Plasmonic Intravascular Photoacoustic Imaging for Detection of Macrophages in Atherosclerotic Plaques Bo Wang, † Evgeniya Yantsen, † Timothy Larson, † Andrei B. Karpiouk, † Shriram Sethuraman, † Jimmy L. Su, † Konstantin Sokolov, †,‡ and Stanislav Y. Emelianov* ,† Department of Biomedical Engineering, UniVersity of Texas at Austin, Austin, Texas 78712, Departments of Biomedical Engineering and Imaging Physics, UniVersity of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 USA Received June 26, 2008; Revised Manuscript Received September 15, 2008 ABSTRACT To detect macrophages in atherosclerotic plaques, plasmonic gold nanoparticles are introduced as a contrast agent for intravascular photoacoustic imaging. The phantom and ex vivo tissue studies show that the individual spherical nanoparticles, resonant at 530 nm wavelength, produce a weak photoacoustic signal at 680 nm wavelength while photoacoustic signal from nanoparticles internalized by macrophages is very strong due to the plasmon resonance coupling effect. These results suggest that intravascular photoacoustic imaging can assess the macrophage- mediated aggregation of nanoparticles and therefore identify the presence and the location of nanoparticles associated with macrophage-rich atherosclerotic plaques. Every year, cardiovascular disease claims more lives in United States than any other disease including cancer. 1 Despite advances in determining risk factors and treating myocardial infarction, there are few techniques available for imaging the development of the atherosclerotic plaques that play a major role in cardiovascular disease. Macrophages are one of the key components involved in the pathology of atherosclerosis. At a relatively early stage in atherosclerotic development, macrophages are present at the “crime scene”: macrophages are formed from the blood monocytes that enter the arterial wall because of the initial inflammation in the arterial endothelial layer. During the progression of the dis- ease, lipid-laden macrophages play a partial role in the formation of atheroma. 2,3 Macrophage infiltration into the fibrous cap of plaques also accelerates disease progression by causing the release of matrix metalloproteinases (MMPs), 4 which weaken the fibrous cap and make the plaques prone to rupture. 5 Clearly, the distribution and activity of mac- rophages provide important information on the development of atherosclerotic plaques. Therefore, it is important to develop robust and cost-effective imaging methods sensitive to the cellular composition of plaques. With almost any imaging technique, imaging the mac- rophages requires a contrast agent. Therefore, different types of contrast agents have to be introduced in various imaging methods, such as magnetic resonance imaging (MRI), computed tomography (CT), optical coherence tomography (OCT) and ultrasound imaging, to image macrophage dis- tribution. 6-9 Nanoparticles have been widely used as a contrast agent to image macrophages by MRI and OCT since macrophages endocytose particles into intracellular vesicles. The imaging contrast is enhanced by the high local concen- tration of contrast agents in macrophages. For example, in optical imaging, gold nanoparticles (Au NPs) become an ideal contrast agent because of their biocompatibility and high optical scattering coefficients. 10-15 Moreover, the optical spectra of Au NPs can be tuned by changing the size and/or shape of the particles, 16 thus providing flexibility in different applications. Recently, intravascular photoacoustic (IVPA) imaging, a catheter-based, minimally invasive imaging technique, was introduced to image atherosclerosis. 17 Generally, photoa- coustic imaging is a technique to ultrasonically image the optical absorption of tissue. Specifically, the tissue is irradiated with a short laser pulse, and photoacoustic transients are generated as the light is absorbed in tissue. These acoustic waves, recorded using an ultrasound sensor, are used to form an image. The differences in optical absorption among arterial tissue components provide contrast in IVPA imaging. Using a laboratory prototype of the IVPA imaging system consisting of a pulsed laser source and an * To whom correspondence should be addressed. Telephone: (512) 471- 1733. Fax: (512) 471-0616. E-mail: emelian@mail.utexas.edu. † University of Texas at Austin. ‡ University of Texas M.D. Anderson Cancer Center. NANO LETTERS 2009 Vol. 9, No. 6 2212-2217 10.1021/nl801852e CCC: $40.75  2009 American Chemical Society Published on Web 10/10/2008