Hierarchically Nanostructured Magnetic Hollow Spheres of Fe3O4 and

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J. Phys. Chem. C 2008, 112, 1851-1856

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Hierarchically Nanostructured Magnetic Hollow Spheres of Fe3O4 and γ-Fe2O3: Preparation and Potential Application in Drug Delivery Shao-Wen Cao, Ying-Jie Zhu,* Ming-Yan Ma, Liang Li, and Ling Zhang State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, People’s Republic of China and Graduate School of Chinese Academy of Sciences, People’s Republic of China ReceiVed: September 17, 2007; In Final Form: NoVember 1, 2007

We report for the first time a novel precursor-templated conversion method for the controlled synthesis of hierarchically nanostructured magnetic hollow spheres assembled by Fe3O4 or γ-Fe2O3 nanosheets with a relatively high saturation magnetization. We synthesized hierarchically nanostructured hollow spheres organized by nanosheets of a layer-structured ferrous precursor by a microwave-assisted hydrothermal method in ethylene glycol (EG). Ferric chloride (FeCl3‚6H2O) was used as the iron source, and EG acted as both a solvent and a reductant to reduce ferric salt to ferrous precursor in the presence of sodium hydroxide (NaOH) and sodium dodecyl benzene sulfonate (SDBS). The precursor was heated to prepare hierarchically nanostructured magnetic hollow spheres assembled by Fe3O4 or γ-Fe2O3 nanosheets, which were surface-modified with poly(ethylene glycol) (PEG). The surface-modified hierarchically nanostructured magnetic hollow spheres were explored as drug carriers. A typical anti-inflammatory drug, ibuprofen, was used for drug loading, and the release behaviors of ibuprofen in a simulated body fluid (SBF) were studied. The results indicate that these hierarchically nanostructured magnetic hollow spheres of Fe3O4 or γ-Fe2O3 have a high drug loading capacity and favorable release property for ibuprofen; thus, they are very promising for application in drug delivery. The samples were characterized by XRD, TEM, SEM, TG/DSC, BET, PPMS, FTIR, and UV-vis.

Introduction The properties of materials composed of building blocks with the same composition but different morphologies could be substantially different.1,2 Scientists have been paying more and more attention to the design and fabrication of functional materials by ordered organization of nanostructures across extended dimensions.3 Formation of highly ordered complex architectures organized by nanostructured building blocks based on spontaneous processes is of great interest. In the past decade, efforts have been made to design and prepare self-assembled nanostructures at the solid-liquid, liquid-liquid, and liquidgas interfaces based on the Langmuir-Blodgett technique, layerby-layer technique, and templating approaches.4-6 In recent years, the synthesis of magnetic nanostructures has become a particularly important research field and is attracting growing interest.7,8 Due to their advantages, such as magnetic properties, chemical stability, biocompatibility, and low toxicity, magnetic nanocrystals have been intensively studied not only for fundamental scientific interest but also potential applications in biomedical fields, especially in the field of targeted drug delivery.9-15 Magnetic nanoparticle-based targeting can reduce or eliminate the side effects of conventional chemotherapy by reducing the systemic distribution of drugs and lower the doses of the cytotoxic compounds. The magnetic nanostructures used for drug delivery systems are usually iron oxides. Recent reports have demonstrated the feasibility of surface-functionalized, superparamagnetic iron oxide nanoparticles for use in a variety of biological applications. The intriguing potential applications of magnetic iron oxide nanostructures have stimulated rapid * To whom correspondence should be addressed. Phone: +86-2152412616. Fax: +86-21-52413122. E-mail: [email protected].

