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PET Imaging of Dll4 Expression in Glioblastoma and Colorectal Cancer Xenografts Using (64)Cu-Labeled Monoclonal
Bin Zhou1,2, Hui Wang2, Ren Liu3
1Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University , Guangzhou 510630, China.
Abstract:
Delta-like ligand 4 (Dll4) expressed in tumor cells plays a key role to promote tumor growth of numerous cancer types. Based on a novel antihuman Dll4 monoclonal antibody (61B), we developed a (64)Cu-labeled probe for positron emission tomography (PET) imaging of tumor Dll4 expression. In this study, 61B was conjugated with the (64)Cu-chelator DOTA through lysine on the antibody. Human IgG (hIgG)-DOTA, which did not bind to Dll4, was also prepared as a control. The Dll4 binding activity of the probes was evaluated through the bead-based binding assay with Dll4-alkaline phosphatase. The resulting PET probes were evaluated in U87MG glioblastoma and HT29 colorectal cancer xenografts in athymic nude mice. Our results demonstrated that the 61B-DOTA retained (77.2 ± 3.7) % Dll4 binding activity of the unmodified 61B, which is significantly higher than that of hIgG-DOTA (0.06 ± 0.03) %. Confocal microscopy analysis confirmed that 61B-Cy5.5, but not IgG-Cy5.5, predominantly located within the U87MG and HT29 cells cytoplasm. U87MG cells showed higher 61B-Cy5.5 binding as compared to HT29 cells. In U87MG xenografts, 61B-DOTA-(64)Cu demonstrated remarkable tumor accumulation (10.5 ± 1.7 and 10.2 ± 1.2%ID/g at 24 and 48 h postinjection, respectively). In HT29 xenografts, tumor accumulation of 61B-DOTA-(64)Cu was significantly lower than that of U87MG (7.3 ± 1.3 and 6.6 ± 1.3%ID/g at 24 and 48 h postinjection, respectively). The tumor accumulation of 61B-DOTA-(64)Cu was significantly higher than that of hIgG-DOTA-(64)Cu in both xenografts models. Immunofluorescence staining of the tumor tissues further confirmed that tumor accumulation of 61B-Cy5.5 was correlated well with in vivo PET imaging data using 61B-DOTA-(64)Cu. In conclusion, 61B-DOTA-(64)Cu PET probe was successfully synthesized and demonstrated prominent tumor uptake by targeting Dll4. 61B-DOTA-(64)Cu has great potential to be used for noninvasive Dll4 imaging, which could be valuable for tumor detection, Dll4 expression level evaluation, and Dll4-based treatment monitoring.
Insights
A novel positron emission tomography (PET) probe targeting Delta-like ligand 4 (Dll4) was developed using a monoclonal antibody (61B). This Dll4-targeting PET probe shows significant tumor accumulation and holds potential for noninvasive cancer imaging and treatment monitoring.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Delta-like ligand 4 (Dll4) is crucial for tumor growth in various cancers.
- Targeting Dll4 offers a potential strategy for cancer therapy and diagnosis.
Purpose of the Study:
- To develop and evaluate a novel (64)Cu-labeled positron emission tomography (PET) probe for imaging tumor Dll4 expression.
- To assess the probe's binding affinity, tumor uptake, and potential for noninvasive Dll4 evaluation.
Main Methods:
- Conjugation of anti-Dll4 antibody (61B) with DOTA chelator for (64)Cu labeling.
- In vitro evaluation of Dll4 binding activity and cellular localization.
- In vivo PET imaging in U87MG glioblastoma and HT29 colorectal cancer xenografts.
Main Results:
- The 61B-DOTA probe retained high Dll4 binding activity.
- The PET probe demonstrated significant and specific tumor accumulation in xenograft models.
- Higher Dll4 expression correlated with increased probe uptake in U87MG compared to HT29.
Conclusions:
- The synthesized 61B-DOTA-(64)Cu PET probe successfully targets Dll4 in tumors.
- This probe is a promising tool for noninvasive Dll4 imaging, aiding in tumor detection and treatment monitoring.
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