Abstract
The transmembrane cell adhesion receptor αVβ3 integrin (αVβ3) has been identified as an important molecular target for cancer imaging and therapy. We have developed a tetrameric cyclic RGD (Arg-Gly-Asp) peptide-based radiotracer (64)Cu-cyclam-RAFT-c(-RGDfK-)4, which successfully captured αVβ3-positive tumors and angiogenesis by PET. Here, we subsequently evaluated its therapeutic potential and side effects using an established αVβ3-positive tumor mouse model. Mice with subcutaneous U87MG glioblastoma xenografts received single administrations of 37 and 74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 (37 MBq/nmol), peptide control, or vehicle solution and underwent tumor growth evaluation. Side effects were assessed in tumor-bearing and tumor-free mice in terms of body weight, routine hematology, and hepatorenal functions. Biodistribution of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 with ascending peptide doses (0.25-10 nmol) and with the therapeutic dose of 2 nmol were determined at 3 hours and at various time points (2 minutes-24 hours) postinjection, respectively, based on which radiation-absorbed doses were estimated. The results revealed that (64)Cu-cyclam-RAFT-c(-RGDfK-)4 dose dependently slowed down the tumor growth. The mean tumor doses were 1.28 and 1.81 Gy from 37 and 74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4, respectively. Peptide dose study showed that the tumor uptake of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 dose dependently decreased at doses ≥1 nmol, indicating a saturation of αVβ3 with the administered therapeutic doses (1 and 2 nmol). Combined analysis of the data from tumor-bearing and tumor-free mice revealed no significant toxicity caused by 37-74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 Our study demonstrates the therapeutic efficacy and safety of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 for αVβ3-targeted radionuclide therapy. (64)Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising theranostic drug for cancer imaging and therapy. Mol Cancer Ther; 15(9); 2076-85. ©2016 AACR.
Highlights
Molecular-targeted radionuclide therapy (MTRT), which is a promising cancer treatment option, is performed by the systemic administration of a specific molecular vehicle, that is, antibody, peptide or small organic molecule that is radiolabeled with a cytocidal energy-releasing radionuclide (a- or bÀ-particle emitter or Auger electron emitter) to elicit a therapeutic effect on the targeted tumoral lesions [1,2,3,4]
Immunofluorescence staining of U87MG xenograft showed positive expression of aVb3 in the majority of tumor cells (Fig. 1C, left), whereas the cells double-stained for the panendothelial marker CD31 and mouse CD61 were identified as the aVb3-positive neoendothelial cells (Fig. 1C, right)
With the addition of GF and Lys, which were previously reported to markedly reduce the renal uptake and slightly increase the tumor uptake of 64Cu-cyclamRAFT-c(-RGDfK-)4 [33], the high renal uptake caused by normal saline (NS)/Tw80 was greatly reduced by 54%, whereas no significant difference was found with the tumor uptake values (Fig. 2B)
Summary
Molecular-targeted radionuclide therapy (MTRT), which is a promising cancer treatment option, is performed by the systemic administration of a specific molecular vehicle, that is, antibody, peptide or small organic molecule that is radiolabeled with a cytocidal energy-releasing radionuclide (a- or bÀ-particle emitter or Auger electron emitter) to elicit a therapeutic effect on the targeted tumoral lesions [1,2,3,4]. The key advantages such as rapid blood clearance, tissue penetration capability, low immunogenicity, and relatively easy and cost-effective production, have.
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