development of the synthetic techniques. To date, a variety of synthetic methods such as coprecipitation,16 microemulsion,17 ultrasound irradiation,18 hydrothermal method,19 and thermal decomposition of organometallic compounds20 have been applied to produce the magnetic iron oxide nanoparticles. Various magnetic nanostructures with different morphologies have been synthesized,21-25 including hollow nanospheres composed of small particles.25 To our knowledge, hierarchically nanostructured hollow spheres assembled from nanosheets of Fe3O4 or γ-Fe2O3 have not been reported until now. These porous, hierarchically nanostructured hollow spheres of Fe3O4 or γ-Fe2O3 with strong magnetization strength will be especially desirable for high-capacity drug loading and targeted drug delivery as well as other biomedical and catalytic applications. Herein, we report for the first time a novel precursortemplated conversion method for the controlled synthesis of hierarchically nanostructured magnetic hollow spheres assembled by Fe3O4 or γ-Fe2O3 nanosheets with a relatively high saturation magnetization. One of the advantages of the method reported here is that both Fe3O4 and γ-Fe2O3 hierarchically nanostructured hollow spheres consisting of organized nanosheets can be synthesized by using the same single-source precursor. We first synthesized hierarchically nanostructured hollow spheres organized by nanosheets of a layer-structured ferrous precursor by a microwave-assisted hydrothermal method in ethylene glycol (EG). Ferric chloride (FeCl3‚6H2O) was used as the iron source, and EG acted as both a solvent and a reductant to reduce ferric salt to ferrous precursor in the presence of sodium hydroxide (NaOH) and sodium dodecyl benzene sulfonate (SDBS). The precursor was heated to prepare hierarchically nanostructured magnetic hollow spheres assembled by Fe3O4 or γ-Fe2O3 nanosheets, which were surface-modified

10.1021/jp077468+ CCC: $40.75 © 2008 American Chemical Society Published on Web 01/23/2008

1852 J. Phys. Chem. C, Vol. 112, No. 6, 2008 SCHEME 1: Illustration of the Main Strategies for the Preparation and Drug Delivery

with poly(ethylene glycol) (PEG), since the PEG modification endowed Fe3O4 and γ-Fe2O3 with satisfactory biocompatibility.26 The surface-modified hierarchically nanostructured magnetic hollow spheres were explored as drug carriers. A typical antiinflammatory drug, ibuprofen, was used for drug loading, and the release behaviors of ibuprofen in a simulated body fluid (SBF) were studied. The results indicate that these hierarchically nanostructured magnetic hollow spheres of Fe3O4 or γ-Fe2O3 have a high drug loading capacity and favorable release property for ibuprofen; thus, they are very promising for application in the drug delivery. The main strategies for the preparation and drug delivery in this work are schematically demonstrated in Scheme 1. Experimental Section All chemicals used in our experiments were purchased and used as received without further purification. Ferric chloride (FeCl3‚6H2O), ethylene glycol (EG), sodium dodecyl benzene sulfonate (SDBS), and poly(ethylene glycol) (PEG) were purchased from Sinopharm Chemical Reagent Co., Ltd. Sodium hydroxide (NaOH) was purchased from Shanghai Ling-Feng Chemical Reagent Co., Ltd. Hexane was purchased from Fisher Scientific. Ibuprofen was purchased from Shanghai Yuan-Ji Chemical Reagent Co., Ltd. In the typical synthetic procedure of the ferrous precursor, solution A was prepared by dissolving 0.541 g of FeCl3‚6H2O and 0.600 g of SDBS in 20 mL of EG, and solution B was prepared by dissolving 0.160 g of NaOH in 10 mL of EG. Then the two solutions were mixed together, and 20 mL of the resultant solution was loaded into a 60 mL Teflon autoclave, sealed, microwave-heated to 200 °C, and kept at this temperature for 90 min. The microwave oven used for sample preparation was a microwave-hydrothermal synthesis system (MDS-6, Sineo, Shanghai, China). After cooling to room temperature, the jade-green precursor was obtained. The products were collected and washed by centrifugation-redispersion cycles with alcohol. The precursor was thermally treated at 300 °C for 1 h under the protection of flowing nitrogen gas to prepare Fe3O4 and thermally treated at 300 °C for 1 h in air to prepare γ-Fe2O3. The black Fe3O4 and reddish brown γ-Fe2O3 were obtained, respectively. A 0.025 g amount of as-prepared Fe3O4 (or γ-Fe2O3) and 0.05 g of PEG 20000 were dissolved in 10 mL of deionized water. The mixture was dispersed in an ultrasonic oscillator for

