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Optics Express

Optics Express

  • Editor: C. Martijn de Sterke
  • Vol. 19, Iss. 5 — Feb. 28, 2011
  • pp: 4009–4016
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Molecular imaging with terahertz waves

Seung Jae Oh, Jihye Choi, Inhee Maeng, Jae Yeon Park, Kwangyeol Lee, Yong-Min Huh, Jin-Suck Suh, Seungjoo Haam, and Joo-Hiuk Son  »View Author Affiliations


Optics Express, Vol. 19, Issue 5, pp. 4009-4016 (2011)
http://dx.doi.org/10.1364/OE.19.004009


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Abstract

We demonstrate a highly sensitive THz molecular imaging (TMI) technique involving differential modulation of surface plasmons induced on nanoparticles and obtain target specific in vivo images of cancers. This technique can detect quantities of gold nanoparticles as small as 15 µM in vivo. A comparison of TMI images with near infrared absorption images shows the superior sensitivity of TMI. Furthermore, the quantification property of TMI is excellent, being linearly proportional to the concentration of nanoparticles. The target specificity issue is also addressed at the ex vivo and cell levels. The high thermal sensitivity of TMI can help extend photonic-based photothermal molecular imaging researches from the in vitro level to the in vivo level. The TMI technique can be used for monitoring drug delivery processes and for early cancer diagnosis.

© 2011 OSA

1. Introduction

Terahertz (THz) imaging has shown promise as the new modality of medical diagnostics due to its non-invasive nature [1

1. 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(2), 533–540 (2006). [CrossRef] [PubMed]

6

6. K. Kawase, Y. Ogawa, Y. Watanabe, and H. Inoue, “Non-destructive terahertz imaging of illicit drugs using spectral fingerprints,” Opt. Express 11(20), 2549–2554 (2003). [CrossRef] [PubMed]

]. However, conventional THz imaging, which measures the signal change originating from the variation of interstitial water content or the alteration of a tissue structure, cannot distinguish between malignant and benign tumors due to the lack of target specificity and the low sensitivity of THz electromagnetic waves to cancerous lesions. A novel THz imaging method with enough sensitivity and target specificity to detect the fine difference at cellular and molecular levels is required to distinguish between the two tumors. The sensitivity of THz imaging can be improved by adopting nanoparticle probes (nanoprobes) [7

7. 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(5), 3469–3475 (2009). [CrossRef] [PubMed]

], which are used in magnetic resonance molecular imaging and optical molecular imaging techniques [8

8. 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(1), 95–99 (2006). [CrossRef] [PubMed]

13

13. S. Santra, C. Kaittanis, J. Grimm, and J. M. Perez, “Drug/dye-loaded, multifunctional iron oxide nanoparticles for combined targeted cancer therapy and dual optical/magnetic resonance imaging,” small 5(16), 1862–1868 (2009). [CrossRef] [PubMed]

]. Nanoprobes are nanocomposites that amplify the response of the signal directly or indirectly by using nanoparticles engineered for particular optical, electrical or magnetic properties. They can also be designed to be target specific to molecules. Among the various properties of nanoprobes, the plasmonic resonance induced on the surface of nanoparticles irradiated by near infrared (NIR) waves enhances the sensitivity of THz imaging [14

14. L. Tong, Q. Wei, A. Wei, and J.-X. Cheng, “Gold nanorods as contrast agents for biological imaging: optical properties, surface conjugation and photothermal effects,” Photochem. Photobiol. 85(1), 21–32 (2009). [CrossRef] [PubMed]

]. The surface plasmon resonance raises the ambient temperature of water in cells and tissues and alters the conformational characteristics of water molecules, which results in a stronger THz response. Strengthening of the THz response via nanoprobes facilitates highly sensitive THz molecular imaging (TMI), which is capable of detecting the difference between tumors at the cellular and molecular levels with a target specificity. In this paper, we demonstrate the principle of TMI and obtain target specific in vivo images of cancers using the technique. The fundamental characteristics of the technique, such as sensitivity, quantification property, and target specificity, are also examined ex vivo and in vivo.

