear medicine applications, because of its properties (half-life of 46.284 h and a decay of energy of 0.808 MeV). Even when the physical properties are different, chemical selectivity and possible reactions between them are similar, so the chemical synthesis methods can be developed in a similar manner for the different isotopes. The samarium has two different crystal structures, rhombohedral at low energy and a cubic system when the material is obtained

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Synthesis and Analysis of Sm Nanoparticles at higher temperatures (up to 917 °C). However, at a nanometric scale, surface energy controls the configuration of metal particles, and face-centered-cubic (fcc)-like clusters used to be the most stable ones because of their tendency to be spherically shaped.12,13 These characteristics of Sm allow prediction of an aggregation process of Sm atoms into a low-energy cluster configuration; in fact, there are already reported results that have demonstrated the production of small nanoparticles of lanthanides in a bimetallic form EuAu23 and for Yb.24 In both cases, the bioreduction method has been successful. Due to the fact that this method fulfills the proposed chemical conditions, we use it for the synthesis of Sm nanoparticles. The electronic structure of the nanoparticles was calculated by a density functional theory method (DFT) to evaluate the possibility to fix the Sm nanoparticles to the DTPA-bis-biotin molecule, identified as a peptide collectable by the cancer tumor. 2. Methods and Techniques Experimental Methods. By means of a bioreduction method, which has been proven for gold25 and ytterbium24 nanoparticles, gold nanorods,26 and even AuEu bimetallic clusters,23 the samarium nanoparticles were synthesized. We used samarium nitrate (Sm(NO3)3‚5H2O) at a 3 × 10-4 M concentration, considering the next equilibrium conditions: M ) n/V, n ) m/MW, and m ) MVMW. So MW ) 426.4 g/mol, V ) 100 mL, and then m ) 0.01279 g/100 mL. Consequently, we used 0.1279 g of Sm(NO3)3‚5H2O dissolved in 100 mL of deionized water. To obtain the nanoparticles, we prepared an alfalfa (Medicago satiVa) powder, whuch was washed, dried, ground, washed with 0.01 M HCl, and dried. A suspension of alfalfa powder in deionized water was prepared to a concentration of 5 mg/mL and placed in an ultrasonic bath to homogenize the suspension for 15 min. Samples were titrated to pH ) 4, 6, 7, and 8 by means of buffer solutions of biphthalates and phosphates, returning the suspension to the ultrasonic bath for 15 min. Then, the suspensions were allowed to rest for 5 min and centrifuged for 15 min, and at once the solution is added to Sm(NO3)3‚ 5H2O with a concentration of 3 × 10-4 M (where the samarium acquires an oxidation state of 3+); the reaction mixture is placed in an ultrasonic bath for homogenization for 20 min. Subsequently, it is incubated in a bath at 25 °C for 4 h and centrifuged for 30 min at 2000 rpm. The reaction mixture is decanted, and the obtained liquid is allowed to rest for 72 h. The production of nanoparticles is based on the synthesis of metals from aqueous solutions, with the Sm cation and the tanins from the alfalfa biomass to produce the typical reduction reaction of a transition metal cation Mn + ne- f M0, which corresponds to a oxidation process, and it depends on a free energy change that must be favorable as is well-supported in the review work of Cushing et al.27 Drops of the produced samples are deposited on the grid for the corresponding analysis by transmission electron microscopy (TEM). Samples were characterized by TEM for studying their size and distribution, while energy dispersive spectroscopy (EDS) allowed us to identify the composition of the samples. These data were obtained using a JEOL JEM2010 microscope with analytical equipment attached. Theoretical Methods. To calculate the minimum energy configuration of a Sm cluster, we used the DMol3 software by Accelrys,28 which is based on a DFT approximation and the local density approximation (LDA) with the Perdew-Wang (PW) functional29 with a field-consistent tolerance of 1 × 10-6 au. However, because of the complexity to converge to Sm