Cao et al. 10 min. Afterward, the mixture was kept at 50 °C for 30 min under shaking at a constant rate. Then the products were separated by centrifugation and washed by deionized water three times and ethanol three times, respectively, in an ultrasonic washer to remove the superfluous PEG and each time kept for 2 min. The typical drug loading and in vitro drug release experiments were performed as follows: 1 g of PEG-coated Fe3O4 (or γ-Fe2O3) was added into 40 mg/mL ibuprofen hexane solution. The suspension was shaken in a sealed vessel for 24 h, during which evaporation of hexane was prevented. Then the PEGcoated Fe3O4 (or γ-Fe2O3) hollow spheres with loaded drug were separated and compacted into disks (each disk 0.3 g) by a pressure of 4 MPa. Each disk was immersed into 200 mL of simulated body fluid (SBF) with pH 7.4 at 37 °C under shaking at a constant rate. The shaking device was a desk-type constanttemperature oscillator (THI-92A, China). The release medium (2 mL) solution was taken out for analysis at given time intervals and replaced with the same volume of fresh preheated SBF. A 2.0 mL amount of extracted medium solution was analyzed by UV-vis absorption spectroscopy at a wavelength of 263 nm. X-ray powder diffraction (XRD) patterns were recorded using a Rigaku D/max 2550 V X-ray diffractometer with highintensity Cu KR radiation (λ ) 1.54178 Å) and a graphite monochromator. The thermogravimetric analysis (TG) and differential scanning calorimetric (DSC) curves were taken with a heating rate of 10 °C in flowing air with a STA 409/PC simultaneous thermal analyzer (Netzsch, Germany). The transmission electron microscopy (TEM) micrographs were taken with a JEOL JEM-2100F field emission transmission electron microscope with an accelerating voltage of 200 kV. Scanning electron microscopy (SEM) was recorded on a JSM-6700F field emission scanning electron microscope. The BET surface area measurement was performed by a surface area meter (JW-04, China). The Fourier transform infrared (FTIR) spectra were taken on a Nexus FTIR spectrometer (Thermo Nicolet). A PPMS was used to evaluate the magnetic properties at room temperature. The UV-vis absorption spectra were taken on a UV 2300 spectrophotometer (Techcomp, China). Results and Discussion The X-ray powder diffraction (XRD) pattern in Figure 1a shows the crystalline, layered structure of the precursor, which is similar to the XRD patterns of Mn-EG and Co-EG.27,28 We found that the precursor could be oxidized in the aqueous solvent with the green color turning to brown, indicating that the ferrous ions were oxidized to form ferric ions. We propose that EG molecules lose protons and the dianions coordinated with ferrous ions. Xia et al. studied the characteristically strong XRD peak around 10 °C in a similar polyol process.29-31 It was considered to be a typical feature from the coordination and alcoholysis of EG with the center metal ions. Figure 1d shows the FTIR spectrum of the precursor. The strong absorption band lying in the 2500-3000 cm-1 range is characteristic of the C-H stretching mode. With the exception of the δH2O vibration at 1620 cm-1, all the bands located below are due to Fe-O, C-C, C-O, and CH2 bonds.27 The precursor is possibly a kind of ferrous alkoxide FeC2H4O2, which is also supported by thermogravimetric analysis, as discussed below. The morphologies of the samples were investigated with scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Figure 2a-d shows typical SEM and TEM micrographs of the precursor. One can see that the precursor consisted of hierarchically nanostructured hollow spheres

