Carbon nanotubes as photoacoustic molecular imaging agents in living mice - PubMed (original) (raw)
doi: 10.1038/nnano.2008.231. Epub 2008 Aug 17.
Cristina Zavaleta, Shay Keren, Srikant Vaithilingam, Sunil Bodapati, Zhuang Liu, Jelena Levi, Bryan R Smith, Te-Jen Ma, Omer Oralkan, Zhen Cheng, Xiaoyuan Chen, Hongjie Dai, Butrus T Khuri-Yakub, Sanjiv S Gambhir
- PMID: 18772918
- PMCID: PMC2562547
- DOI: 10.1038/nnano.2008.231
Carbon nanotubes as photoacoustic molecular imaging agents in living mice
Adam De la Zerda et al. Nat Nanotechnol. 2008 Sep.
Abstract
Photoacoustic imaging of living subjects offers higher spatial resolution and allows deeper tissues to be imaged compared with most optical imaging techniques. As many diseases do not exhibit a natural photoacoustic contrast, especially in their early stages, it is necessary to administer a photoacoustic contrast agent. A number of contrast agents for photoacoustic imaging have been suggested previously, but most were not shown to target a diseased site in living subjects. Here we show that single-walled carbon nanotubes conjugated with cyclic Arg-Gly-Asp (RGD) peptides can be used as a contrast agent for photoacoustic imaging of tumours. Intravenous administration of these targeted nanotubes to mice bearing tumours showed eight times greater photoacoustic signal in the tumour than mice injected with non-targeted nanotubes. These results were verified ex vivo using Raman microscopy. Photoacoustic imaging of targeted single-walled carbon nanotubes may contribute to non-invasive cancer imaging and monitoring of nanotherapeutics in living subjects.
Figures
Figure 1. Characterization of the photoacoustic properties of single-walled carbon nanotubes
a, Illustration of plain single-walled carbon nanotubes (plain SWNT) and SWNT – RGD. The phospholipid binds to the sidewall of the single-walled carbon nanotubes connecting the PEG5000 to the nanotubes. The RGD allows the single-walled carbon nanotubes to bind to tumour integrins such as αvβ3. b, The photoacoustic spectra of plain single-walled carbon nanotubes and SWNT –RGD are overlaid on the known optical absorbance of HbO2 and Hb. The spectral overlap between plain single-walled carbon nanotubes and SWNT –RGD suggests that the RGD conjugation does not perturb the photoacoustic signal. c, The photoacoustic signal produced by single-walled carbon nanotubes was observed to be linearly dependent on the concentration (_R_2 = 0.9997).
Figure 2. Photoacoustic detection of single-walled carbon nanotubes in living mice
a, Mice were injected subcutaneously with single-walled carbon nanotubes at concentrations of 50– 600 nM. One vertical slice in the 3D photoacoustic image (green) was overlaid on the corresponding slice in the ultrasound image (grey). The skin is visible in the ultrasound images, and the photoacoustic images show the single-walled carbon nanotubes. The dotted lines on the images identify the edges of each inclusion. b, The photoacoustic signal from each inclusion was calculated. The background level represents the endogenous signal measured from tissues. The error bars represent standard error (n = 3). The linear regression is calculated on the five most concentrated inclusions (_R_2 = 0.9929).
Figure 3. Single-walled carbon nanotube targets tumour in living mice
a, Ultrasound (grey) and photoacoustic (green) images of one vertical slice (white dotted line) through the tumour. The ultrasound images show the skin and tumour boundaries. Subtraction images were calculated as the 4 h post-injection image minus the pre-injection image. The high photoacoustic signal in the mouse injected with plain single-walled carbon nanotubes (indicated with a white arrow) is not seen in the subtraction image, suggesting that it is due to a large blood vessel and not single-walled carbon nanotubes. b, Mice injected with SWNT –RGD showed a significantly higher photoacoustic signal than mice injected with plain single-walled carbon nanotubes (P < 0.001). The error bars represent standard error (n = 4). *P < 0.05.
Figure 4. Validation of the in vivo photoacoustic images by Raman ex vivo microscopy
a, Photographs of the tumours in mice and the corresponding photoacoustic subtraction images (green) shown as horizontal slices through the tumours. After the photoacoustic scan, the tumours were excised and scanned using a Raman microscope (red). Mice injected with plain single-walled carbon nanotubes (left-hand column) showed both low photoacoustic and Raman signals compared with mice injected with SWNT – RGD (right-hand column). The tumours are in the same orientation in all images. b, Comparison between the photoacoustic signal of the tumours in vivo (left) and the Raman signal acquired from the excised tumours (right). *P < 0.05.
Figure 5. Comparison between photoacoustic imaging using single-walled carbon nanotubes and fluorescence imaging using quantum dots
a, Fluorescence image (red) of a mouse injected with QD– RGD. The white arrow indicates the tumour location. The other bright spots on the image represent the different organs in which QD– RGD non-specifically accumulated. b, Tumor photograph. c, Horizontal (xy plane) and d, vertical (xz plane) slices in the 3D photoacoustic image of a mouse injected with SWNT – RGD. The black dotted line shows the vertical slice orientation and the white dotted line shows the height of the horizontal slice in the vertical slice. The location of the single-walled carbon nanotubes in the tumour is visualized with high spatial resolution.
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