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Imaging Experimental Atherosclerotic Lesions in ApoE Knockout Mice: Enhanced Targeting with Z₂D₃-Anti-DTPA Bispecific Antibody and ^99mTc-Labeled Negatively Charged Polymers

¹ Center for Cardiovascular Targeting, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts; and ² Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, New York

Correspondence: For correspondence or reprints contact: Ban-An Khaw, PhD, Center for Cardiovascular Targeting, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA 02115 E-mail: b.khaw{at}neu.edu

In vivo molecular imaging may be improved if specific radioactivity at the target site could be increased while maintaining low background activity. Bispecific antibody complexes and ^99mTc-labeled negatively charged chelating polymers that react specifically with the capture arm of the bispecific antibody complex were used to demonstrate the feasibility of imaging very small atherosclerotic lesions in ApoE knockout mice. Methods: Left femoral artery denudation in ApoE^–/– mice on a hyperlipidemic diet was used to induce accelerated atherosclerotic lesions. Approximately 40 µg of bispecific antibodies were injected intravenously after 2 wk of endothelial denudation. The next day, 15.0 MBq ^99mTc-DTPA–succinyl-polylysine (2 µg; DTPA is diethylenetriaminepentaacetic acid) were injected intravenously. Results: In vivo -images showed that lesions were observed unequivocally by 2–3 h. Sham-operated right femoral regions showed no radiotracer accumulation. Ex vivo -scintillation counting corrected for sham-operated nonspecific activity and lesion mass showed that the mean lesion activity was 10.10 ± 6.76 %ID/g (percentage injected dose per gram), whereas nonspecific human IgG bispecific control (NSB control) also corrected similarly was 0.939 ± 0.877 %ID/g (P < 0.03). Atherosclerotic lesions were confirmed by immunohistochemical staining. Computer planimetry of immunohistograms showed the mean lesion size to be 2.64 ± 2.46 mg. Conclusion: Use of bispecific antibody complexes and ^99mTc-DTPA–succinyl-polylysine enabled in vivo visualization of very small atherosclerotic lesions in ApoE knockout mice.

Key Words: bispecific antibody • pretargeting • radiolabeled polymer