| COMMENTARIES |
Potential Applications of Nanotechnology for Atherosclerosis Imaging
Paul Schoenhagen, M.D., Imaging Institute and Heart & Vascular Institute, Cleveland Clinic, Cleveland, OH
Please address correspondence to:
Paul Schoenhagen, M.D., FAHA
Imaging Institute and Heart & Vascular Institute
Cleveland Clinic
9500 Euclid Ave. Desk HB-6.
Cleveland OH 44195
Tel: (216) 445-7579
Fax: (216) 445-6855
Email: schoenp1@ccf.org
Imaging of atherosclerotic plaque and in particular features of plaque vulnerability is an area of intense clinical research [1]. Initial invasive imaging with grey-scale intravascular ultrasound (IVUS), comparing lesion morphology in stable and unstable patients found low-echodenity, small “spotty” calcium deposits, and positive remodeling to be more prevalent in unstable patients [2-4]. Advanced analysis of the IVUS backscatter information (IVUS radiofrequency analysis, RFA) and optical coherence tomography allows further plaque differentiation [5,6]. Non-invasive imaging of atherosclerotic plaque has more recently become possible. Similar to previous IVUS studies, initial results with computed tomography (CT) suggest that mixed calcified lesions with spotty calcification are related to plaque vulnerability [7-9].
However, a major limitation is the fact that imaging criteria of vulnerability are typically not limited to unstable lesions and morphology is often identical for culprit and non-culprit vessels. It is likely that additional features of individual plaques including inflammatory activity need to be evaluated using emerging molecular imaging approaches [10]. Molecular imaging describes diagnostic strategies targeting biomarkers associated with the development of atherosclerotic lesions [11,12]. Using image probes such as radiolabeled substrates and targeted contrast agents and ligands, the assessment of specific biochemical pathways involved in atherosclerotic disease development or drug effect is becoming possible. Miniaturized imaging equipment and imaging probes have already been applied to study animal models of disease, such as transgenic and knockout mice. In the future, these technologies could be used to non-invasively detect and monitor disease development. While most data has evolved from PET and MRI [13,14], a very interesting modality is micro-computed tomography. The technique has been successfully used in the visualization of the microvasculature and a recent study examined the feasibility of micro-CT for the analysis of the coronary artery wall [15].
The field of nanotechnology is currently undergoing rapid development and is expected to play a critical role in various biomedical applications. Nanotechnology is expected to contribute to molecular strategies in the diagnosis and treatment of CAD [16-18]. Of particular interest are small bioengineered nanoparticles, which can be utilized as transport vehicles for diagnostic or therapeutic agents. Imaging applications range from non-directed (e.g. blood pool) to directed particles, characterized by molecular recognition factors such as antibodies, peptides, anti-angiogenic factors, and other disease specific moieties. Multiple examples of nanoparticles bioengineered for in vivo imaging applications have been reported. Examples include quantum dots, liposomes, metal oxides, dendrimers, nanotubes, and nanoshells. In the case of e.g. quantum dots and nanoshells, physical properties inherent to the nanoparticle itself give rise to imaging capabilities. In contrast, other particles act diagnostically by associating traditional imaging agents, associated by encapsulation or attachment. Novel therapeutic strategies include the development of targeted transport vehicles allowing drug delivery to specific cells or cell structures.
The validity of plaque burden as an intermediate endpoint in progression/regression trials is documented for carotid ultrasound (CIMT) and coronary intravascular ultrasound (IVUS). Serial volumetric IVUS progression/regression trials have already become an integral part of anti-atherosclerotic drug development and have already changed treatment approaches for patients with CAD [19]. The relationship between plaque burden and clinical events is likely complex and modified by disease activity, and in particular inflammatory processes. Non-invasive imaging of early atherosclerotic changes and disease activity with specially designed contrast agents to localize the targeted molecular signature could results in in vivo detection and quantification of subclinical coronary atherosclerosis and plaque vulnerability. Nano-technology has promising applications in atherosclerosis imaging but rigorous scientific evaluation is necessary, including definitive evidence that these particles are inert and not associated with toxicity. Further development is required before nanotechnology can be applied clinically.
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