Journal of Infrared, Millimeter, and Terahertz Waves

, Volume 32, Issue 4, pp 506–512

Characteristics of Gadolinium Oxide Nanoparticles as Contrast Agents for Terahertz Imaging

Authors

  • Dong-Kyu Lee
    • Laboratory for Terahertz Biophotonics, Department of PhysicsUniversity of Seoul
  • Hyeongmun Kim
    • Laboratory for Terahertz Biophotonics, Department of PhysicsUniversity of Seoul
  • Taekhoon Kim
    • Nanochemistry Laboratory, Department of ChemistryKorea University
  • Byungkyu Cho
    • Nanochemistry Laboratory, Department of ChemistryKorea University
  • Kwangyeol Lee
    • Nanochemistry Laboratory, Department of ChemistryKorea University
    • Laboratory for Terahertz Biophotonics, Department of PhysicsUniversity of Seoul
Article

DOI: 10.1007/s10762-011-9776-7

Cite this article as:
Lee, D., Kim, H., Kim, T. et al. J Infrared Milli Terahz Waves (2011) 32: 506. doi:10.1007/s10762-011-9776-7

Abstract

For the application of gadolinium oxide (Gd2O3) nanoparticles as terahertz contrast agents, their optical properties in a solvent were studied using terahertz time-domain spectroscopy. The power absorption and refractive index of the samples were measured with various concentrations of nanoparticles. The power absorption was extremely large, as much as three orders of magnitude higher than that of water, so that a few ppms of Gd2O3 nanoparticles were distinguished in terms of their power absorption capacity. The results show that the interaction between the terahertz electromagnetic waves and the Gd2O3 nanoparticles is strong enough to allow their exploitation as contrast agents for terahertz medical imaging.

Keywords

Terahertz time-domain spectroscopyTerahertz imagingGadolinium oxideNanoparticle

1 Introduction

Terahertz (THz) technology has many potential applications in medicine and biology, because 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 cancer 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 cancer were diagnosed [24], 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 different kind of cancer 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 [5]. Nanoparticles have also been used to improve the THz image quality and have significantly increased the sensitivity of cancer detection [6].

Many kinds of nanoparticles have been developed for MRI, which include magnetic gold nanocomposites [7], biodegradable nanoparticles [8], and smart drug-loaded polymer gold nanoshells [9]. Nano-sized colloidal metal oxides have recently been synthesized. Among them, gadolinium oxide (Gd2O3) nanoparticles (GONPs) are 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 [10]. Gadolinium is a paramagnetic material that has been used as the core of contrast agents such as gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) for T1 imaging in MRI. The Gd-DTPA has low toxicity but it is easily removed by renal excretion due to its low molecular weight. Therefore, a new gadolinium composite that has the form of a nano-sized colloidal nanoparticle has been required. The gadolinium composite can also be a good THz contrast agent because gadolinium significantly absorbs electromagnetic waves.

In this paper, the characteristics of nanoplate-shaped GONPs as a potential contrast agents for THz molecular imaging are studied. Fundamental issues on molecular imaging, such as sensitivity and quantification, are also discussed.

2 Experiments

For this study, the GONPs were made from slurries of Gd(acac)3 (Gadolinium (III) acetylacetonate), 1-hexadecylamine, palmitic acid, and trioctylamine prepared in a 100 ml 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 the solution was heated at 90°C. After 24 hours of heating, a stacked triangle of Gd2O3 nanoplates was made. The resulting mixture was heated at 320°C in a preheated furnace for 2 hours under an N2 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 [11]. A transmission electron microscopy (TEM) image of these GONPs was taken, as shown in Fig. 1(a), and the morphology of the GONPs 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 dilute the amount of GONPs in each sample.
https://static-content.springer.com/image/art%3A10.1007%2Fs10762-011-9776-7/MediaObjects/10762_2011_9776_Fig1_HTML.gif
Fig. 1

Morphology of the GONPs. a TEM image of the GONPs and b illustration of the GONPs in the square area in (a).

The THz optical properties of the GONP samples with various concentrations 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 a p-InAs wafer, and the other, the probe beam, was guided to the detector that consisted of a photoconductive dipole antenna fabricated on a low-temperature-grown GaAs wafer. The generated THz pulses proceeded to the detector through the quartz cell, and the transmitted signal was 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 quartz cell that contained the GONP samples dispersed in toluene was rectangular parallelepiped-shaped, with a path length of 10 mm and a window thickness of 1.25 mm. The entire setup, including the sample cell, was kept in a tight box purged with dry air to avoid the absorption by water vapors.

3 Results

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 the frequency-domain through fast Fourier transformation (FFT), as shown in Fig. 2(b). As the GONP concentration increased, the spectral amplitude showed reductions similar to those in the time-domain data. The inset in Fig. 2(b) shows the amplitudes at 0.8 THz that were dependent on the GONP concentrations.
https://static-content.springer.com/image/art%3A10.1007%2Fs10762-011-9776-7/MediaObjects/10762_2011_9776_Fig2_HTML.gif
Fig. 2

a Time domain waveforms and concentration-dependent peak amplitude (inset), and b frequency domain waveforms and amplitude at 0.8 THz (inset).

