⁸⁹Zr-Nanoparticle PET Imaging of Carotid Plaques in a Murine Model of Atherosclerosis

Objectives: Arterial plaque detection and monitoring remains difficult, especially with unstable non-calcified plaques that do not greatly attenuate on CT. These plaques do show a large degree of CD68+ monocyte and macrophage infiltration, giving a good biological target for nuclear imaging. Here we use a ⁸⁹Zr-labeled nanoparticle, Feraheme (FH), to image this inflammation in a murine model of carotid artery atherosclerosis. FH is an FDA-approved drug which is known to be preferentially phagocytosed by monocytes and macrophages, and ⁸⁹Zr-FH has previously been used for imaging monocyte trafficking by PET.

Methods: 8-week-old male FVB/NJ mice (n = 4) were fed a 0.2% high-cholesterol diet (TD 88137, Envigo Teklad, Hackensack, NJ) for eight weeks after initial acclimation. Streptozotocin (40 mg/kg i.p.) was injected for 8 consecutive days at week 4 to induce diabetes. Two weeks after inducing diabetes, the left carotid artery (LCA) was surgically ligated to accelerate atherosclerosis. The intact right carotid artery (RCA) served as a negative control. At week 8, mice were injected retro-orbitally with ⁸⁹Zr-FH (178±32 µCi). Mice were imaged by microPET/CT at 4,24, & 96 hours after injection with ⁸⁹Zr-FH. After the final imaging time point, carotid arteries were removed and exposed on autoradiography film.

Results: PET imaging revealed an increasing signal in the LCA over 96 hours. PET imaging also showed activity in injured carotids was significantly (p=0.017) higher than in the contralateral artery at 96 hours after injection (Fig. 1a). At the final imaging timepoint, activity in the injured vessel showed an SUV increase of 59.9% over contralateral controls (Fig. 1b). Ex vivo autoradiography results confirmed in vivo imaging, showing much greater signal in the LCA over the control RCA (Fig. 1c).

Conclusions: ⁸⁹Zr-FH appears to be a strong tool in imaging and detection of atherosclerotic plaques. This nanoparticle offers a quantitative, non-invasive, and clinically translatable tool for monitoring the location of unstable plaques. In addition to its utility in detection of vulnerable plaques, this tool could also be used in drug development and monitoring response to therapy, quantifying response to treatment. Acknowledgements: Support for this work came from the National Heart, Lung, and Blood Institute and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under award numbers R00HL127180 , T32EB013180, & P41EB022544.

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