2. Experiments

The system consisted of two parts as shown in Fig. 1
Fig. 1 Schematic of the THz molecular imaging system.
. One was the conventional reflection-mode THz time-domain imaging system and the other was the NIR laser for inducing SPPs. For the THz imaging system, a mode-locked Ti:sapphire laser with 80-fs pulses at a central wavelength of 800 nm was split into two beams. One of the beams was focused on a p-InAs wafer to emit THz pulses, and the other was focused on a photoconductive switch fabricated on a low-temperature-grown GaAs to probe the THz pulses. The THz waveforms were obtained via sampling of the cross-correlated signal between the optical probe pulse and the THz pulse at the detector by a fast scanner operating at 20 Hz. The generated THz pulses were focused on a sample with two parabolic mirrors, and the reflected THz pulses from the sample were guided to the detector by using two other parabolic mirrors. For modulating the SPPs, the continuous wave diode laser, providing a beam with a wavelength of 808 nm, was modulated by a mechanical shutter. The NIR laser beam was made to overlap with the THz beam at the same diameter of 0.8 mm on the sample surface. The sample was located at the focus of the THz beam and the image was obtained by two-dimensional scanning of the sample. The entire system was sealed in a dry airtight box to prevent the absorption of water vapor.

We employed the gold nanorod (GNR) composite covered in polyethylene glycol (PEGylate) and conjugated with Cetuximab for epidermal growth factor receptor (EGFR) specific tumor-cell targeting. To conjugate Cetuximab with PGNRs (PEG-GNRs), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC, 2.9 μmol), N-hydroxysulfosuccini-mide (Sulfo-NHS, 2.5 μmol), and 200 μL of Cetuximab (1 mg/mL) were added to 2 mL of the PGNR solution (259.8 μg of Au/200 μL) and reacted at 4°C for 6 h. After the reaction, the by-products were removed by centrifugation at 15,000 rpm for 30 min and redispersed in 4 mL of phosphate buffered saline (PBS).

For the in vivo measurements, the collected A431 epidermoid carcinoma tumor cells (5 × 106 cells), suspended in 50 μL of PBS (pH 7.4, 1 mM), were injected subcutaneously into the proximal thigh region of male BALB/c-nude mice 5–8 weeks of age; the mice were obtained from the Institute of Medical Science (University of Tokyo). All experiments were conducted with the approval of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International.

3. Results and discussion

High sensitivity TMI was achieved by measuring the THz signal change caused by surface plasmon polaritons (SPPs) induced on the surface of metallic nanoprobes under optical beam illumination. The optically generated SPPs converted most of their energy into nonradiative heat around the surface of the nanoprobes, elevating the temperature of the ambient media [14

14. L. Tong, Q. Wei, A. Wei, and J.-X. Cheng, “Gold nanorods as contrast agents for biological imaging: optical properties, surface conjugation and photothermal effects,” Photochem. Photobiol. 85(1), 21–32 (2009). [CrossRef] [PubMed]

]. The temperature change was monitored using THz electromagnetic waves to yield a TMI signal. The absorption and reflection of THz waves by water depends on the temperature because most of the conformational motions of water correspond to the THz range [4

4. J.-H. Son, “Terahertz electromagnetic interactions with biological matter and their applications,” J. Appl. Phys. 105(10), 102033 (2009). [CrossRef]

, 15

15. C. Ro̸nne, L. Thrane, P.-O. Åstrand, A. Wallqvist, K. V. Mikkelsen, and S. R. Keiding, “Investigation of the temperature dependence of dielectric relaxation in liquid water by THz reflection spectroscopy and molecular dynamics simulation,” J. Chem. Phys. 107(14), 5319–5331 (1997). [CrossRef]

]. The temperature sensitivity of THz waves for water is much higher than those of NIR or visible waves [16

