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Pre- and Intraoperative Visualization of GRPR-Expressing Solid Tumors: Preclinical Profiling of Novel Dual-Modality
Marjolein Verhoeven1, Maryana Handula1, Lilian van den Brink1
1Department of Radiology and Nuclear Medicine, Erasmus Medical Center, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.
Abstract:
Image-guided surgery using a gastrin-releasing peptide receptor (GRPR)-targeting dual-modality probe could improve the accuracy of the resection of various solid tumors. The aim of this study was to further characterize our four previously developed GRPR-targeting dual-modality probes that vary in linker structures and were labeled with indium-111 and sulfo-cyanine 5. Cell uptake studies with GRPR-positive PC-3 cells and GRPR-negative NCI-H69 cells confirmed receptor specificity. Imaging and biodistribution studies at 4 and 24 h with 20 MBq/1 nmol [111In]In-12-15 were performed in nude mice bearing a PC-3 and NCI-H69 xenograft, and showed that the probe with only a pADA linker in the backbone had the highest tumor-to-organ ratios (T/O) at 24 h after injection (T/O > 5 for, e.g., prostate, muscle and blood). For this probe, a dose optimization study with three doses (0.75, 1.25 and 1.75 nmol; 20 MBq) revealed that the maximum image contrast was achieved with the lowest dose. Subsequently, the probe was successfully used for tumor excision in a simulated image-guided surgery setting. Moreover, it demonstrated binding to tissue sections of human prostate, breast and gastro-intestinal stromal tumors. In summary, our findings demonstrate that the developed dual-modality probe has the potential to aid in the complete surgical removal of GRPR-positive tumors.
Insights
A novel dual-modality probe targeting the gastrin-releasing peptide receptor (GRPR) shows promise for image-guided surgery. The optimized probe demonstrated high tumor specificity and aided in successful simulated tumor excision.
Area of Science:
- Biomedical Imaging
- Molecular Imaging
- Surgical Oncology
Background:
- Image-guided surgery enhances tumor resection accuracy.
- Gastrin-releasing peptide receptor (GRPR) is a target for solid tumors.
- Dual-modality probes offer combined imaging and therapeutic potential.
Purpose of the Study:
- To characterize novel GRPR-targeting dual-modality probes for image-guided surgery.
- To evaluate the impact of linker structures on probe performance.
- To assess probe specificity, biodistribution, and efficacy in preclinical models.
Main Methods:
- Synthesis and labeling of four GRPR-targeting dual-modality probes with 111In and sulfo-cyanine 5.
- In vitro cell uptake studies using GRPR-positive (PC-3) and GRPR-negative (NCI-H69) cell lines.
- In vivo imaging and biodistribution studies in mice bearing xenografts, followed by dose optimization and simulated surgical excision.
Main Results:
- Receptor specificity confirmed by cell uptake studies.
- The probe with a pADA linker exhibited the highest tumor-to-organ ratios (>5) at 24 hours post-injection.
- Maximum image contrast was achieved with the lowest tested dose (0.75 nmol).
- Successful simulated image-guided tumor excision was demonstrated.
- Probe binding observed in human tumor tissue sections (prostate, breast, GIST).
Conclusions:
- The developed GRPR-targeting dual-modality probe is a promising tool for image-guided surgery.
- Optimized linker structure and low dosage enhance probe efficacy.
- The probe facilitates accurate tumor visualization and excision, potentially improving patient outcomes.
