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Uniform intratumoral distribution of radioactivity produced using two different radioagents, (64)Cu-cyclam-RAFT-c(-RGDfK-)(4) and (64)Cu-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 examined the efficacy of a combination of a tetrameric cyclic Arg-Gly-Asp (cRGD) peptide-based radiophar...

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Detalles Bibliográficos
Autores principales: Jin, Zhao-Hui, Tsuji, Atsushi B., Degardin, Mélissa, Sugyo, Aya, Yoshii, Yukie, Nagatsu, Kotaro, Zhang, Ming-Rong, Fujibayashi, Yasuhisa, Dumy, Pascal, Boturyn, Didier, Higashi, Tatsuya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008272/
https://www.ncbi.nlm.nih.gov/pubmed/29923139
http://dx.doi.org/10.1186/s13550-018-0407-3
Descripción
Sumario: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 examined the efficacy of a combination of a tetrameric cyclic Arg-Gly-Asp (cRGD) peptide-based radiopharmaceutical, (64)Cu-cyclam-RAFT-c(-RGDfK-)(4) ((64)Cu-RaftRGD, an α(V)β(3) integrin [α(V)β(3)] tracer), and (64)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM, a supposed tracer for hypoxic metabolism) in a small animal tumor model. RESULTS: Mice with subcutaneous α(V)β(3)-positive U87MG glioblastoma xenografts were used. The intratumoral distribution of a near-infrared dye, Cy5.5-labeled RAFT-c(-RGDfK-)(4) (Cy5.5-RaftRGD), (64)Cu-RaftRGD, and (64)Cu-ATSM was visualized by fluorescence imaging and autoradiography of the co-injected Cy5.5-RaftRGD with (64)Cu-RaftRGD or (64)Cu-ATSM at 3 h postinjection. Mice were treated with a single intravenous dose of the vehicle solution (control), 18.5 or 37 MBq of (64)Cu-RaftRGD or (64)Cu-ATSM, or a combination (18.5 MBq of each agent). The tumor volume, tumor cell proliferation, body weight, survival, and tumor and organ uptake of radiopharmaceuticals were assessed. It was shown that Cy5.5-RaftRGD colocalized with (64)Cu-RaftRGD and could be used as a surrogate for the radioactive agent. The intratumoral distribution of Cy5.5-RaftRGD and (64)Cu-ATSM was discordant and nearly complementary, indicating a more uniform distribution of radioactivity achievable with the combined use of (64)Cu-RaftRGD and (64)Cu-ATSM. Neither (64)Cu-RaftRGD nor (64)Cu-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 (64)Cu-RaftRGD alone, but lower than that of (64)Cu-ATSM alone. The kidneys showed the highest uptake of (64)Cu-RaftRGD, whereas the liver exhibited the highest uptake of (64)Cu-ATSM. No obvious adverse effects were observed in all treated mice. CONCLUSIONS: The combination of (64)Cu-RaftRGD and (64)Cu-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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13550-018-0407-3) contains supplementary material, which is available to authorized users.