16. J. R. Collins, “Change in the infra-red absorption spectrum of water with temperature,” Phys. Rev. 26(6), 771–779 (1925). [CrossRef]

]. Thus, when using TMI, the distribution of minute quantities of nanoprobes can be precisely determined through the measurement of the temperature around the nanoprobes. To achieve a more sensitive THz response, the optical beam inducing SPPs was modulated to give differential THz signals responding to the heat change only. This differential THz detection technique offers a high contrast image due to the exclusive presence of signals from the nanoprobes and the highly sensitive nature of THz waves. We modulated the period and intensity of the NIR optical beam inducing SPPs on the nanoprobes (Fig. 2(a)
Fig. 2 THz response under NIR modulation. (a) shows the NIR signal modulated by a mechanical shutter (black line). (b) shows the THz responses of water using GNRs under NIR irradiation (red line), GNRs without NIR irradiation (green line), and without GNRs under NIR irradiation (blue line). The power of the NIR beam was 15 W/cm2 and the diameters of the THz and NIR beams were 0.8 mm. The GNR solution was 100 μM. The time dependent THz signals were acquired by an oscilloscope triggered by the modulation signal of the NIR beam.
). The modulated beam altered the temperature of the water through the SPPs, and the temperature change was monitored by studying the THz signal (Fig. 2(b)). However, if the GNRs were not present, or in the absence of NIR beam irradiation, the THz signals showed little change.

The differential THz signal modulated by the NIR beam was used to construct THz images of the nanoprobes. GNRs with an absorption peak of approximately 800 nm were used [7

7. 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(5), 3469–3475 (2009). [CrossRef] [PubMed]

]. The THz signals were used to construct high contrast molecular images. The images were target specific because the signal originated only from the nanoprobes designed to be delivered to certain molecules.

The application of TMI allowed target specific imaging of cancerous tumors in vivo. A mouse bearing the A431 epidermoid carcinoma tumor (Figs. 3(a) and (b)
Fig. 3 In vivo and ex vivo THz molecular images of tumors. (a) and (b) show visible images of the mouse with an A431 tumor (size = 2.1 cm3). (c) shows the THz molecular image of (b). (d) shows the visible images of the tumor, liver, spleen, kidney, and brain. (e) shows the THz molecular image of (d). The power of the NIR beam was 80 W/cm2 and the diameters of the THz and NIR beams were 0.8 mm. The image was taken with a scan step of 250 μm and a time delay of 3 s per pixel, 24 h after the injection of 100 μL of CET-PGNRs at a concentration of 1 mM.
) was prepared and the nanoprobes were injected into the mouse through the tail-vein with 100 μL of CET-PGNRs at a concentration of 1 mM. The image was acquired using the peak amplitude of the time domain impulse function obtained by inverse Fourier transformation of the difference between the reflectivity of the THz signals with and without NIR beam irradiation. Although the visual image (Fig. 3(b)) displayed only a superficial shape of tumors on the skin, a high contrast THz image revealed the location and size of tumors targeted with nanoprobes, without being distorted by ambient anatomical structure or chemical distribution, as shown in Fig. 3(c).

These TMI images were compared with those produced from NIR absorption imaging (NAI). This was an in vivo macroscopic imaging technique based on photonics using nanoprobes. Unlike TMI, NAI measures the images before and after injecting nanoprobes and compares the relative difference of brightness allowing the qualitative determination of the nanoprobe delivery. Due to its low sensitivity, NAI was unable to observe the enhancement by nanoprobes for detection of the small tumor shown in Fig. 3(c) by comparing the images in Figs. 4(a) and (b)
Fig. 4 In vivo and ex vivo NIR absorption images. (a) and (b) show the NIR absorption images of the mouse shown in Fig. 2 before the injection of nanoprobes and 24 h after the injection. (c) and (d) show the NIR absorption images of the tumor, spleen, kidney, liver, and brain before and after the injection of nanoprobes.
, although the larger tumors were detected by both techniques. After taking in vivo images, the mouse injected with nanoprobes was sacrificed to show the targeting moiety at specific locations. The tumor, liver, spleen, kidney, and brain were surgically removed, as shown in Fig. 3(d). The TMI images are shown in Fig. 3(e). The amplitudes of the TMI images for the tumor, liver, and spleen were higher than those for the brain and kidney, although the brightness of the THz images of the organs from a mouse without injection of CET-PGNRs were almost identical. This showed that the nanoprobes were delivered into the targeted tumor through the circulation system of the mouse and were remained in the liver and spleen before being eliminated from the mouse body by kidney [17

