A low molecular weight zinc2+-dipicolylamine-based probe detects apoptosis during tumour treatment better than an annexin V-based probe
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Molecular imaging of apoptosis is frequently discussed for monitoring cancer therapies. Here, we compare the low molecular weight phosphatidylserine-targeting ligand zinc2+-dipicolylamine (Zn2+-DPA) with the established but reasonably larger protein annexin V.
Molecular apoptosis imaging with the fluorescently labelled probes annexin V (750 nm, 36 kDa) and Zn2+-DPA (794 nm, 1.84 kDa) was performed in tumour-bearing mice (A431). Three animal groups were investigated: untreated controls and treated tumours after 1 or 4 days of anti-angiogenic therapy (SU11248). Additionally, μPET with 18 F-FDG was performed. Imaging data were displayed as tumour-to-muscle ratio (TMR) and validated by quantitative immunohistochemistry.
Compared with untreated control tumours, TUNEL staining indicated significant apoptosis after 1 day (P < 0.05) and 4 days (P < 0.01) of treatment. Concordantly, Zn2+-DPA uptake increased significantly after 1 day (P < 0.05) and 4 days (P < 0.01). Surprisingly, annexin V failed to detect significant differences between control and treated animals. Contrary to the increasing uptake of Zn2+-DPA, 18 F-FDG tumour uptake decreased significantly at days 1 (P < 0.05) and 4 (P < 0.01).
Increase in apoptosis during anti-angiogenic therapy was detected significantly better with the low molecular weight probe Zn2+-DPA than with the annexin V-based probe. Additionally, significant treatment effects were detectable as early using Zn2+-DPA as with measurements of the glucose metabolism using 18 F-FDG.
• The detection of apoptosis by non-invasive imaging is important in oncology.
• A new low molecular weight probe Zn 2+-DPA shows promise in depicting anti-angiogenic effects.
• The small Zn 2+-DPA ligand appears well suited for monitoring therapy.
• Treatment effects are detectable just as early with Zn 2+-DPA as with 18 F-FDG.
KeywordsApoptosis Molecular imaging Tumour Therapy monitoring Optical imaging Annexin V Zn2+-DPA
positron emission tomography
brand name of fluorescently labelled Zn2+-DPA
region of interest
This work was supported by the HighTech.NRW/EU-Zeal 2-Program (EFRE); ForSaTum. The probe PSVue794 and the control probe to PSVue794 were kindly provided by Molecular Targeting Technologies, Inc. (West Chester, PA, USA). The authors Brian D. Gray and Koon Y. Pak are employees of Molecular Targeting Technologies, Inc. At all times, the other authors had full control over the study data and interpretation.
Moritz Palmowski and Fabian Kiessling contributed equally to this work.