Ultrahigh Sensitivity Carbon Nanotube Agents for Photoacoustic Molecular Imaging in Living Mice

Abstract

Photoacoustic imaging is an emerging modality that overcomes to a great extent the resolution and depth limitations of optical imaging while maintaining relatively high-contrast. However, since many diseases will not manifest an endogenous photoacoustic contrast, it is essential to develop exogenous photoacoustic contrast agents that can target diseased tissue(s). Here we present a novel photoacoustic contrast agent, Indocyanine Green dye-enhanced single walled carbon nanotube (SWNT-ICG). We conjugated this contrast agent with cyclic Arg-Gly-Asp (RGD) peptides to molecularly target the α v β 3 integrins, which are associated with tumor angiogenesis. Intravenous administration of this tumor-targeted contrast agent to tumor-bearing mice showed significantly higher photoacoustic signal in the tumor than in mice injected with the untargeted contrast agent. The new contrast agent gave a markedly 300-times higher photoacoustic contrast in living tissues than previously reported SWNTs, leading to sub-nanomolar sensitivities. Finally, we show that the new contrast agent can detect ~20-times fewer cancer cells than previously reported SWNTs.Photoacoustic imaging is an emerging modality based on the photoacoustic effect where light is converted into ultrasound waves that are detected outside the subject of interest 1 . Photoacoustic imaging has been used in numerous applications where intrinsic contrast is available such as visualizing blood vessels structure 2 , thermal burns 3 and melanoma 4 . However, most diseases will not show photoacoustic contrast, thereby requiring the use of an exogenous contrast agent which will target the diseased tissue. The main challenge in designing such contrast agent remains creating an agent that produces sufficient photoacoustic signal in order to be detected in low concentration, while being able to target the diseased tissue(s). In * sgambhir@stanford.edu; hdai1@stanford.edu. † These authors contributed equally to this work Supporting Information Description of particles synthesis, photoacoustic imaging instrument, experimental procedures, statistical methods, and in-vitro characterization of the particles including serum-stability, photobleaching and cell-uptake study.

Hydroxyapatite-Nanotube Composites and Coatings for Orthopedic Applications

“…Lai et al have shown α υ β integrins to mediate osteoblast response with many bone matrix proteins [146]. CNTs also have specific affinity to integrins [148][149][150][151]. Functionalized CNTs were shown to have high affinity to α υ β 3 integrin and have been proposed for tumor targeting to deliver radioisotope drugs in cancer therapy [148][149][150][151].…”

The Advances of Carbon Nanotubes in Cancer Diagnostics and Therapeutics

“…Gold coating can increase the inherent photoacoustic signal of SWNTs, so some researchers have developed "golden nanotubes" (GNTs) [79]. Moreover, some NIR dyes such as indocyanine green (IGG) molecules [80] can be loaded on PEGylated SWNTs to improve the optical density, which result in the presence of multiplexed PAI probes [81].…”

Biomedical photoacoustics: fundamentals, instrumentation and perspectives on nanomedicine

“…have been designed as contrast agents for PA molecular imaging (Figure 3). [42][43][44] Issues related to biosafety of these advanced nanomaterials are being focused on so that these nanomaterials can be translated to clinical uses. Apart from that, prominent sensitivity, proper stability and Abbreviations: PAM, photoacoustic microscopy; 3D, three-dimensional; 2D, two-dimensional; He, hematoxylin-eosin.…”

“…Higher PA signals in the tumor region were observed than the non-conjugated control ( Figure 5). 44 Although the toxicity of SWNTs is still under investigation, a number of studies have disclosed their applications in PAI as promising contrast agents for tumor neovasculature imaging, SLN mapping as well as PPT.…”