17. R. Bardhan, W. Chen, M. Bartels, C. Perez-Torres, M. F. Botero, R. W. McAninch, A. Contreras, R. Schiff, R. G. Pautler, N. J. Halas, and A. Joshi, “Tracking of multimodal therapeutic nanocomplexes targeting breast cancer in vivo,” Nano Lett. 10(12), 4920–4928 (2010). [CrossRef]

]. The result verified that TMI is sensitive enough to classify the difference of targeted nanoprobes quantitatively. These images were also taken using NAI as shown in Figs. 4(c) and (d). Although the brightness of the NAI liver image with CET-PGNRs was darker than that without CET-PGNRs, the brightness of the tumor, spleen, and kidney images looked almost similar, or became even brighter after the injection of CET-PGNRs. It can thus be inferred that NAI cannot detect the nanoprobe delivery to organs, with the exception of the liver, due to its poor sensitivity.

The minimum detection sensitivity and the quantification linearity of the TMI measurement were characterized in a solution and in vivo using an artificial tumor. As shown in Fig. 5(a)
Fig. 5 Quantification of THz molecular imaging in solution. (a) shows the THz molecular images of the solutions with various concentrations of CET-PGNRs from 332 μM to 10 μM (n/2 for each concentration). (b) shows the THz reflectivity of the solutions with various concentrations of CET-PGNRs from 3.3 mM to 10 μM (n/2 for each concentration) (solid circles). The experimental data were fitted by a linear line (red line).
, a 10 μM concentration of CET-PGNRs in water could be imaged, while water presented almost no THz reflectivity signal. The THz reflectivity was reduced linearly proportional to the decreasing concentration of the CET-PGNRs and reached 1% at the concentration of 10 μM, as shown in Fig. 5(b). The linearity between the concentration and the THz signal was excellent with a correlation coefficient of 0.992. These sensitivity and quantification properties were also demonstrated in vivo using an artificial tumor of Matrigel in a mouse. The Matrigels, with various concentrations of nanoprobes, were subcutaneously injected into the right lower back of mice using 20 μL of mixture. A Matrigel without nanoprobes injected into the left lower back of the mice served as a control. The image of the tumor could be seen down to 15 μM of CET-PGNRs as shown Fig. 6(a)
Fig. 6 Quantification of THz molecular imaging in vivo. (a) shows the in vivo THz molecular images of artificial tumors with various concentrations of CET-PGNRs. (b) shows the peak values from the images of (a) (solid circles). The experimental data is fitted with a linear line (red line).
. The peak values of the THz images displayed a linear correlation of 0.999 with the concentration of nanoprobes, as shown in Fig. 6(b). This excellent linear correlation confirms the capability of quantitative in vivo imaging.

We also displayed the superiority of TMI by comparing it with NAI. Owing to its poor sensitivity, NAI was not able to detect the concentration of 62 μM, as shown in Fig. 7
Fig. 7 In vivo quantification of detection sensitivity by the NIR absorption imaging technique. Shown is the top view of in vivo NIR absorption images of artificial tumors with various concentrations of CET-PGNRs. The artificial tumors on the left leg are without nanoprobes and the artificial tumors on the right leg are with nanoprobes.
. This performance was at least four times inferior to the minimum detectable concentrations using TMI.