J. Phys. Chem. B, Vol. 109, No. 18, 2005 8807 structures, a thermal occupancy was fixed at 0.05 au, which involves a small numerical mistake but keeps the physical meaning and band-gap proportion in relation to the number of atoms and the lowest-energy configuration. Similar calculations were also made for the peptide model, to apply the Pearson theory,30 which predicts the interaction between a donor and an acceptor based on the hardness or softness of the molecular species. To understand the chemical interaction, we obtained a model for the DTPA-bis-biotin molecular structure and also for the lowest-energy configurations of the smallest clusters of Sm atoms up to 55 atoms. Considering rhombohedral and fcc-like configurations, the minimal-energy structures were determined for the selected number of atoms (2-9, 12, 13, 19, 38, and 55) by means of geometry optimization based on the DFT method. In all cases, the geometry optimization was followed by a singlepoint energy calculation for obtaining the electrostatic potential, highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO respectively), and Fukui function distributions. 3. Results and Discussion Synthesis of Sm Nanoparticles. The synthesis of nanoparticles was carried out at different pH values (4, 6, 7, and 8) to identify the best conditions to reduce the sizes of the nanoparticles. There is an important influence of the alfalfa origin on the optimum conditions for the synthesis, so a compositional analysis of the biomass was also made. In Figure 1, three different EDS spectra are shown for (a) the biomass and the samples prepared at (b) pH ) 4 and (c) pH ) 6. It is clear that the biomass over the copper grid (where the samples are placed to be analyzed by TEM) has the common organic elements and a contribution from Ca, Si, and K, which are observed in all of the samples with and without Sm. Besides, the sample with Sm obtained at pH ) 4 shows small peaks at 5.8 and 6.3 keV, while the sample prepared at pH ) 6 shows peaks at 5.8, 6.3, 6.7, and 7.3 keV. The low-level signal is associated with the amount of Sm in the analyzed zone of the matrix. For the other cases of pH ) 7 and pH ) 8, no evidence of Sm was distinguished in the analyses, presenting similar spectra to the pure biomass sample; since we could not find aggregation of Sm atoms, it was impossible to find clusters and consequently enough characteristic X-ray counts in the EDS spectra. Multiple zones were analyzed, and none showed the signal from Sm, which is directly related to a dispersed distribution of the Sm atoms, which implies that considering the preparation at pH ) 7 and pH ) 8 there is no successful production of nanoparticles and the Sm atoms must be coordinated to the biomass without the option to aggregate into metallic clusters. In Figure 2, common TEM images of the obtained nanoparticles obtained in the samples are shown. In Figure 2a, clusters of approximately 10 nm are observed, they have a welldefined and a regular profile, and the distribution observed presents a kind of partial array with rounded-like nanoparticles. It is also evident that they show a thickness effect and defects, as is shown in the particle marked with an arrow; nanoparticles overlapping are also observed. These observed characteristics allow understanding of a low interaction between nanoparticles and biomass. Besides, the nanoparticles formed in the samples obtained at pH ) 6 show a strong interaction with the biomass, which produces an agglomeration mechanism and a diffused contrast over the images, as can be observed in Figure 2b. The shapes of the clusters for the pH ) 6 samples are quite irregular, and the size is widely variable. It is also clear that the samples

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Figure 1. EDS spectra for the (a) biomass and sample with Sm prepared at (b) pH ) 4 and (c) pH)6.

Figure 2. TEM images of Sm nanoparticles in samples synthesized at (a) pH ) 4 and (b) pH ) 6.

produce multiple scattering, which reduces the possibility to distinguish between heavy elements and zones of dense biomass. This contrast is associated with the strong interaction between the biomass and the lanthanide nanoparticles. In the cases of the pH ) 7 and pH ) 8 samples, there was no contrast from the nanoparticles as was expected from the EDS analysis, so we can identify an important influence of the pH on the possibility to aggregate Sm atoms and to reduce the interaction

Figure 3. TEM analysis of dispersed particles from samples synthesized at (a) pH ) 4 and (b) pH ) 6.

between the biomass and the Sm. In fact, this agrees with the effect observed in the pH ) 6 samples, where there is an effect of biomass interaction with the lanthanide atoms, while for the pH ) 4 samples the interaction is reduced until well-defined shapes with more free surface are produced, with the secondary

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Figure 4. Size distribution of Sm nanoparticles for samples synthesized at pH ) 4 and pH ) 6. The corresponding values for the plot and density are also shown in the figure.

