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Imaging of Oxidation-Specific Epitopes with Targeted Nanoparticles to Detect High-Risk Atherosclerotic Lesions: Progress and Future Directions

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Abstract

Oxidation-specific epitopes (OSE) within developing atherosclerotic lesions are key antigens that drive innate and adaptive immune responses in atherosclerosis, leading to chronic inflammation. Oxidized phospholipids and malondialdehyde-lysine epitopes are well-characterized OSE present in human atherosclerotic lesions, particularly in pathologically defined vulnerable plaques. Using murine and human OSE-specific antibodies as targeting agents, we have developed radionuclide and magnetic resonance based nanoparticles, containing gadolinium, manganese or lipid-coated ultrasmall superparamagnetic iron oxide, to non-invasively image OSE within experimental atherosclerotic lesions. These methods quantitate plaque burden, allow detection of lesion progression and regression, plaque stabilization, and accumulation of OSE within macrophage-rich areas of the artery wall, suggesting they detect the most active lesions. Future studies will focus on using “natural” antibodies, lipopeptides, and mimotopes for imaging applications. These approaches should enhance the clinical translation of this technique to image, monitor, evaluate efficacy of novel therapeutic agents, and guide optimal therapy of high-risk atherosclerotic lesions.

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Acknowledgements

Drs. Tsimikas and Witztum are co-inventors of and receive royalties from patents on oxidation-specific antibodies and mimotopes owned by the University of California San Diego. Dr. Tsimikas holds a dual appointment at the University of California San Diego and as an employee of Isis Pharmaceuticals, Inc. Dr. Witztum has received honoraria for consulting for Isis Pharmaceuticals, Inc., Regulus Therapeutics Inc., and Intercept Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Sources of Funding and Disclosure

This study was funded by grants from the National Institutes of Health R01-HL119828, R01-HL093767, P01-HL055798, P01-HL088093, and U54-HL119893 (to Drs. Witztum and Tsimikas).

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Authors and Affiliations

  1. Department of Basic Science and Craniofacial Biology, New York University, New York, NY, USA

    Karen Briley-Saebo

  2. Division of Cardiovascular Medicine, University of California San Diego, BSB-1080, La Jolla, CA, 92093-0682, USA

    Calvin Yeang, Joseph L. Witztum & Sotirios Tsimikas

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  1. Karen Briley-Saebo
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  2. Calvin Yeang
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  3. Joseph L. Witztum
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  4. Sotirios Tsimikas
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Correspondence to Sotirios Tsimikas.

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Associate Editor Paul J. R. Barton oversaw the review of this article.

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Briley-Saebo, K., Yeang, C., Witztum, J.L. et al. Imaging of Oxidation-Specific Epitopes with Targeted Nanoparticles to Detect High-Risk Atherosclerotic Lesions: Progress and Future Directions. J. of Cardiovasc. Trans. Res. 7, 719–736 (2014). https://doi.org/10.1007/s12265-014-9590-4

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