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Published on: September 3, 2013
A novel dual-modality imaging agent targeting folate receptor of tumor for molecular imaging and fluorescence-guided
Myoung Hyoun Kim1, Seul-Gi Kim2, Dae-Weung Kim3,4
1Department of Nuclear Medicine and Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, 344-2 Shinyong-Dong, Iksan, Jeollabuk-do, 570-711, Republic of Korea.
Objective:
Folate receptor (FR) is an ideal target for cancer imaging because it is frequently overexpressed in major types of human tumor, whereas its expression in normal organs is highly limited. Combining nuclear and fluorescence-imaging techniques provides a novel approach for cancer imaging and monitoring the surgery. The objective of this study was to report the synthesis and characteristics of a dual-modality imaging agent, Tc-99m Folate-Gly-His-Glu-Gly-Glu-Cys-Gly-Lys(-5-carboxy-X-rhodamine)-NH2 (Folate-ECG-ROX), and verify its feasibility as both molecular imaging agent and intra-operative guidance.
Methods:
Folate-ECG-ROX was synthesized using Fmoc solid-phase peptide synthesis. Radiolabeling of Folate-ECG-ROX with Tc-99m was done using ligand exchange via tartrate. Binding affinity and in vitro cellular uptake studies were performed. Gamma camera imaging, biodistribution and ex vivo imaging studies were performed using KB and HT-1080 tumor-bearing murine models. Tumor tissue slides were prepared and analyzed with immunohistochemistry staining and confocal microscopy. Surgical removal of tumor nodules in murine models with peritoneal carcinomatosis was performed under the fluorescence-imaging system.
Results:
After radiolabeling procedures with Tc-99m, Tc-99m Folate-ECG-ROX complexes were prepared in high yield (> 97%). The binding affinity value (Kd) of Tc-99m Folate-ECG-ROX for KB cells was estimated to be 6.9 ± 0.9 nM. In gamma camera imaging, tumor to normal muscle uptake ratio of Tc-99m Folate-ECG-ROX increased with time (3.4 ± 0.4, 4.4 ± 0.7, and 6.6 ± 0.8 at 1, 2, and 3 h, respectively). In biodistribution study, %IA/g for KB tumor was 2.50 ± 0.80 and 4.08 ± 1.16 at 1 and 3 h, respectively. Confocal microscopy with immunohistochemistry staining detected strong Tc-99m Folate-ECG-ROX fluorescence within KB tumor tissue which is correlating with the fluorescent activity of anti-FR antibody. Under real-time optical imaging, the removal of visible nodules was successfully performed.
Conclusions:
In vivo and in vitro studies revealed substantial and specific uptake of Tc-99m Folate-ECG-ROX in FR-positive tumors. Thus, Tc-99m Folate-ECG-ROX could provide both pre-operative molecular imaging and fluorescence image-guidance for tumor.
Insights
This study developed a dual-modality imaging agent, Tc-99m Folate-ECG-ROX, for folate receptor-positive tumors. It demonstrated specific uptake in tumors, enabling both pre-operative molecular imaging and intra-operative surgical guidance.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Folate receptor (FR) is overexpressed in many human tumors, making it a promising target for cancer detection.
- Dual-modality imaging agents combining nuclear and fluorescence techniques offer enhanced capabilities for cancer imaging and surgical monitoring.
- Current imaging techniques require novel agents for precise tumor visualization and surgical guidance.
Purpose of the Study:
- To synthesize and characterize a novel dual-modality imaging agent, Tc-99m Folate-Gly-His-Glu-Gly-Glu-Cys-Gly-Lys(-5-carboxy-X-rhodamine)-NH2 (Folate-ECG-ROX).
- To evaluate the feasibility of Folate-ECG-ROX as both a pre-operative molecular imaging agent and an intra-operative surgical guidance tool.
Main Methods:
- Folate-ECG-ROX was synthesized using Fmoc solid-phase peptide synthesis and radiolabeled with Tc-99m.
- In vitro studies included binding affinity and cellular uptake assessments.
- In vivo studies involved gamma camera imaging, biodistribution, ex vivo imaging in tumor-bearing murine models, and fluorescence-guided surgical removal of tumors.
Main Results:
- Tc-99m Folate-ECG-ROX was prepared with high radiolabeling yield (>97%) and demonstrated strong binding affinity (Kd = 6.9 ± 0.9 nM) for FR-positive cells.
- Gamma camera imaging showed increasing tumor-to-muscle uptake ratios over time, with significant accumulation in FR-positive tumors.
- Confocal microscopy confirmed strong fluorescence within tumor tissues, and successful surgical removal of visible nodules was achieved under fluorescence guidance.
Conclusions:
- Tc-99m Folate-ECG-ROX exhibits substantial and specific uptake in folate receptor-positive tumors.
- This dual-modality agent holds significant potential for both pre-operative molecular imaging and intra-operative fluorescence-guided tumor surgery.
- The findings support the clinical utility of Folate-ECG-ROX in improving cancer diagnosis and surgical outcomes.
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