Characteristics of gadolinium oxide nanoparticles as contrast agents for terahertz imaging

Transcription

1 Characteristics of gadolinium oxide nanoparticles as contrast agents for terahertz imaging Dong-Kyu Lee, a Hyeongmun Kim, a Taekhoon Kim, b Byungkyu Cho, b Kwangyeol Lee, b and Joo-Hiuk Son a a Department of Physics, University of Seoul, Seoul , Korea b Department of Chemistry, Korea University, Seoul , Korea Abstract The optical properties of gadolinium oxide (Gd 2 O 3 ) nanoparticles in a solvent were studied using terahertz time-domain spectroscopy. The power absorption and index of refraction of samples were measured with various concentrations of nanoparticles. A few ppms of Gd 2 O 3 nanoparticles were distinguished in terms of their power absorption capacity. The results showed that the interaction between terahertz electromagnetic waves and Gd 2 O 3 nanoparticles is strong enough to allow their exploitation as contrast agents for the terahertz medical imaging system. Keywords : terahertz time-domain spectroscopy, gadolinium oxide, nanoparticle (phone) (FAX) joohiuk@uos.ac.kr 1

2 Terahertz (THz) technology has many potential applications in medicine and biology, because the THz electromagnetic waves are sensitive to water molecules and because the characteristic energies of biological molecules lie in the THz region. 1 One of the promising applications of THz technology in medicine is the diagnosis of cancers due to the change in the THz characteristics of tumors that mainly result from the alteration of the cell structure and the water content. With this principle, skin and breast cancers were diagnosed, 2,3 although the difference between the malignant and benign tissues was too slight to allow the technology to be utilized in clinics. The most conventional way of diagnosing cancers is with the use of the magnetic resonance imaging (MRI) technique. The MRI technique has recently adopted nanoparticle probes to enhance the sensitivity of its measurements. 4 Nanoparticles have also been used to improve the THz image quality and have significantly increased the sensitivity of cancer detection. 5 Many kinds of nanoparticles have been developed for MRI, which include magnetic gold nanocomposites, 6 biodegradable nanoparticles, 7 and smart drug-loaded polymer gold nanoshells. 8 Gadolinium oxide (Gd 2 O 3 ) nanoparticles (GONPs) have recently been receiving attention as candidate multi-functional contrast agents that can be targeted towards a specific cell by attaching an antigen or an antibody to them and delivering drugs to abnormal cells. 9 Nano-sized colloidal metal oxides have recently been synthesized. Gadolinium is a paramagnetic material that can be used as the core of contrast agents such as gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) for T1 imaging in MRI. Gd-DTPA is not a complex functional contrast agent, however, so the gadolinium composite that takes the form of a nanosized colloidal nanoparticle has been required. 2

3 In this paper, the characteristics of nanoplate-shaped GONPs that have been made to interact with THz electromagnetic waves as candidate contrast agents for THz molecular imaging along with the use of MRI were studied. Fundamental issues on molecular imaging, such as sensitivity and quantification, were also discussed. For this study, the GONPs were made from slurries of Gd(acac) 3, 1-hexadecylamine, palmitic acid, and trioctylamine prepared in a 100ml schlenk tube that was connected to a bubbler. The mixture was heated at 90 C with vigorous stirring for 24 hours. Hydrazine monohydrate was added to the solution, after which it was heated at 90 C. After 24 hours of heating, a stacked triangle of Gd 2 O 3 nanoplates was made. The resulting mixture was heated at 320 C in a preheated furnace for 2 hours under an N 2 flow without stirring. The resulting reaction mixture was cooled to room temperature to produce a yellowish solution. Toluene (5 ml) was added to the solution, precipitated by methanol (30 ml), to achieve the final product. 10 A transmission electron microscopy (TEM) image of these GONPs was taken, as shown in Fig. 1 (a), and the morphology of the GONPs, which were shaped in the form of trigonal plates, was arranged in a row, as illustrated in Fig. 1 (b). The concentration of the undiluted GONP sample was measured via inductively coupled plasma - atomic emission spectroscopy (ICP-AES). Other samples with different concentrations were made by adding toluene to change the amount of GONPs in each sample. The optical properties of the GONP samples with various concentrations in the THz frequency region were measured via conventional terahertz time-domain spectroscopy (THz-TDS) 1. The femtosecond pulses produced by a Ti:sapphire laser were separated into two paths. One of the beams, the pump beam, generated THz waves on the p-inas wafer, and the other, the probe beam, was guided to the detector that consisted of a 3