Magnetic Hollow Spheres of Fe3O4 and γ-Fe2O3

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Figure 2. SEM (a-c) and TEM (d) micrographs of the precursor, (e, f) SEM micrographs of Fe3O4, and (g, h) SEM micrographs of γ-Fe2O3. Figure 1. (a) XRD pattern of the precursor, (b) XRD pattern of Fe3O4, (c) XRD pattern of γ-Fe2O3, (d) FTIR spectrum of the precursor, and (e) TG and DSC curves of the precursor.

organized by nanosheets. The SEM micrograph in the inset of Figure 2c shows the cross-section of the shell of one broken hollow sphere, which suggests that the spheres were composed of nanosheets. The high-magnification SEM micrograph of the sphere surface (Figure 2c) shows that the nanosheets were organized to form three-dimensional networks and thus form porous structures in the wall of the hollow spheres. The SEM micrograph in the inset of Figure 2a indicates the hollow interior of the sphere, which is proved by TEM observation (Figure 2d), i.e., the hierarchically nanostructured spheres organized by precursor nanosheets were hollow. The diameters of hollow spheres assembled by nanosheets were ranging between 2 and 4 µm. SDBS played an important role in the formation of hierarchically nanostructured hollow spheres. The hierarchically nanostructured hollow spheres organized by precursor nanosheets could not form in the absence of SDBS. These interesting morphological features of the precursor are crucial for its roles as both a source material and a morphological template in the subsequent formation of Fe3O4 or γ-Fe2O3 nanostructured architectures with similar morphologies. In order to determine the appropriate temperature for thermal conversion of the precursor to Fe3O4 or γ-Fe2O3, we investigated the thermal behavior of the precursor in air. The thermogravimetric analysis (TG) and differential scanning calorimetric (DSC) curves of the precursor are shown in Figure 1e, which

shows that there is an obvious exothermic peak in the DSC curve and a corresponding sharp mass loss around 260 °C, indicating that the decomposition temperature of the precursor was at around 260 °C. The total mass loss between 220 and 500 °C was 33%, which agrees with the theoretical value of 31% calculated from the following equation

4FeC2H4O2 + 11O2 f 2Fe2O3 + 8CO2 + 8H2O This result supports that the precursor is possibly a kind of ferrous alkoxide FeC2H4O2. According to the DSC and TG curves, we chose a temperature of 300 °C for thermal treatment of the precursor to ensure its complete decomposition. The precursor was heated at 300 °C for 1 h to prepare crystalline Fe3O4 under the protection of nitrogen gas and prepare crystalline γ-Fe2O3 in air. The XRD patterns (Figure 1b and c) confirmed formation of black crystalline Fe3O4 (JCPDS No. 190629) and reddish crystalline γ-Fe2O3 (JCPDS No. 39-1346). One of the advantages of the method reported here is that both Fe3O4 and γ-Fe2O3 hierarchically nanostructured hollow spheres consisting of organized nanosheets can be synthesized using the same single-source precursor. Figure 2e and f shows SEM micrographs for the Fe3O4 sample and Figure 2g and h for the γ-Fe2O3 sample, from which one can see hierarchically nanostructured hollow spheres consisting of organized Fe3O4 or γ-Fe2O3 nanosheets, very similar to those of the precursor, i.e., the morphology of the precursor was successfully maintained after thermal transformation to Fe3O4 or γ-Fe2O3. The SEM observation of broken spheres indicates the hollow structure of

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Figure 3. (a) N2 adsorption-desorption isotherm of Fe3O4 hollow spheres and the corresponding pore size distribution; (b) N2 adsorptiondesorption isotherm of γ-Fe2O3 hollow spheres and the corresponding pore size distribution.