effects of twins common in metallic nanoparticles in many other methods reduced. In another stage of analysis and after a longer ultrasonic bath treatment, smaller nanoparticles are found in the pH ) 4 sample, as shown in Figure 3a, where many particles around 1-3 nm are found; the spherical shape is evident, but no atomistic resolution can be distinguished for any particle. Similarly, in a more dispersed pH ) 6 sample, multiple particles are found in the range of 2-8 nm (Figure 3b); however, high-resolution contrast was impossible to be observed. It must be mentioned that when the electron beam current was increased by trying to improve the resolution the cluster images oscillated, so we can relate the poor resolution and the oscillating effect to the strong magnetic behavior of Sm particles at this range. A detailed study with more than 40 micrographs of each kind of sample, size distribution, and a density study was made. Results of this analysis are shown in Figure 4, where the plot for the percentage of nanoparticles for each size is presented for both pH conditions. In the figure, the density values and the data for each size range are also shown for clarity. It is clear that even when the amount of nanoparticles produced for pH ) 4 is lower (782 p/µm2) than in the case of pH ) 6 samples (1092 np/µm2), the size distribution of the Sm clusters obtained with pH ) 4 is preferably found in the region of particles smaller than 6 nm (∼63%), while the size distribution for the obtained clusters at pH ) 6 is more dispersed and they tend to be larger than 8 nm (∼71.4%). These data correspond to an evaluation of more than 500 particles in each kind of sample, with a linear extrapolation to establish the corresponding density per square micrometer. Coordination Analysis between Sm Nanoparticles and DTPA-bis-biotin Molecules. This report shows the real possibility of obtaining Sm nanoparticles with a small quantity of

atoms, which can be used for medicine applications. However, the application of Sm nanoparticles in nuclear medicine depends on the possibility to fix Sm atoms to the peptide (that is the selective agent in the detection and treatment of cancer tumors), so we analyzed the chemical selectivity of the peptide based on Pearson’s theory, which considers the characteristic hardness that involves the HOMO-LUMO gap with the preferential interaction of molecular systems.31 And we also analyzed the geometrical and exposed sites distributions in both the peptide and Sm aggregate, which must match the donor zones of the peptide with the acceptor atoms of the Sm nanoparticles, which can be identified by means of the electrophilic f(-) and nucleophilic f(+) Fukui fields.31 Chemical selectivity behavior is based on the chemical potential of the systems µ, which measures the tendency of electrons to escape from a molecular species, and it is known as the chemical thermodynamic potential or electronegativity.32 This potential is related to the energy of the system by means of

µ)

∂E (∂N )

υ

(1)

where E corresponds to the energy of the system and N to the number of atoms considering a constant volume (υ). The corresponding changes in the electronegativity µ ) µ(N,υ) are related directly to the reactivity features and conditions. In that way, Pearson theory allows for a numerical relation of the chemical selectivity with the calculation of the frontier orbital eigenvalues as

η)

LUMO - HOMO 2

which is directly related to the observed selectivity.25

(2)

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Figure 5. Theoretical analysis of (a) 2, (b) 4, (c) 13, and (d) 55 Sm atoms. In each case, the distribution and sites of the electrostatic potential (EP) and the corresponding electrophilic (f (-)) and nucleophilic (f (+)) fields are provided.

To study the chemical selectivity and the corresponding options to coordinate the Sm clusters with the peptides, the electronic effects of the size of the nanoparticles in the electrostatic potential and Fukui fields are shown in Figure 5. These parameters are displayed for the structures formed for the two-atom interaction (Figure 5a), where the electrostatic potential (EP) distribution shows a well-defined polarization around both atoms, while the electrophilic (f (-)) and nucleo-

philic (f (+)) fields have no differences in their distribution isosurfaces. This behavior is associated with the undefined preferential zones of movement of electrons around the atoms. In the four-atom-cluster case (Figure 5b), the atoms form a homogeneous geometry with a tetrahedron structure with a symmetric electrostatic potential (EP) and Fukui field isosurfaces, which are located around all of the atoms with no preference for any of them. So then, we need to evaluate