4 photoconductive dipole antenna fabricated on a low-temperature-grown GaAs wafer. The generated THz pulses proceeded to the detector through the rectangular parallelepiped quartz cell that contained the GONP samples dispersed in toluene, and were measured using a photoconductive sampling technique by which the DC signals were read on a lock-in amplifier with respect to the change in the optical path length between the pump and the probe beams. The entire setup, including the sample cell, was kept in a tight box that was purged with dry air to avoid its absorption of water vapor. The time-domain waveforms that passed through the GONP samples were measured at various concentrations, as shown in Fig. 2 (a). As the concentration of the GONPs increased, the peak amplitude and phase of each sample were reduced and delayed, respectively. The inset in Fig. 2 (a) shows the concentration dependency of the peak amplitude of each waveform. The time-domain waveforms were transformed into frequency-domain waveforms through fast Fourier transformation (FFT), as shown in Fig. 2 (b). As the GONP concentration increased, the spectral amplitude showed similar reductions in the time-domain data. The inset in Fig. 2 (b) shows that the amplitude at 0.8 THz was dependent on the GONP concentrations. The complex optical constants, such as the refractive index and the power absorption, were obtained by comparing the reference and sample waveforms in the frequency domain. 11 The relationship of these two waveforms is represented as follows: d ( ) 2 Eout ( ) E ( ) exp( αω π ω = in ω ) exp( i n1 ( ω) d), (1) 2 λ wherein Eout ( ω ) refers to the output signals that passed through the sample in the quartz cell, and Ein( ω ) refers to the input signals that passed through the empty quartz cell. αω ( ) and n ( ω) 1 are the absorption coefficient and the real part of the complex refractive index, respectively, and d is the thickness of the 4

5 sample. The power absorption was extracted from the difference between the amplitudes that passed through the sample and the reference, and was related to the imaginary part of the refractive index, n 2 ( ω ). The real part of the refractive index, n 1 ( ω ), was obtained from the phase difference between the two signals, as provided by: and φi φo n1( ω) = 1+ λ0 (2) 2π d 2 E ( ω) 4π n αω ( ) ln( ) = out 2 d Ein ( ω) = λ, (3) 0 wherein φ I is the phase of the reference signals, φ O is the phase of the signal that penetrated the samples, and λ 0 is the wavelength. The refractive indices and power absorptions are shown in Fig. 3 (a) and (b), respectively. The refractive indices of the GONP samples decreased and the power absorptions increased with the frequency increment. As the concentrations increased from 15 μm to 472 μm, which are equivalent to 4.6 ppm and 148 ppm, respectively, the power absorptions and refraction indices of the samples increased. The refractive index and power absorption of the 472 μm, 236 μm, and 118 μm samples showed a limited spectrum because the data were over the dynamic range of the experiment due to the large absorption. Fig. 3 (b) shows that the power absorption was proportional to the frequency and the concentration of the GONPs. For the detailed discussion, the properties of only the GONPs in each sample were determined by excluding the effect of toluene. The power absorption can be represented as: 12 wherein C G, t αω ( ) = C α ( ω) + Cα( ω), (4) G G t t C, and α ( ω ) are the volume fractions of the GONPs and toluene, and the power absorption t 5

6 of toluene, respectively. The volume fractions were calculated with the density of bulk gadolinium oxide, 13 which is 7.07 g/cm 3, and that of toluene, which is g/cm 3. The power absorptions of only the GONPs, α ( ) G ω, are shown in Fig. 4 at various concentrations. The figure shows extremely high absorption of the GONPs, at two to three orders of magnitude larger than that of water. 14 The results showed, however, that the deviation was dependent on the concentration, which is regarded as the effect of the aggregation of the GONPs. The inset in Figure 4 shows that the power absorption of the GONPs only decreased as the concentration of the GONPs increased. This can be explained by the decrease of the surface absorption of each GONP that was not proportional to the volume fraction of the GONPs in the solution, because the aggregation formed the cluster of the GONPs that gave rise to a smaller surface area than the sum of the surface areas of the GONPs. Therefore, the power absorption of the GONPs only in the high-concentration samples could have been lower than that in the low-concentration samples. For the application of the GONPs as contrast agents, the decrease in their power absorption at high concentrations is not a problem because they will be used at minimal concentrations to reduce their side effects on the human body. It is desirable, however, to have linearity in the power absorption as in the lower concentration without the aggregation effect for the quantification of molecular imaging with THz waves. In summary, the concentration-dependent optical constants of GONPs with THz-TDS were measured. Even a few μms of GONPs could be easily detected from the power absorption change, which was almost three orders of magnitude larger than that of water. Therefore, the GONPs can significantly improve the contrast in THz images. To quantify the THz images, the aggregation problem of GONPs must be solved. Although GONPs were initially proposed as multi-functional contrast agents for MRI, they can also be 6

