Long-Term Therapeutic Effects of Ac-DOTA-E[c(RGDfK)] Induced by Radiosensitization via G2/M Arrest in Pancreatic Ductal Adenocarcinoma.

: Alpha radionuclide therapy has emerged as a promising novel strategy for cancer treatment; however, the therapeutic potential of Ac-labeled peptides in pancreatic cancer remains uninvestigated. : In the cytotoxicity study, tumor cells were incubated with Ac-DOTA-RGD. DNA damage responses (γH2AX and 53BP1) were detected using flowcytometry or immunohistochemistry analysis. Biodistribution and therapeutic studies were carried out in BxPC-3-bearing mice. : Ac-DOTA-RGD demonstrated potent cytotoxicity against cells expressing αβ or αβ integrins and induced G2/M arrest and γH2AX expression as a marker of double-stranded DNA breaks. Ac-DOTA-RGD (20, 40, 65, or 90 kBq) showed favorable pharmacokinetics and remarkable tumor growth inhibition without severe side effects in the BxPC-3 mouse model. In vitro studies revealed that 5 and 10 kBq/mL of Ac-DOTA-RGD swiftly induced G2/M arrest and elevated γH2AX expression. Furthermore, to clarify the mechanism of successful tumor growth inhibition for a long duration in vivo, we investigated whether short-term high radiation exposure enhances radiation sensitivity. Initially, a 4 h induction treatment with 5 and 10 kBq/mL of Ac-DOTA-RGD enhanced both cytotoxicity and γH2AX expression with 0.5 kBq/mL of Ac-DOTA-RGD compared to a treatment with only 0.5 kBq/mL of Ac-DOTA-RGD. Meanwhile, the γH2AX expression induced by 5 or 10 kBq/mL of Ac-DOTA-RGD alone decreased over time. : These findings highlight the potential of using Ac-DOTA-RGD in the treatment of intractable pancreatic cancers, as its ability to induce G2/M cell cycle arrest enhances radiosensitization, resulting in notable growth inhibition.