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Figure 6. Theoretical analysis of a DTPA-bis-biotin molecule, its (a) electrostatic potential, (b) HOMO, (c) LUMO, and (d) nucleophilic field distributions are shown.

structures with larger shell configurations, as those formed by fcc-like structures, which proved to be the most stable ones for more than 13 atoms, which represents the smallest configuration with a central atom and an external shell of 12 exposed atoms. In Figure 5c, the electronic structure for the 13 Sm atom fcclike particle is shown. It is clear that electrostatic potential (EP), electrophilic (f (-)) and nucleophilic (f (+)) distributions are homogeneously found on the surface of the cluster; in the case of Fukui fields, the highest intensity is located at the vertex atoms. Basically, even when the numerical values could be different between f (-) and f (+), the distribution zones are similar, and no preferential atoms can be associated with possible coordination to the peptide. The case of the Sm cluster with 55 atoms (42 external) is shown in Figure 5d; while the electrostatic potential is very homogeneous, the Fukui fields show different zones for interacting with donor and acceptor structures. It is clear that the external atoms are defined as electrophilic sites, mainly those located in the center of the {001} faces; similarly, the nucleophilic sites are identified inside the cluster, so there are no exposed f (+) atoms. In fact, the Sm nanoparticles with more than two shells show active sites, specifically electrophilic ones, which can be coordinated to

nucleophilic sites in nearby molecules. The site of the active atoms also implies an interaction with more than one atom for each larger cluster. So larger Sm clusters with {001} faces will have more active sites to fix donor molecules. To evaluate the possibility of a real coordination of the nanoparticles with the peptide, the corresponding analysis was made for the DTPA-bis-biotin molecular structure. In Figure 6, the electrostatic potential, HOMO, LUMO, and nucleophilic sites for the peptide minimum-energy configuration are shown. The minimum-energy structure matches the previously reported values,1 and the electrostatic potential (Figure 6a) denotes why the selective zones are related to the rings in the extremities of the molecules, where a polarization is defined the same as for the oxygen atoms in the middle of the molecule, as it was identified to be coordinated to the 153Sm and 188Re atoms.1,11 Besides, the main distributions of the HOMO and LUMO are shown in Figures 6b and 6c, respectively, and both are located around the rings that have sulfur atoms. Finally, because we can recognize the preferential donor behavior of the peptide to share electrons with the Sm, in the Figure 6d the nucleophilic field is shown; it is clear that the molecule presents an interesting behavior of f (+) distribution zones in the central

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TABLE 1: Values of HOMO, LUMO, Gap, and Hardness for the Minimum-Energy Configurations structure

HOMO (eV)

LUMO (eV)

gap (eV)

η (eV)

2 Sm atoms 3 Sm atoms 4 Sm atoms 5 Sm atoms 6 Sm atoms 7 Sm atoms 9 Sm atoms 13 Sm atoms 38 Sm atoms 55 Sm atoms DTPA

-20.176762 -20.201333 -3.963592 -4.096897 -4.334340 -4.405551 -4.532571 -3.911210 -3.988626 -4.008870 -4.937442

-3.274639 -3.573850 -3.396354 -3.423319 -3.468952 -3.545959 -3.793251 -3.544299 -3.712925 -3.879129 -4.843564

16.902123 16.627483 0.567238 0.673578 0.865388 0.859592 0.739320 0.366911 0.275701 0.129741 0.093878

8.4510615 8.3137415 0.2836193 0.3367891 0.4326941 0.4297962 0.3696601 0.1834555 0.1378505 0.0648705 0.0469392

