Long-Term Therapeutic Effects of <sup>225</sup>Ac-DOTA-E[c(RGDfK)]<sub>2</sub> Induced by Radiosensitization via G2/M Arrest in Pancreatic Ductal Adenocarcinoma
<b>Background</b>: Alpha radionuclide therapy has emerged as a promising novel strategy for cancer treatment; however, the therapeutic potential of <sup>225</sup>Ac-labeled peptides in pancreatic cancer remains uninvestigated. <b>Methods</b>: In the cytotoxicity s...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
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| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/17/1/9 |
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| Summary: | <b>Background</b>: Alpha radionuclide therapy has emerged as a promising novel strategy for cancer treatment; however, the therapeutic potential of <sup>225</sup>Ac-labeled peptides in pancreatic cancer remains uninvestigated. <b>Methods</b>: In the cytotoxicity study, tumor cells were incubated with <sup>225</sup>Ac-DOTA-RGD<sub>2</sub>. 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. <b>Results</b>: <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> demonstrated potent cytotoxicity against cells expressing α<sub>v</sub>β<sub>3</sub> or α<sub>v</sub>β<sub>6</sub> integrins and induced G2/M arrest and γH2AX expression as a marker of double-stranded DNA breaks. <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> (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 <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> 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 <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> enhanced both cytotoxicity and γH2AX expression with 0.5 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> compared to a treatment with only 0.5 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub>. Meanwhile, the γH2AX expression induced by 5 or 10 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> alone decreased over time. <b>Conclusions</b>: These findings highlight the potential of using <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> in the treatment of intractable pancreatic cancers, as its ability to induce G2/M cell cycle arrest enhances radiosensitization, resulting in notable growth inhibition. |
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| ISSN: | 1999-4923 |