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PSMA and Integrin αvβ3 Dual-Targeted Radioligands for Prostate Cancer Targeted Radionuclide Therapy
Xunhao Qi1, Zhihao Li1, Junhong Wang1
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, Suzhou215123, China.
Abstract:
Prostate cancer, particularly its metastatic castration-resistant form, presents major challenges due to tumor heterogeneity and limited treatment efficacy. The inherent limitations of single-target radiopharmaceuticals, such as variable antigen expression, underscore the need for innovative strategies. To address this, we developed a novel dual-targeting radioligand, 177Lu-PSMA-3-RGD, via solid-phase synthesis and click chemistry, designed to simultaneously bind prostate-specific membrane antigen (PSMA) and integrin αvβ3. The ligand demonstrated high radiochemical purity, excellent radiostability, and selective uptake in PSMA-positive cells. In vivo studies using xenograft models revealed rapid tumor accumulation and prolonged retention, with specificity confirmed through competitive receptor-blocking. Furthermore, therapeutic administration of 177Lu-PSMA-3-RGD resulted in significantly greater tumor growth delay compared to single-targeted radioligands, without inducing observable systemic toxicity. Ultimately, this dual-targeted mechanism proves highly effective, identifying the radioligand as a promising theranostic candidate for prostate cancer that merits further preclinical and clinical investigation.
Insights
This study introduces a new dual-targeting radioligand for prostate cancer, showing improved tumor targeting and growth inhibition. This innovative approach offers a promising theranostic option for metastatic castration-resistant prostate cancer.
Area of Science:
- Nuclear medicine
- Oncology
- Radiopharmaceutical chemistry
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) poses significant treatment challenges due to tumor heterogeneity.
- Single-target radiopharmaceuticals have limitations, including variable antigen expression, necessitating novel therapeutic strategies.
Purpose of the Study:
- To develop and evaluate a novel dual-targeting radioligand for prostate cancer.
- To assess the efficacy and safety of the dual-targeting radioligand in preclinical models.
Main Methods:
- Solid-phase synthesis and click chemistry were used to create the dual-targeting radioligand 177Lu-PSMA-3-RGD.
- The ligand was designed to bind both prostate-specific membrane antigen (PSMA) and integrin αvβ3.
- In vitro and in vivo studies were conducted using PSMA-positive cells and xenograft models.
Main Results:
- The radioligand demonstrated high radiochemical purity and stability, with selective uptake in PSMA-positive cells.
- In vivo studies showed rapid tumor accumulation, prolonged retention, and specificity.
- Therapeutic administration led to significant tumor growth delay compared to single-targeted agents without systemic toxicity.
Conclusions:
- The dual-targeting radioligand 177Lu-PSMA-3-RGD is a highly effective theranostic candidate for prostate cancer.
- This approach overcomes limitations of single-target therapies.
- Further preclinical and clinical investigations are warranted.