For addressing the target sensitivity on specific biomolecular, two kinds of epidermoid carcinoma cells, A431 (EGFR over-expressed) and MCF7 (EGFR less expressed), were prepared. These cells were incubated in a solution with CET-PGNRs at concentrations of 166 μM and 41 μM for 24 h and cleaned with PBS to obtain the cells embedded with CET-PGNRs only. The THz responses of the A431 cells with the CET-PGNRs were 4 times greater than those of the MCF7 cells for both concentrations (Fig. 8
Fig. 8 In vitro target specificity and sensitivity of THz molecular imaging. The grey bar is the THz response from the A431 cells without nanoprobes serving as a control. The red bars represent the A431 cells targeted with nanoprobes. The blue bars represent the MCF7 cells targeted with nanoprobes. The bars and the error bars are the mean values and standard deviations, respectively, at four random positions of each cell.
). The responses of the MCF7 cells were similar to those of the A431 cells without CET-PGNRs, which served as a control, showing that TMI could differentiate cancers at cell level sensitively, with target specificity arising from the conjugation of nanoprobes.

4. Conclusion

We have demonstrated molecular imaging with THz waves by using nanoparticle probes. TMI is sensitive enough to detect 15 μM of nanoprobes in vivo, which implies that it is four times more sensitive than the conventional NAI technique. In addition to the superior sensitivity, TMI offers excellent quantification property, being linearly proportional to the concentration of nanoprobes. By delivering the nanoprobes exclusively to an epidermal growth_factor_receptor_over-expressed A431 carcinoma cell, TMI proved to be target specific at the cell level, and the cancerous tumors were non-invasively imaged in vivo with high sensitivity and contrast. Thus, TMI can facilitate the early diagnosis of cancers, the monitoring of drug delivery processes, and the study of biological phenomena at the molecular level.

Acknowledgment

This study was supported by a grant from the Korean Health Technology R&D Project of the Ministry for Health, Welfare & Family Affairs, Republic of Korea (A101954); a National Research Foundation of Korea (NRF) grants funded by the Ministry of Education Science & Technology, Republic of Korea (20100020647, 20100001979, 20100015989, 20100011934, 20090054519); Business for Cooperative R&D between Industry, Academy, and Research Institute funded Korea Small and Medium Business Administration in 2010 (000428380110).

References and links

1.

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(2), 533–540 (2006). [CrossRef] [PubMed]

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(1), 72–78 (2003). [CrossRef] [PubMed]

3.

E. Pickwell and V. P. Wallace, “Biomedical applications of terahertz technology,” J. Phys. D Appl. Phys. 39(17), R301–R310 (2006). [CrossRef]

4.

J.-H. Son, “Terahertz electromagnetic interactions with biological matter and their applications,” J. Appl. Phys. 105(10), 102033 (2009). [CrossRef]

5.

B. Ferguson and X.-C. Zhang, “Materials for terahertz science and technology,” Nat. Mater. 1(1), 26–33 (2002). [CrossRef]

6.

K. Kawase, Y. Ogawa, Y. Watanabe, and H. Inoue, “Non-destructive terahertz imaging of illicit drugs using spectral fingerprints,” Opt. Express 11(20), 2549–2554 (2003). [CrossRef] [PubMed]

7.

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(5), 3469–3475 (2009). [CrossRef] [PubMed]

8.

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(1), 95–99 (2006). [CrossRef] [PubMed]

9.

R. Weissleder and V. Ntziachristos, “Shedding light onto live molecular targets,” Nat. Med. 9(1), 123–128 (2003). [CrossRef] [PubMed]

10.

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, and S. Haam, “Multifunctional magnetic gold nanocomposites: human epithelial cancer detection via magnetic resonance imaging and localized synchronous therapy,” Adv. Funct. Mater. 18(2), 258–264 (2008). [CrossRef]

11.

J. Yang, C.-H. Lee, H.-J. Ko, J.-S. Suh, H.-G. Yoon, K. Lee, Y.-M. Huh, and S. Haam, “Multifunctional magneto-polymeric nanohybrids for targeted detection and synergistic therapeutic effects on breast cancer,” Angew. Chem. Int. Ed. Engl. 46(46), 8836–8839 (2007). [CrossRef] [PubMed]

12.

