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Uniform intratumoral distribution of radioactivity produced using two different radioagents, Cu-cyclam-RAFT-c(-RGDfK-) and Cu-ATSM, improves therapeutic efficacy in a small animal tumor model. | LitMetric

AI Article Synopsis

Article Abstract

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, Cu-cyclam-RAFT-c(-RGDfK-) (Cu-RaftRGD, an αβ integrin [αβ] tracer), and Cu-diacetyl-bis (N-methylthiosemicarbazone) (Cu-ATSM, a supposed tracer for hypoxic metabolism) in a small animal tumor model.

Results: Mice with subcutaneous αβ-positive U87MG glioblastoma xenografts were used. The intratumoral distribution of a near-infrared dye, Cy5.5-labeled RAFT-c(-RGDfK-) (Cy5.5-RaftRGD), Cu-RaftRGD, and Cu-ATSM was visualized by fluorescence imaging and autoradiography of the co-injected Cy5.5-RaftRGD with Cu-RaftRGD or 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 Cu-RaftRGD or 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 Cu-RaftRGD and could be used as a surrogate for the radioactive agent. The intratumoral distribution of Cy5.5-RaftRGD and Cu-ATSM was discordant and nearly complementary, indicating a more uniform distribution of radioactivity achievable with the combined use of Cu-RaftRGD and Cu-ATSM. Neither Cu-RaftRGD nor 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 Cu-RaftRGD alone, but lower than that of Cu-ATSM alone. The kidneys showed the highest uptake of Cu-RaftRGD, whereas the liver exhibited the highest uptake of Cu-ATSM. No obvious adverse effects were observed in all treated mice.

Conclusions: The combination of Cu-RaftRGD and 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008272PMC
http://dx.doi.org/10.1186/s13550-018-0407-3DOI Listing

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