Abstract
BackgroundThe 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, 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD, an αVβ3 integrin [αVβ3] tracer), and 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM, a supposed tracer for hypoxic metabolism) in a small animal tumor model.ResultsMice with subcutaneous αVβ3-positive U87MG glioblastoma xenografts were used. The intratumoral distribution of a near-infrared dye, Cy5.5-labeled RAFT-c(-RGDfK-)4 (Cy5.5-RaftRGD), 64Cu-RaftRGD, and 64Cu-ATSM was visualized by fluorescence imaging and autoradiography of the co-injected Cy5.5-RaftRGD with 64Cu-RaftRGD or 64Cu-ATSM at 3 h postinjection. Mice were treated with a single intravenous dose of the vehicle solution (control), 18.5 or 37 MBq of 64Cu-RaftRGD or 64Cu-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 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 observed in all treated mice.ConclusionsThe 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.
Highlights
The present study proposed a new concept for targeted radionuclide therapy (TRT) to improve the intratumoral distribution of radioactivity using two different radiopharmaceuticals
There are many types of TRT agents that can target various biological properties; combining different agents may achieve a homogeneous distribution of radionuclides, resulting in delivery of sufficient radiation throughout the entire tumor. 64Cu is a promising theranostic radionuclide owing to its suitable half-life (12.7 h) with multiple decay modes, including β+ (18%), which is used for positron emission tomography (PET) imaging, β− (39%, 0.95−1.4 mm tissue range) [2], and Auger electron (43%, ~ 126 nm tissue range) [3], which are used for therapeutic radiation
We previously developed a tetrameric cyclic Arg-Gly-Asp peptide-based radiopharmaceutical, 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD) [4] for targeting αVβ3 integrin, a transmembrane glycoprotein receptor that is highly expressed on both the angiogenic endothelial and tumor cells and plays important roles in tumor growth, invasion, metastasis, and angiogenesis [5, 6]
Summary
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, 64Cu-cyclam-RAFT-c(-RGDfK-) (64Cu-RaftRGD, an αVβ3 integrin [αVβ3] tracer), and 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM, a supposed tracer for hypoxic metabolism) in a small animal tumor model. There are many types of TRT agents that can target various biological properties; combining different agents may achieve a homogeneous distribution of radionuclides, resulting in delivery of sufficient radiation throughout the entire tumor. We previously developed a tetrameric cyclic Arg-Gly-Asp (cRGD) peptide-based radiopharmaceutical, 64Cu-cyclam-RAFT-c(-RGDfK-) (64Cu-RaftRGD) [4] for targeting αVβ3 integrin (αVβ3), a transmembrane glycoprotein receptor that is highly expressed on both the angiogenic endothelial and tumor cells and plays important roles in tumor growth, invasion, metastasis, and angiogenesis [5, 6]. We focused on another Cu(II)-based theranostic agent, 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), which supposedly accumulates in regions of hypoxic metabolism within the tumor [10, 11]
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