J. R. McCarthy and R. Weissleder, “Multifunctional magnetic nanoparticles for targeted imaging and therapy,” Adv. Drug Deliv. Rev. 60(11), 1241–1251 (2008). [CrossRef] [PubMed]

13.

S. Santra, C. Kaittanis, J. Grimm, and J. M. Perez, “Drug/dye-loaded, multifunctional iron oxide nanoparticles for combined targeted cancer therapy and dual optical/magnetic resonance imaging,” small 5(16), 1862–1868 (2009). [CrossRef] [PubMed]

14.

L. Tong, Q. Wei, A. Wei, and J.-X. Cheng, “Gold nanorods as contrast agents for biological imaging: optical properties, surface conjugation and photothermal effects,” Photochem. Photobiol. 85(1), 21–32 (2009). [CrossRef] [PubMed]

15.

C. Ro̸nne, L. Thrane, P.-O. Åstrand, A. Wallqvist, K. V. Mikkelsen, and S. R. Keiding, “Investigation of the temperature dependence of dielectric relaxation in liquid water by THz reflection spectroscopy and molecular dynamics simulation,” J. Chem. Phys. 107(14), 5319–5331 (1997). [CrossRef]

16.

J. R. Collins, “Change in the infra-red absorption spectrum of water with temperature,” Phys. Rev. 26(6), 771–779 (1925). [CrossRef]

17.

R. Bardhan, W. Chen, M. Bartels, C. Perez-Torres, M. F. Botero, R. W. McAninch, A. Contreras, R. Schiff, R. G. Pautler, N. J. Halas, and A. Joshi, “Tracking of multimodal therapeutic nanocomplexes targeting breast cancer in vivo,” Nano Lett. 10(12), 4920–4928 (2010). [CrossRef]

18.

D. Boyer, P. Tamarat, A. Maali, B. Lounis, and M. Orrit, “Photothermal imaging of nanometer-sized metal particles among scatterers,” Science 297(5584), 1160–1163 (2002). [CrossRef] [PubMed]

19.

M. C. Skala, M. J. Crow, A. Wax, and J. A. Izatt, “Photothermal optical coherence tomography of epidermal growth factor receptor in live cells using immunotargeted gold nanospheres,” Nano Lett. 8(10), 3461–3467 (2008). [CrossRef] [PubMed]

20.

D. C. Adler, S.-W. Huang, R. Huber, and J. G. Fujimoto, “Photothermal detection of gold nanoparticles using phase-sensitive optical coherence tomography,” Opt. Express 16(7), 4376–4393 (2008). [CrossRef] [PubMed]

OCIS Codes
(170.3880) Medical optics and biotechnology : Medical and biological imaging
(170.6795) Medical optics and biotechnology : Terahertz imaging

ToC Category:
Medical Optics and Biotechnology

History
Original Manuscript: December 20, 2010
Revised Manuscript: February 2, 2011
Manuscript Accepted: February 2, 2011
Published: February 15, 2011

Virtual Issues
Vol. 6, Iss. 3 Virtual Journal for Biomedical Optics

Citation
Seung Jae Oh, Jihye Choi, Inhee Maeng, Jae Yeon Park, Kwangyeol Lee, Yong-Min Huh, Jin-Suck Suh, Seungjoo Haam, and Joo-Hiuk Son, "Molecular imaging with terahertz waves," Opt. Express 19, 4009-4016 (2011)
http://www.opticsinfobase.org/oe/abstract.cfm?URI=oe-19-5-4009


