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|標題:||Evaluating the potential of Re-188-SOCTA-trastuzumab as a new radioimmunoagent for breast cancer treatment||作者:||Luo, T.Y.
|關鍵字:||SOCTA;Bifunctional chelator;Radioimmunotherapy;Re-188-SOCTA-trastuzumab;herceptin fab fragments;monoclonal-antibodies;radioimmunotherapy;biodistribution;xenografts;carcinoma;her2/neu;optimization;trastuzumab;expression||Project:||Nuclear Medicine and Biology||期刊/報告no：:||Nuclear Medicine and Biology, Volume 36, Issue 1, Page(s) 81-88.||摘要:||
Introduction: Radioimmunotherapy, which utilizes monoclonal antibodies and therapeutic radioisotopes against antigen-expressing tumor tissues, is an attractive therapeutic approach for cancer therapy. Trastuzumab (Herceptin) is a humanized anti-HER-2/neu monoclonal antibody for breast cancer treatment. In this paper, we introduce a new radioimmunoagent, Re-188-trastuzumab, via a bifunctional ligand, succinimidyl 3,6-diaza-5-oxo-3-[2-((triphenymethyl)thio)ethyl]-8-[(triphenylmethyl)thio]octanoate (SOCTA), and evaluate its potential to be a therapeutic radiopharmaceutical for breast cancer treatment. Methods: Equimolar amounts of SOCTA and trastuzumab were selected to react, and the conjugation ratio of SOCTA-trastuzumab was evaluated by the MALDI-TOF method. The immunoreactivity of SOCTA-trastuzumab was compared with nonconjugated trastuzumab in HER-2/neu overexpressing human breast cancer cell BT-474. Biodistribution experiment and microSPECT/CT images of Re-188-SOCTA-trastuzumab being administered intravenously to SCID mice hearing xenografted BT-474 breast cancer were investigated to evaluate the tumor-targeting capability. Results: The covalent attachment of SOCTA to trastuzumab (at 1: 1 molar ratio) resulted in the averaged conjugation ratio of 0.27 +/- 0.06 (n=3). The complex Could easily be labeled with Re-188 and achieve 95% radiochemical purity (RCP) after 1 h of reaction at room temperature. The in vitro stability study also revealed that the RCP of Re-188-SOCTA-trastuzumab was at a value of more than 85% after 48 h Of incubation with human serum. The immunoreactivity evaluation showed that SOCTA-trastuzumab and nonconjugated trastuzumab had similar binding capacity (B,) to HER-2/neu receptor in BT-474 cells. The animal experiments showed that Re-188-SOCTA-trastuzumab accumulated more intensively in the tumor site as compared to normal tissue. Conclusion: We suggest that Re-188-SOCTA-trastuzumab could be a potential candidate for radioimmunotherapy. (C) 2009 Elsevier Inc. All rights reserved.
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