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Updated: Sep 11, 2025
Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
Click Covalent-Targeted Radionuclide Therapy for Prostate Cancer
Weipeng Yong1, Shu Zhang2, Zhoudong Zhang3
1State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
Abstract:
Targeted radionuclide therapy represents a promising therapeutic method for treating cancer. However, currently approved radioligands still require improvement in terms of tumor uptake and retention. This study employed molecular simulation to design a novel radioligand, designated PSMA-MAL-5, which covalently binds to the prostate-specific membrane antigen (PSMA). This ligand can be efficiently radiolabeled with the beta emitter (177Lu) and the alpha emitter (225Ac) and exhibits a high level of radiostability. Autoradiography confirmed that 177Lu-PSMA-MAL-5 binds covalently to PSMA. In vivo experiments demonstrated that the radioligand can effectively target PSMA-positive tumors, with an area under the curve of tumor uptake higher than that observed for 177Lu-PSMA-617 (2517 ± 499 h %ID/cm3 vs 575 ± 75 h %ID/cm3). Tumor inhibition studies indicated that the radioligand exhibited a notable tumor inhibitory effect on tumor growth, showing promise as a tool for targeted radionuclide therapy of PSMA-positive prostate cancer.
Insights
A novel radioligand, PSMA-MAL-5, shows improved tumor uptake and retention for targeted radionuclide therapy. This advancement offers a promising new tool for treating prostate cancer by effectively targeting PSMA-positive tumors.
Area of Science:
- Nuclear medicine
- Radiopharmaceutical chemistry
- Molecular imaging and therapy
Background:
- Targeted radionuclide therapy (TRT) is a promising cancer treatment.
- Current radioligands need enhanced tumor uptake and retention for improved efficacy.
- Prostate-specific membrane antigen (PSMA) is a key target in prostate cancer therapy.
Purpose of the Study:
- To design and evaluate a novel PSMA-targeting radioligand, PSMA-MAL-5, for targeted radionuclide therapy.
- To assess the radiolabeling efficiency, radiostability, and in vivo performance of PSMA-MAL-5.
- To compare the efficacy of PSMA-MAL-5 with an established radioligand, 177Lu-PSMA-617.
Main Methods:
- Molecular simulation was used to design PSMA-MAL-5 for covalent binding to PSMA.
- PSMA-MAL-5 was radiolabeled with 177Lu and 225Ac.
- Autoradiography confirmed covalent binding to PSMA.
- In vivo studies in PSMA-positive tumor models evaluated tumor uptake, retention, and therapeutic efficacy.
Main Results:
- PSMA-MAL-5 demonstrated efficient radiolabeling and high radiostability.
- Autoradiography confirmed covalent binding of 177Lu-PSMA-MAL-5 to PSMA.
- In vivo studies showed significantly higher tumor uptake for 177Lu-PSMA-MAL-5 compared to 177Lu-PSMA-617 (2517 ± 499 h %ID/cm³ vs 575 ± 75 h %ID/cm³).
- PSMA-MAL-5 exhibited notable tumor growth inhibition in PSMA-positive prostate cancer models.
Conclusions:
- PSMA-MAL-5 is a novel, highly effective PSMA-targeting radioligand.
- Its superior tumor uptake and retention show significant potential for targeted radionuclide therapy.
- PSMA-MAL-5 represents a promising advancement for treating PSMA-positive prostate cancer.