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References

  1. 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(2), 533–540 (2006). [CrossRef] [PubMed]
  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(1), 72–78 (2003). [CrossRef] [PubMed]
  3. E. Pickwell and V. P. Wallace, “Biomedical applications of terahertz technology,” J. Phys. D Appl. Phys. 39(17), R301–R310 (2006). [CrossRef]
  4. J.-H. Son, “Terahertz electromagnetic interactions with biological matter and their applications,” J. Appl. Phys. 105(10), 102033 (2009). [CrossRef]
  5. B. Ferguson and X.-C. Zhang, “Materials for terahertz science and technology,” Nat. Mater. 1(1), 26–33 (2002). [CrossRef]
  6. K. Kawase, Y. Ogawa, Y. Watanabe, and H. Inoue, “Non-destructive terahertz imaging of illicit drugs using spectral fingerprints,” Opt. Express 11(20), 2549–2554 (2003). [CrossRef] [PubMed]
  7. 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(5), 3469–3475 (2009). [CrossRef] [PubMed]
  8. 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(1), 95–99 (2006). [CrossRef] [PubMed]
  9. R. Weissleder and V. Ntziachristos, “Shedding light onto live molecular targets,” Nat. Med. 9(1), 123–128 (2003). [CrossRef] [PubMed]
  10. 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, and S. Haam, “Multifunctional magnetic gold nanocomposites: human epithelial cancer detection via magnetic resonance imaging and localized synchronous therapy,” Adv. Funct. Mater. 18(2), 258–264 (2008). [CrossRef]
  11. J. Yang, C.-H. Lee, H.-J. Ko, J.-S. Suh, H.-G. Yoon, K. Lee, Y.-M. Huh, and S. Haam, “Multifunctional magneto-polymeric nanohybrids for targeted detection and synergistic therapeutic effects on breast cancer,” Angew. Chem. Int. Ed. Engl. 46(46), 8836–8839 (2007). [CrossRef] [PubMed]
  12. J. R. McCarthy and R. Weissleder, “Multifunctional magnetic nanoparticles for targeted imaging and therapy,” Adv. Drug Deliv. Rev. 60(11), 1241–1251 (2008). [CrossRef] [PubMed]
  13. S. Santra, C. Kaittanis, J. Grimm, and J. M. Perez, “Drug/dye-loaded, multifunctional iron oxide nanoparticles for combined targeted cancer therapy and dual optical/magnetic resonance imaging,” small 5(16), 1862–1868 (2009). [CrossRef] [PubMed]
  14. L. Tong, Q. Wei, A. Wei, and J.-X. Cheng, “Gold nanorods as contrast agents for biological imaging: optical properties, surface conjugation and photothermal effects,” Photochem. Photobiol. 85(1), 21–32 (2009). [CrossRef] [PubMed]
  15. C. Ro̸nne, L. Thrane, P.-O. Åstrand, A. Wallqvist, K. V. Mikkelsen, and S. R. Keiding, “Investigation of the temperature dependence of dielectric relaxation in liquid water by THz reflection spectroscopy and molecular dynamics simulation,” J. Chem. Phys. 107(14), 5319–5331 (1997). [CrossRef]
  16. J. R. Collins, “Change in the infra-red absorption spectrum of water with temperature,” Phys. Rev. 26(6), 771–779 (1925). [CrossRef]
  17. R. Bardhan, W. Chen, M. Bartels, C. Perez-Torres, M. F. Botero, R. W. McAninch, A. Contreras, R. Schiff, R. G. Pautler, N. J. Halas, and A. Joshi, “Tracking of multimodal therapeutic nanocomplexes targeting breast cancer in vivo,” Nano Lett. 10(12), 4920–4928 (2010). [CrossRef]
  18. D. Boyer, P. Tamarat, A. Maali, B. Lounis, and M. Orrit, “Photothermal imaging of nanometer-sized metal particles among scatterers,” Science 297(5584), 1160–1163 (2002). [CrossRef] [PubMed]
  19. M. C. Skala, M. J. Crow, A. Wax, and J. A. Izatt, “Photothermal optical coherence tomography of epidermal growth factor receptor in live cells using immunotargeted gold nanospheres,” Nano Lett. 8(10), 3461–3467 (2008). [CrossRef] [PubMed]
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