the spheres. The diameters of hierarchically nanostructured hollow spheres assembled by Fe3O4 or γ-Fe2O3 nanosheets were also similar to those of the precursor. These results indicate that the simple method reported here is very suitable for the synthesis of hierarchically nanostructured hollow spheres assembled by Fe3O4 or γ-Fe2O3 nanosheets. The Brunauer-Emmett-Teller (BET) gas sorptometry measurement revealed that the specific surface areas of Fe3O4 and γ-Fe2O3 samples were 62 and 56 m2/g, respectively, which are higher than the values of iron oxide nanoparticles reported32,33 and favorable for application in drug delivery. Figure 3a and b shows the N2 adsorption-desorption isotherm and the corresponding pore size distribution of Fe3O4 and γ-Fe2O3 hierarchically nanostructured hollow spheres. It can be clearly seen that two peaks appear on the pore size distribution curve. One peak was located at around 3 nm, corresponding to filling of the pores formed in the nanosheets. The other peak was centered at around 10 nm, corresponding to filling of the pores formed among the stacking nanosheets. The BJH (Barett-Joyner-Halenda) desorption average pore size of Fe3O4 is 10.2 nm, and the singlepoint adsorption total volume at P/P0 ) 0.976 of Fe3O4 is 0.131 cm3/g. The BJH desorption average pore size of γ-Fe2O3 is 16.3 nm, and the single-point adsorption total volume at P/P0 ) 0.971 of γ-Fe2O3 is 0.159 cm3/g. PEG surface modification of Fe3O4 and γ-Fe2O3 hierarchically nanostructured hollow spheres organized by nanosheets was performed for subsequent drug loading and release experiments. Figure 4a and b shows the FTIR spectra of PEG-coated hierarchically nanostructured hollow spheres organized by nanosheets of Fe3O4 and γ-Fe2O3, respectively. The characteristic band of PEG (C-O-C stretching) was observed at 1068 (spectrum a) and 1091 cm-1 (spectrum b), which was not

Cao et al.

Figure 4. FTIR spectra of PEG-coated Fe3O4 hollow spheres (a), PEGcoated γ-Fe2O3 hollow spheres (b), uncoated Fe3O4 hollow spheres (c), and uncoated γ-Fe2O3 hollow spheres (d), room-temperature magnetic hysteresis loops of PEG-coated Fe3O4 hollow spheres (e), and PEGcoated γ-Fe2O3 hollow spheres (f).

observed in the uncoated Fe3O4 (spectrum c) and γ-Fe2O3 (spectrum d), indicating that PEG molecules were indeed adsorbed on the surface of PEG-coated hollow spheres of Fe3O4 and γ-Fe2O3. The magnetic property of the surface-modified Fe3O4 and γ-Fe2O3 hierarchically nanostructured hollow spheres organized by nanosheets was also investigated. Figure 4e and f shows the room-temperature magnetic hysteresis loops of PEG-coated Fe3O4 and PEG-coated γ-Fe2O3, respectively. Both PEG-coated Fe3O4 and PEG-coated γ-Fe2O3 hollow spheres exhibited a superparamagnetic characteristic. The saturation magnetization of PEG-coated Fe3O4 and PEG-coated γ-Fe2O3 hollow spheres was 31.4 and 48.3 emu/g, respectively, at a magnetic field of 20 000 Oe, implying the strong magnetic response to a magnetic field. These saturation magnetization values of the two systems are much higher than reported values,8,34-36 which is promising for drug delivery application. We investigated the drug loading and release behaviors of hierarchically nanostructured magnetic hollow spheres assembled by Fe3O4 or γ-Fe2O3 nanosheets as drug carriers. The as-prepared PEG-coated Fe3O4 or PEG-coated γ-Fe2O3 hollow spheres were added into the hexane solution containing ibuprofen for drug loading. Then the magnetic PEG-coated Fe3O4 or PEG-coated γ-Fe2O3 hollow spheres with loaded drug were separated and compacted into disks. The disks were immersed into simulated body fluid (SBF) with pH 7.4 under shaking at a constant rate at 37 °C. The release medium solution (2 mL) was taken out for analysis at given time intervals and replaced with the same volume of fresh preheated SBF. The UV-vis absorption spectra of the hexane solution containing ibuprofen before and after ibuprofen loading in hollow spheres are shown

