225Ac-iPSMA-RGD for Alpha-Therapy Dual Targeting of Stromal/Tumor Cell PSMA and Integrins

Prostate-specific membrane antigens (PSMAs) are frequently overexpressed in both tumor stromal endothelial cells and malignant cells (stromal/tumor cells) of various cancers. The RGD (Arg-Gly-Asp) peptide sequence can specifically detect integrins involved in tumor angiogenesis. This study aimed to preclinically evaluate the cytotoxicity, biokinetics, dosimetry, and therapeutic efficacy of 225Ac-iPSMA-RGD to determine its potential as an improved radiopharmaceutical for alpha therapy compared with the 225Ac-iPSMA and 225Ac-RGD monomers. HEHA-HYNIC-iPSMA-RGD (iPSMA-RGD) was synthesized and characterized by FT-IR, UV-vis, and UPLC mass spectroscopy. The cytotoxicity of 225Ac-iPSMA-RGD was assessed in HCT116 colorectal cancer cells. Biodistribution, biokinetics, and therapeutic efficacy were evaluated in nude mice with induced HCT116 tumors. In vitro results showed increased DNA double-strand breaks through ROS generation, cell apoptosis, and death in HCT116 cells treated with 225Ac-iPSMA-RGD. The results also demonstrated in vivo cytotoxicity in cancer cells after treatment with 225Ac-iPSMA-RGD and biokinetic and dosimetric properties suitable for alpha therapy, delivering ablative radiation doses up to 237 Gy/3.7 kBq to HCT116 tumors in mice. Given the phenotype of HCT116 cancer cells, the results of this study warrant further dosimetric and clinical studies to determine the potential of 225Ac-iPSMA-RGD in the treatment of colorectal cancer.

 

Comments:

This study explores a potential radiopharmaceutical, 225Ac-iPSMA-RGD, for treating colorectal cancer. The focus is on its cytotoxicity, biodistribution, biokinetics, dosimetry, and therapeutic efficacy compared to other monomers.

The compound was synthesized and characterized, then tested on HCT116 colorectal cancer cells. In vitro results suggest that 225Ac-iPSMA-RGD induces DNA double-strand breaks, generates reactive oxygen species (ROS), and triggers cell apoptosis and death in these cells.

Moreover, in vivo studies in mice with induced HCT116 tumors showed promising results. The treatment exhibited cytotoxicity in cancer cells, and the compound's biokinetic and dosimetric properties seem suitable for alpha therapy, delivering high radiation doses to tumors.

The study concludes by suggesting further research, particularly in dosimetry and clinical studies, to explore the potential of 225Ac-iPSMA-RGD for treating colorectal cancer based on its observed effects on HCT116 cells.

This approach seems promising, potentially offering a targeted and effective treatment option for colorectal cancer.

Related Products

Cat.No.	Product Name	Information
S8008	RGD (Arg-Gly-Asp) Peptides	RGD (Arg-Gly-Asp) Peptides is a cell adhesion motif which can mimic cell adhesion proteins and bind to integrins.

Related Targets

Integrin