Uniform intratumoral distribution of radioactivity produced using two different radioagents, 64Cu-cyclam-RAFT-c(-RGDfK-)4 and 64Cu-ATSM, improves therapeutic efficacy in a small animal tumor model.
Background: The present study proposed a new concept for targeted radionuclide therapy (TRT) to improve the intratumoral distribution of radioactivity using two different radiopharmaceuticals. We examd. the efficacy of a combination of a tetrameric cyclic Arg-Gly-Asp (cRGD) peptide-based radiopharmaceutical, 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD, an $\alpha$V$\beta$3 integrin [$\alpha$V$\beta$3] tracer), and 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM, a supposed tracer for hypoxic metab.) in a small animal tumor model. Results: Mice with s.c. $\alpha$V$\beta$3-pos. U87MG glioblastoma xenografts were used. The intratumoral distribution of a near-IR dye, Cy5.5-labeled RAFT-c(-RGDfK-)4 (Cy5.5-RaftRGD), 64Cu-RaftRGD, and 64Cu-ATSM was visualized by fluorescence imaging and autoradiog. of the co-injected Cy5.5-RaftRGD with 64Cu-RaftRGD or 64Cu-ATSM at 3 h postinjection. Mice were treated with a single i.v. dose of the vehicle soln. (control), 18.5 or 37 MBq of 64Cu-RaftRGD or 64Cu-ATSM, or a combination (18.5 MBq of each agent). The tumor vol., tumor cell proliferation, body wt., survival, and tumor and organ uptake of radiopharmaceuticals were assessed. It was shown that Cy5.5-RaftRGD colocalized with 64Cu-RaftRGD and could be used as a surrogate for the radioactive agent. The intratumoral distribution of Cy5.5-RaftRGD and 64Cu-ATSM was discordant and nearly complementary, indicating a more uniform distribution of radioactivity achievable with the combined use of 64Cu-RaftRGD and 64Cu-ATSM. Neither 64Cu-RaftRGD nor 64Cu-ATSM showed significant effects on tumor growth at 18.5 MBq. The combination of both (18.5 MBq each) showed sustained inhibitory effects against tumor growth and tumor cell proliferation and prolonged the survival of the mice, compared to that by either single agent at 37 MBq. Interestingly, the uptake of the combination by the tumor was higher than that of 64Cu-RaftRGD alone, but lower than that of 64Cu-ATSM alone. The kidneys showed the highest uptake of 64Cu-RaftRGD, whereas the liver exhibited the highest uptake of 64Cu-ATSM. No obvious adverse effects were obsd. in all treated mice. Conclusions: The combination of 64Cu-RaftRGD and 64Cu-ATSM achieved an improved antitumor effect owing to the more uniform intratumoral distribution of radioactivity. Thus, combining different radiopharmaceuticals to improve the intratumoral distribution would be a promising concept for more effective and safer TRT. [on SciFinder(R)]
Références
- Titre
- Uniform intratumoral distribution of radioactivity produced using two different radioagents, 64Cu-cyclam-RAFT-c(-RGDfK-)4 and 64Cu-ATSM, improves therapeutic efficacy in a small animal tumor model.
- Type de publication
- Article de revue
- Année de publication
- 2018
- Auteurs
- Jin, Zhao-hui, Tsuji Atsushi B., Degardin Melissa, Sugyo Aya, Yoshii Yukie, Nagatsu Kotaro, Zhang Ming-Rong, Fujibayashi Yasuhisa, Dumy Pascal, Boturyn Didier, and Higashi Tatsuya.
- Revue
- EJNMMI Res.
- Volume
- 8
- Pagination
- 1–10
- ISSN
- 2191-219X
Soumis le 5 avril 2019