Magnetic Hollow Spheres of Fe3O4 and γ-Fe2O3

J. Phys. Chem. C, Vol. 112, No. 6, 2008 1855 hollow spheres, respectively). The formula of the standard curve obtained by UV-vis absorption spectra is given below

y ) 0.04196 + 1.29522x

(1)

where y represents the absorbance value and x represents the concentration value. Figure 5d and e shows the release behavior of ibuprofen from ibuprofen-loaded PEG-coated Fe3O4 and PEG-coated γ-Fe2O3 hollow spheres in SBF over a time period of 136 h. One can see that both drug release curves show a sustained release behavior and the drug was progressively released by desorption and diffusion to the SBF solution. The drug release rates from both systems are similar in the medium of SBF with pH 7.4. For ibuprofen-loaded PEG-coated Fe3O4 hollow spheres, about 37% of the loaded drug was released for the first 24 h and 67% for 72 h, and then the drug release rate decreased and reached a value 74% for 136 h. Similarly, for ibuprofen-loaded PEG-coated γ-Fe2O3 hollow spheres about 45% of the loaded drug was released for the first 24 h and 69% for 72 h. Then the release rate decreased and reached a value of 76% for 136 h. These results indicate that the two magnetic hollow sphere systems have a big uptake amount of ibuprofen and favorable ibuprofen release property. The release behaviors of both magnetic hollow sphere systems are similar, which may owe to their similarly hierarchical structures and thus similar drug release mechanisms. On the other hand, the -OH group of PEG and -COOH group of ibuprofen molecules may form hydrogen bonds, leading to the sustained and progressive release behavior of the drug. We studied the relationship between the drug release amount and square root of time in the time period from 2 to 77 h. We found that it showed a linear relation, which indicates that the drug release behavior followed the typical Fick’s law of diffusion. Conclusions

Figure 5. UV-vis absorption spectra: (a) the hexane solution containing ibuprofen before ibuprofen loading in hollow spheres, (b) the hexane solution containing ibuprofen after ibuprofen loading in PEG-coated Fe3O4 hierarchically nanostructured hollow spheres assembled by nanosheets, and (c) the hexane solution containing ibuprofen after ibuprofen loading in PEG-coated γ-Fe2O3 hierarchically nanostructured hollow spheres assembled by nanosheets. (d) Ibuprofen release curve from ibuprofen-PEG-coated Fe3O4 hollow spheres in simulated body fluid. (e) Ibuprofen release curve from ibuprofen-PEGcoated γ-Fe2O3 hollow spheres in simulated body fluid.

in Figure 5a-c. One can see that the absorption spectra of ibuprofen in hexane solution show the characteristic absorption peaks, for example, at 263 nm, which are similar to those reported in the literature. On the basis of the calculation from the standard concentration calibration curve dependent on absorbance of ibuprofen at 263 nm, we obtained that the ibuprofen storage in PEG-coated Fe3O4 and PEG-coated γ-Fe2O3 hollow spheres was 297 and 237 mg/g, respectively. This result indicates the good ibuprofen storage capacity of the two drug carrier systems. The higher loading capacity of ibuprofen in PEG-coated Fe3O4 hollow spheres than in PEG-coated γ-Fe2O3 hollow spheres is consistent with the specific surface area results (62 and 56 m2/g for PEG-coated Fe3O4 and PEG-coated γ-Fe2O3