OH groups and the exposed rings, where we had also identified the HOMO and LUMO distributions. Therefore, the nanoparticles must be coordinated with the sites that were identified in the molecule, and apart from the identification of the possible coordinated atoms, the chemical selectivity based on the mentioned hardness is associated with eqs 1 and 2. The numerical value of the LUMO-HOMO gap can be found in Table 1, where the hardness has lower values when the size is increased up to a value close to the DTPAbis-biotin (DTPA) molecule. The values allow identifying the largest configuration analyzed, which has {001} faces and more than one shell as the optimum requirements to be used for coordination to the DTPAbis-biotin molecule. Even when the calculations are not accurate enough to predict measurable data, both the behavior and the influence of the size, especially of the second shell of atoms that induce an extra influence of the core atoms on the exposed ones, are clearly defined. While the size of the nanoparticles is significantly smaller when the synthesis is made at pH ) 4, when the particles are obtained at conditions of pH ) 6, the size control is lower. This is a very important parameter to be used in nanotechnology. It is evident that the electronic structure of the clusters implies the possibility of fixing clusters to the peptide molecule. This can be analyzed in the identification of the active sites in Figures 4 and 5 for the Sm clusters and the corresponding sites for the peptide, but it may also be analyzed with the help of the hardness values reported in Table 1. 4. Conclusions The development of this kind of nanoparticle added to the corresponding interaction study allows us to identify the parameters for the application of these nanostructures as nanobots in nuclear medicine. In fact, it provides the conditions for having a sensor, a smart control to determine the region by chemical selectivity (given by the peptide), and a well-controlled dose or manipulation tool, which is the task of the Sm nanoparticles in this proposed system for nuclear medicine. We can conclude that it is possible to synthesize particles of just a few samarium atoms by using the bioreduction method. The pH condition is the main parameter to be considered in the synthesis of Sm nanoparticles, because the nanoparticles can be formed just at pH ) 4 and pH ) 6 conditions, but also the size and electronic structure depend directly on this. The effect of the pH conditions could be also observed in the plausible interaction with the biomass for lower pH values, since pH ) 6 produces nanoparticles with a high interaction with the biomass and in the cases of pH ) 7 and pH ) 8 the interaction must be so high that it makes it impossible to aggregate pure lanthanide atoms to produce nanoparticles. The molecular simulation calculations showed an important molecular chemical selectivity for fixing the cluster to the peptide in particles with at least 55 Sm atoms.

