PET imaging of apoptosis with 64Cu-labeled streptavidin following pretargeting of phosphatidylserine with biotinylated annexin-V
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In vivo detection of apoptosis is a diagnostic tool with potential clinical applications in cardiology and oncology. Radiolabeled annexin-V (anxV) is an ideal probe for in vivo apoptosis detection owing to its strong affinity for phosphatidylserine (PS), the molecular flag on the surface of apoptotic cells. Most clinical studies performed to visualize apoptosis have used 99mTc-anxV; however, its poor distribution profile often compromises image quality. In this study, tumor apoptosis after therapy was visualized by positron emission tomography (PET) using 64Cu-labeled streptavidin (SAv), following pre-targeting of apoptotic cells with biotinylated anxV.
Apoptosis was induced in tumor-bearing mice by photodynamic therapy (PDT) using phthalocyanine dyes as photosensitizers, and red light. After PDT, mice were injected i.v. with biotinylated anxV, followed 2 h later by an avidin chase, and after another 2 h with 64Cu-DOTA-biotin-SAv. PET images were subsequently recorded up to 13 h after PDT.
PET images delineated apoptosis in treated tumors as early as 30 min after 64Cu-DOTA-biotin-SAv administration, with tumor-to-background ratios reaching a maximum at 3 h post-injection, i.e., 7 h post-PDT. Omitting the administration of biotinylated anxV or the avidin chase failed to provide a clear PET image, confirming that all three steps are essential for adequate visualization of apoptosis. Furthermore, differences in action mechanisms between photosensitizers that target tumor cells directly or via initial vascular stasis were clearly recognized through differences in tracer uptake patterns detecting early or delayed apoptosis.
This study demonstrates the efficacy of a three-step 64Cu pretargeting procedure for PET imaging of apoptosis. Our data also confirm the usefulness of small animal PET to evaluate cancer treatment protocols.
KeywordsAnnexin V Molecular imaging Cancer Apoptosis imaging PET tracer Small animal PET
This work was supported by the Canadian Institutes for Health Research (CIHR grants MOP-44065 and MOP-15348). J.E.v.L. is the holder of the Jeanne and J.-Louis Lévesque Chair in Radiobiology.
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