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 [12]. The relationship between these two waveforms is represented as follows:
$$ {E_{{out}}}(\omega ) = {E_{{in}}}(\omega ) \cdot \exp ( - \frac{{d\alpha (\omega )}}{2}) \cdot \exp (i\frac{{2\pi }}{\lambda }{n_1}(\omega )d) $$
(1)
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. α(ω) and n1(ω) are the absorption coefficient and the real part of the complex refractive index, respectively, and d is the thickness of the sample. The refractive indices n1(ω) and power absorptions α(ω) were obtained by solving the aforementioned relation while eliminating the Fabry-Perot effect in between the windows of the quartz cell [13]. They 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 refractive indices and power absorptions of the samples increased. The data for 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. Figure 3(b) shows the power absorption proportional to the frequency and the concentration of the GONPs.
https://static-content.springer.com/image/art%3A10.1007%2Fs10762-011-9776-7/MediaObjects/10762_2011_9776_Fig3_HTML.gif
Fig. 3

a Refractive indices and b power absorptions at various concentrations of GONPs.

For a detailed discussion, the properties of the GONPs alone in each sample were obtained by excluding the effect of toluene [14]. The total power absorption that both the GONPs and toluene contributed can be represented as:
$$ \alpha (\omega ) = {C_G}{\alpha_G}(\omega ) + {C_t}{\alpha_t}(\omega ) $$
(2)
wherein CG, Ct, and αt(ω) are the volume fractions of the GONPs and toluene, and the power absorption of toluene, respectively. The volume fractions were calculated with the density of the bulk gadolinium oxide [15], which was 7.07 g/cm3, and with that of toluene, which was 0.867 g/cm3. The power absorptions of the GONPs alone, αG(ω), are shown in Fig. 4 at various concentrations. The figure shows extremely high absorption of the GONPs which is two to three orders of magnitude larger than that of water. The absorption coefficient of water is 75 to 300 cm−1 from 0.1 to 1.6 THz [16]. The result showed, however, that the absorption was dependent on the concentration. The inset in Fig. 4 shows that the power absorption of the GONPs alone decreased as the concentration of the GONPs increased, which could be explained by the aggregation effect of GONPs and by the limitation of Eq. 2 which is valid for mixtures of liquids. As can be seen in Fig. 1, the GONPs were shaped like a trigonal plate with limited thickness. Therefore, the absorption occurred mainly on the surfaces of the trigonal plates, and the total absorption was proportional to the total surface area of the GONPs. The total surface area per unit concentration was smaller at a higher concentration because the GONPs were aggregated more by stacking them as the concentration increased. 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 a minimal concentration to reduce their side-effects on the human body. It is desirable, however, to have their power absorption linearly proportional to their concentration without the aggregation effect, for the quantification of their molecular imaging with THz waves. The aggregation can be circumvented by encapsulating the GONPs with inorganic polymer.
https://static-content.springer.com/image/art%3A10.1007%2Fs10762-011-9776-7/MediaObjects/10762_2011_9776_Fig4_HTML.gif
Fig. 4

Power absorption of the GONPs alone, excluding the effect of the solvent. The inset figure shows the concentration-dependent power absorptions of the GONPs at 0.4 and 0.8 THz.

4 Conclusion

In summary, the concentration-dependent optical constants of GONPs with THz-TDS were measured. It was found that even a few μMs of GONPs could be detected due to their power absorption capacity, which is almost three orders of magnitude larger than that of water. Therefore, GONPs can significantly improve the contrast in THz images. To quantify THz images, the aggregation problem of GONPs must be solved via encapsulation. The encapsulation can be done with biocompatible materials. By coating, GONPs will become a safer material for human body compared with Gd-DTPA which is based on Gd3+ ion. It can also be modified and engineered to be a target specific contrast agent by antibody phase conjugating. Although GONPs were initially proposed as multi-functional contrast agents for MRI, they can also be utilized as contrast agents for molecular imaging with THz waves. The MRI technology has difficulty to acquire the images from a surface that is not surrounded by water such as human skin or digestive organs. THz medical imaging technology, however, has uniqueness on the surface measurement of biological samples such as epithelial cancers. Therefore, THz imaging along with nanoparticle contrast agents can be one of the strongest imaging technique for certain diagnosis [17].

Acknowledgements

This research was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (Nos. 2009–0083512, 2009–0054519, 2009–0076933, 2009–0093432, and 2009–0084187), by the grant of the Korean Health Technology R&D Project (No. A101954) funded by the Ministry for Health, Welfare & Family Affairs, Republic of Korea, and by Korea Small and Medium Business Administration in 2010 (00042838–1). DKL acknowledges the support of the Seoul Science Fellowship program.

Copyright information

© Springer Science+Business Media, LLC 2011