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The pre-clinical characterization of an alpha-emitting sigma-2 receptor targeted radiotherapeutic
Mehran Makvandi1, Brian P Lieberman1, Ben LeGeyt1
1Radiological Chemistry and Biology Laboratories, Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, PA, 19104.
Rationale:
The sigma-2 receptor is a protein with a Heme binding region and is capable of receptor-mediated endocytosis. It is overexpressed in many cancers making it a potential vector for therapeutic drug delivery. Our objective was to introduce an alpha-emitting radionuclide, astatine-211, into a selective sigma-2 ligand moiety to provide cytotoxic capabilities without adversely altering the pharmacological characteristics. In this study we investigated the in vitro/in vivo tumor targeting and estimated dosimetry of alpha-emitting sigma-2 ligand, 5-(astato-(211)At)-N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2,3-dimethoxybenzamide ((211)At-MM3), in a pre-clinical human breast cancer model.
Methods:
Astatine-211 was produced in a cyclotron and isolated by dry distillation. Radiosynthesis of (211)At-MM3 was performed using a tin precursor through radioastatodestannylation. In vitro sigma-2 binding experiments using (211)At-MM3 were carried out in live EMT6 and MDA-MB-231 breast cancer cells and liver homogenate tissue. In vivo biodistribution experiments were performed using EMT6 mouse breast cancer cells in BALB/c female mice. Approximately 370 kBq of (211)At-MM3 was administered intravenously and at time points of 5 min, 1, 2, 4, 8, and 24 h organs/tissue were harvested. Estimated human dosimetry was extrapolated from biodistribution data using OLINDA/EXM (VU e-Innovations).
Results:
Astatine-211 was successfully produced and isolated in quantities suitable for in vitro and small animal in vivo experiments. Radiosynthesis of (211)At-MM3 was reproducible with high radiochemical purity. Astatine-211-MM3 exhibited picomolar affinity to the sigma-2 receptor in contrast to the iodinated analog that had nanomolar affinity. Prolonged tumor targeting was measured through biodistribution studies with a maximal tumor to muscle ratio of 9.02 at 4h. Estimated human dosimetry revealed doses of up to 370 MBq in an adult female patient were below organ radiation limits with the potential to provide a high therapeutic dose to tumors.
Conclusion:
The sigma-2 receptor could serve as a suitable targeting platform for designing radiotherapeutics. (211)At-MM3 showed tumor targeting properties in vitro/in vivo and favorable estimated human dosimetry establishing the proof of concept for future development as a radiotherapeutic for the treatment of breast cancer.
Insights
This study developed a novel alpha-emitting radioligand, (211)At-MM3, targeting the sigma-2 receptor for breast cancer therapy. It demonstrated effective tumor targeting and favorable dosimetry, establishing its potential as a new radiotherapeutic agent.
Area of Science:
- Nuclear Medicine
- Radiopharmaceutical Chemistry
- Oncology
Background:
- The sigma-2 receptor is overexpressed in various cancers, making it a promising target for cancer therapy.
- Astatine-211 (211At) is an alpha-emitting radionuclide with potential for targeted cancer treatment.
- Developing selective sigma-2 receptor ligands labeled with 211At could enhance therapeutic efficacy.
Purpose of the Study:
- To synthesize and characterize a novel alpha-emitting sigma-2 receptor ligand, 5-(astato-(211)At)-N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2,3-dimethoxybenzamide ((211)At-MM3).
- To evaluate the in vitro and in vivo tumor targeting capabilities of (211)At-MM3 in a pre-clinical breast cancer model.
- To estimate the human dosimetry of (211)At-MM3 for potential clinical application.
Main Methods:
- Astatine-211 was produced via cyclotron and isolated.
- (211)At-MM3 was synthesized using radioastatodestannylation.
- In vitro sigma-2 receptor binding assays were performed on breast cancer cell lines (EMT6, MDA-MB-231).
- In vivo biodistribution studies were conducted in mice bearing EMT6 tumors.
- Human dosimetry was estimated using OLINDA/EXM software.
Main Results:
- Successful production and isolation of 211At suitable for experiments.
- (211)At-MM3 demonstrated high radiochemical purity and reproducible synthesis.
- The radioligand exhibited picomolar affinity for the sigma-2 receptor.
- Biodistribution studies showed prolonged tumor targeting with a maximal tumor-to-muscle ratio of 9.02 at 4 hours.
- Estimated human dosimetry indicated doses within safe organ radiation limits for therapeutic administration.
Conclusions:
- The sigma-2 receptor is a viable targeting platform for developing novel radiotherapeutics.
- (211)At-MM3 possesses promising in vitro and in vivo tumor targeting properties.
- Favorable estimated human dosimetry supports the potential of (211)At-MM3 as a breast cancer radiotherapeutic.