We successfully developed a novel two-step precursortemplated conversion method to prepare hierarchically nanostructured magnetic hollow spheres assembled by Fe3O4 or γ-Fe2O3 nanosheets. Hierarchically nanostructured hollow spheres assembled by the precursor nanosheets have been successfully prepared by a microwave-hydrothermal method using FeCl3‚ 6H2O, SDBS, and NaOH in EG at 200 °C for 90 min. The hollow spheres of the precursor can be used as the iron source and morphological template for subsequent thermal transformation to prepare hierarchically nanostructured hollow spheres assembled by Fe3O4 or γ-Fe2O3 nanosheets. Both Fe3O4 and γ-Fe2O3 hierarchically nanostructured hollow spheres consisting of organized nanosheets have been prepared by thermal treatment of the precursor at 300 °C for 1 h under the protection of nitrogen gas and in air, respectively. One of the advantages of the method reported here is that both Fe3O4 and γ-Fe2O3 hierarchically nanostructured hollow spheres consisting of organized nanosheets can be synthesized using the same singlesource precursor. Hierarchically nanostructured hollow spheres assembled by Fe3O4 or γ-Fe2O3 nanosheets could be surfacemodified with poly(ethylene glycol) (PEG). The hierarchically nanostructured hollow spheres of Fe3O4 and γ-Fe2O3 had specific surface areas of 62 and 56 m2/g, respectively. The saturation magnetization of PEG-coated Fe3O4 and PEG-coated γ-Fe2O3 hollow spheres were relatively high (31.4 and 48.3 emu/ g, respectively, at a magnetic field of 20 000 Oe). Ibuprofen could be stored in these hierarchically nanostructured hollow spheres with an uptake amount of 297 and 237 mg/g for PEGcoated Fe3O4 and PEG-coated γ-Fe2O3, respectively. The drug release rates are suitable for drug delivery application, and most

1856 J. Phys. Chem. C, Vol. 112, No. 6, 2008 of the drug molecules incorporated could be released to SBF in 136 h. These hierarchically nanostructured hollow spheres assembled by Fe3O4 or γ-Fe2O3 nanosheets are very promising for application in targeted drug delivery in the future. Acknowledgment. Financial support from the National Natural Science Foundation of China (50472014, 50772124), the Chinese Academy of Sciences under the Program for Recruiting Outstanding Overseas Chinese (Hundred Talents Program), the Program of Shanghai Subject Chief Scientist (07XD14031), and the key project for innovative research and the Director Fund of Biomaterials Research Center from the Shanghai Institute of Ceramics is gratefully acknowledged. References and Notes (1) Huynh, W. U.; Dittmer, J. J.; Alivisatos, A. P. Science 2002, 295, 2425. (2) El-Sayed, M. A. Acc. Chem. Res. 2001, 34, 257. (3) Colfen, H.; Mann, S. Angew. Chem., Int. Ed. 2003, 42, 2350. (4) Zheng, L.; Li, J. J. Phys. Chem. B 2005, 109, 1108. (5) Khomutov, G. B. AdV. Colloid Interface Sci. 2004, 111, 79. (6) Lahav, M.; Sehayek, T.; Vakevich, A.; Rubinstein, I. Angew. Chem., Int. Ed. 2003, 42, 5576. (7) Yu, D. B.; Sun, X. Q.; Zou, J. W.; Wang, Z. R.; Wang, F.; Tang, K. J. Phys. Chem. B 2006, 110, 21667. (8) Arruebo, M.; Gala´n, M.; Navascue´s, N.; Te´llez, C.; Marquina, C.; Ibarra, M. R.; Santamarı´a, J. Chem. Mater. 2006, 18, 1911. (9) Nam, J. M.; Thaxton, C. S.; Mirkin, C. A. Science 2003, 301, 1884. (10) Willner, I.; Katz, E. Angew. Chem. 2003, 115, 4724; Angew. Chem., Int. Ed. 2003, 42, 4576. (11) Zhao, M.; Kircher, M. F.; Josephson, L.; Weissleder, R. Bioconjugate Chem. 2002, 13, 840. (12) Hogemann, D.; Ntziachristos, V.; Josephson, L.; Weissleder, R. Bioconjugate Chem. 2002, 13, 116. (13) Hu, F.; Wei, L.; Zhou, Z.; Ran, Y. L.; Li, Z.; Gao, M. Y. AdV. Mater. 2006, 18, 2553. (14) Bra¨hler, M.; Georgieva, R.; Buske, N.; Mu¨ller, A.; Mu¨ller, S.; Pinkernelle, J.; Teichgra¨ber, U.; Voigt, A.; Ba¨umler, H. Nano Lett. 2006, 6, 2505.

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