Besides, an interesting magnetic effect has been observed in the smallest nanoparticles of Sm; since the electron beam of the electron microscope could not be fixed to acquire an image, the magnitude of the magnetic field must be significant for future applications in different devices that require a high magnetic field produced by small sources. Acknowledgment. We are indebted to L. Rendon for his technical support in the transmission electron microscopy and to C. Zorrilla for his help in technical activities. References and Notes (1) Ferro-Flores, G.; Ramirez, F. M.; Tendilla, J. I.; Pimentel-Gonza´lez, G.; Murphy, C. A.; Mele´ndez-Alafort, L.; Ascencio, J. A.; Croft, B. Y. Bioconjugate Chem. 1999, 10, 726. (2) Kolan, H.; Li, J.; Thakur, M. L. Pept. Res. 1996, 9, 144. (3) Krenning, E. P.; Bakker, W. H.; Kooij, P. P. M.; Breeman, W. A. P.; Oei, H. Y.; Jong, M.; Reubi, J. C.; Visser, T. J.; Bruns, C.; Kwekke, D. J.; Reijs, A. E. M.; van Hagen, P. M.; Koper, J. W.; Lamberts, S. W. J. J. Nucl. Med. 1992, 33, 652. (4) Krenning, E. P.; Kwekkeboom, D. J.; Bakker, W. H.; Breeman, W. A. P.; Kooij, P. P. M.; Oei, H. Y.; van Hagen, M.; Postema, P. T. E.; de Jong, M.; Reubi, J. C.; Visser, T. J.; Reijs, A. E. M.; Hofland, L. J.; Koper, J. W.; Lambert, S. W. J. Eur. J. Nucl. Med. 1993, 20, 716. (5) Kwekkeboom, D. J.; Kooij, P. P.; Bakker, W. H.; Macke, H. R.; Krenning, E. P. J. Nucl. Med. 1999, 40, 762. (6) Otte, A.; Jermann, E.; Behe, M.; Goetze, M.; Bucher, H. C.; Roser, H. W.; Heppeler, A.; Mueller-Brand, J.; Maecke, H. R. Eur. J. Nucl. Med. 1997, 24, 792. (7) Thakur, M. L. J. Labelled Compd. Radiopharm. 1993, 32, 365. (8) Smith-Jones, P. M.; Bischof, C.; Leimer, M.; Gludovacz, D.; AngelBerger, P.; Pangerl, T.; Peck-Radosavljevic, M.; Hamilton, G.; Kaserer, K.; Kofler, A.; Schlengbauer-Wadl, H.; Traub, T.; Virgolini, I. Endocrinology 1999, 140, 5136. (9) Virgolini, I.; Szilvasi, I.; Smith-Jones, P.; Angelberger, P.; Kurtaran, A. Eur. J. Nucl. Med. 1997, 24, 874. (10) Virgolini, I.; Szilvasi, I.; Kurtaran, A.; Angelberger, P.; Raderer, M.; Havlik, E.; Vorbeck, F.; Bishof, C.; Leimer, M.; Dormer, G.; Kletter, K.; Niederle, B.; Scheithaver, W.; Smith-Jones, P. J. Nucl. Med. 1998, 39, 1928. (11) Garcia-Salinas, L.; Pedraza-Lopez, M.; Ferro-Flores, G.; MurphyStack, E.; Chavez-Mercado, L.; Ascencio, J. A.; Hernandez-Gutierrez, S. Nucl. Med. Biol. 2001, 28, 319. (12) Jose´-Yacaman, M.; Ascencio, J. A.; Liu, H. B. J. Vac. Sci. Technol., B 2001, 19, 1091. (13) Ascencio, J. A.; Gutie´rrez-Wing, C.; Espinosa-Pesqueira, M. E.; Marı´n, M.; Tehuacanero, S.; Zorrilla, C.; Jose´-Yacaman, M. Surf. Sci. 1998, 396, 349. (14) Rao, C. N. R.; Kulkarni, G. U.; Govindaraj, A.; Satishkumar, B. C.; Thomas, P. J. Pure Appl. Chem. 2000, 72, 21. (15) Raveendran, P.; Fu, J.; Wallen, S. L. J. Am. Chem. Soc. 2003, 125, 13940. (16) Schulz, F.; Franzka, S.; Schmid, G. AdV. Funct. Mater. 2002, 12, 532. (17) Voisin, C.; Christofilos, D.; Del Fatti, N.; Valle´e, F.; Pre´vel, B.; Cottancin, E.; Lerme´, J.; Pellarin, M.; Broyer, M. Phys. ReV. Lett. 2000, 85, 2200. (18) Thrall, J. H. Radiology 2002, 230, 315. (19) Shoji, Y.; Nakashima, H. Curr. Pharm. Design 2004, 10, 785. (20) Bagwe, R. P.; Zhao, X. J.; Tan, W. H. J. Dispersion Sci. Technol. 2003, 24, 453. (21) Roco, M. C. Curr. Opin. Biotechnol. 2003, 14, 337. (22) Deasy, J. O.; Wickerhauser, M. V.; Picard, M. Med. Phys. 2002, 29, 2366. (23) Ascencio, J. A.; Mejia, Y.; Liu, H. B.; Angeles, C.; Canizal, G. Langmuir 2003, 19, 5882. (24) Ascencio, J. A.; Rodrı´guez-Monroy, A. C.; Liu, H. B.; Canizal, G. Chem. Lett. 2004, 33, 1056. (25) Gardea-Torresday, J.; Tiemman, K.; Gamez, G.; Dokken, K.; Tehuacanero, S.; Jose-Yacaman, M. J. Nanopart. Res. 2000, 1, 65. (26) Canizal, G.; Ascencio, J. A.; Gardea-Torresday, J.; Jose´-Yacaman, M. J. Nanopart. Res. 2001, 3, 475. (27) Cushing, B. L.; Kolesnichenko, V. L.; O’Connor, Ch. J. Chem. ReV. 2004, 104, 3893. (28) DMol3 module of Cerius2; Accelrys: San Diego, 1999. (29) Perdew, J. P.; Wang, Y. Phys. ReV. B 1992, 45, 13244. (30) Gazquez, J. L. J. Phys. Chem. A 1997, 101, 8969. (31) Boyd, R. J.; Markus, G. E. J. Chem. Phys. 1981, 75, 5385. (32) Pearson, R. G. J. Am. Chem. Soc. 1988, 110, 2092.