7 utilized as multi-functional contrast agents for the molecular imaging technique with THz waves. Acknowledgments This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Nos , , , and ). DKL acknowledges the support by Seoul Science Fellowship program. 1. J.-H. Son, Terahertz electromagnetic interactions with biological matter and their applications, J. Appl. Phys. 105, (2009). 2. R. M. Woodward, V. P. Wallace, R. J. Pye, B. E. Cole, D. D. Arnone, E. H. Linfield, and M. Pepper, Terahertz Pulse Imaging of ex vivo Basal Cell Carcinoma, J. Invest. Dermatol. 120, (2003). 3. A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, Terahertz pulsed imaging of human breast tumors, Radiology 239, (2006). 4. J.-H. Lee, Y.-M. Huh, Y.-W. Jun, J.-W. Seo, J.-T. Jang, H.-T. Song, S. Kim, E.-J. Cho, H.-G. Yoon, J.-S. Suh, and J. Cheon, Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging, Nat. Med. 13, (2007). 5. S. J. Oh, J. Kang, I. Maeng, J.-S. Suh, Y.-M. Huh, S. Haam, and J.-H. Son, Nanoparticle-enabled terahertz imaging for cancer diagnosis Opt. Express 17, (2009). 6. J. Lee, J. Yang, H. Ko, S. J. Oh, J. Kang, J.-H. Son, K. Lee, S.-W. Lee, H.-G. Yoon, J.-S. Suh, Y.-M. Huh, 7

8 and S. Haam, Multifunctional Magnetic Gold Nanocomposites: Human Epithelial Cancer Detection via Magnetic Resonance Imaging and Localized Synchronous Therapy, Adv. Funct. Mater. 18, (2008). 7. J. Kang, J. Yang, J. Lee, S. J. Oh, S. Moon, H. J. Lee, S. C. Lee, J.-H. Son, D. Kim, K. Lee,J.-S. Suh,Y.-M. Huh and S. Haam, Gold-layered calcium phosphate plasmonic resonants for localized photothermal treatment of human epithelial cancer, J. Mater. Chem., 19, (2009). 8. J. Yang, J. Lee, J. Kang, S. J. Oh, H.-J. Ko, J.-H. Son, K. Lee, J.-S. Suh, Y.-M. Huh, and S. Haam, Smart Drug-Loaded Polymer Gold Nanoshells for Systemic and Localized Therapy of Human Epithelial Cancer, Adv. Mater. 21, (2009). 9. J.-L. Bridot, A.-C. Faure, S. Laurent, C. Rivière, C. Billotey, B. Hiba, M. Janier, V. Josserand, J.-L. Coll, L. V. Elst, R. Muller, S. Roux, P. Perriat, and O. Tillement, Hybrid Gadolinium Oxide Nanoparticles: Multimodal Contrast Agents for in Vivo Imaging, J. Am. Chem. Soc. 129, (2007). 10. J. Paek, C. H. Lee, J. Choi, S.-Y. Choi, A. Kim, J. W. Lee, and K. Lee, Gadolinium Oxide Nanoring and Nanoplate: Anisotropic Shape Control, Cryst. Growth Des. 7, (2007). 11. C. Kang, I. Maeng, S. J. Oh, S. C. Lim, K. H. An, Y. H. Lee, and J.-H. Son, Terahertz optical and electrical properties of hydrogen-functionalized carbon nanotubes, Phys. Rev. B, 75, (2007). 12. S. J. Oh, J.-H. Son, O. Yoo, and D.-H. Lee, Terahertz characteristics of electrolytes in aqueous Luria- Bertani media, J. Appl. Phys. 102, (2007). 13. P. Patnaik, GADOLINIUM(III) OXIDE in Handbook of Inorganic Chemicals, pp , McGraw- Hill Professional, New York, (2002) 8

9 14. J. Zhang and D. Grischkowsky, Waveguide terahertz time-domain spectroscopy of nanometer water layers, Opt. Lett. 29, (2004). Figure captions Fig. 1. Morphology of the GONPs. (a) TEM image of the GONPs and (b) illustration of the GONPs in the square area in Fig. 1 (a). Fig. 2. (a) Time-domain waveforms and concentration-dependent peak amplitude (inset) and (b) frequency domain waveform and amplitude at 0.8 THz (inset). Fig. 3. (a) Refractive index and (b) power absorption at various concentrations of GONPs. Fig. 4. Power absorption of the GONPs only in the mixed samples. The inset figure shows the concentrationdependent power absorption of the GONPs only at 0.4 and 0.8 THz. 9

10 Fig 1. 10

11 Fig 2. (a) Amplitude ( na ) Peak Amplitude ( na ) Concentration ( μm ) 472 μm 236 μm 118 μm 59 μm 29 μm 15 μm toluene Time ( ps ) 1 (b) 472 μm 236 μm 118 μm 59 μm μm 15 μm toluene Spectral Amplitude ( a.u. ) E-3 Amplitude ( a. u. ) THz Concentration ( μm ) Frequency ( THz ) 11

12 Fig 3. Refractive index (a) 472 μm 236 μm 118 μm 59 μm 29 μm 15 μm toluene Absorption ( cm -1 ) (b) Frequency ( THz ) 12

13 Fig α G (cm -1 ) α G ( 10 5 cm -1 ) THz 0.8 THz Concentration ( μm ) 472 μm 236 μm 118 μm 59 μm 29 μm 15 μm Frequency ( THz ) 13