論文 - 詳細
| RRC ID | 54813 |
|---|---|
| 著者 | Ren Q, Mohri K, Warashina S, Wada Y, Watanabe Y, Mukai H. |
| タイトル | Improved Immuno-PET Imaging of HER2-Positive Tumors in Mice: Urokinase Injection-Triggered Clearance Enhancement of 64Cu-Trastuzumab. |
| ジャーナル | Mol Pharm |
| Abstract |
Immuno-positron emission tomography (immuno-PET) is expected to improve the specificity of small chemical tracers such as 18F-fluorodeoxyglucose. Whole antibodies significantly accumulate in target molecule-expressing tumors but frequently persist too long in the blood circulation for imaging purposes. We investigated the utility of whole antibodies, 64Cu-labeled via a urokinase-substrate linker, and their exogenous urokinase-responsive cleavage to enhance clearance of immuno-PET probes from the blood and shorten the time required to develop adequate imaging contrast. Specifically, we used 64Cu-labeled trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive tumor-bearing mice. 64Cu-labeled trastuzumab with a urokinase-cleavage site (64Cu-CB-TE1A1P-USL-trastuzumab) was synthesized using a bifunctional chelator incorporating an urokinase substrate peptide. Urokinase cleavage was analyzed in vitro by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and radio-gel permeation-high-performance liquid chromatography. Improvements in radioisotope clearance and HER2-imaging by urokinase injection were evaluated by PET imaging and ex vivo biodistribution studies in A431 tumor-bearing mice. 64Cu-CB-TE1A1P-USL-trastuzumab was cleaved into smaller radioactive fragments by 20 000 IU/mL urokinase treatment in vitro at an efficacy of ∼95%. The probe targeted HER2 in A431 tumors in mice within 24 h post-injection, and approximately two-thirds of the probe in the blood circulation was eliminated via renal clearance of radioactive fragments after three urokinase injections. Therefore, the tumor/blood ratio increased 3.0-fold. Without urokinase injection, the tumor accumulation of 64Cu-CB-TE1A1P-USL-trastuzumab slowly increased, and the blood radioactivity decreased over 72 h. However, the tumor/blood ratios in mice after three urokinase injections were higher at 24 h than those in mice without injections at 72 h. The results indicate that our approach shortened the time required to develop adequate imaging contrast of immuno-PET by >2 days. Therefore, this approach can benefit high-sensitivity imaging under lower radioactive decay conditions and can decrease patient radiation exposure. In addition, it could reduce other adverse effects of radioimmunotherapy. |
| 巻・号 | 16(3) |
| ページ | 1065-1073 |
| 公開日 | 2019-3-4 |
| DOI | 10.1021/acs.molpharmaceut.8b01052 |
| PMID | 30633529 |
| MeSH | Animals Cell Line, Tumor Chelating Agents / chemistry Copper Radioisotopes / chemistry* Fluorodeoxyglucose F18 Heterocyclic Compounds, 2-Ring / chemistry Heterografts Humans Injections, Intravenous Male Mice Mice, Inbred BALB C Mice, Nude Neoplasm Transplantation Neoplasms / diagnostic imaging* Neoplasms / pathology Organophosphonates / chemistry Positron-Emission Tomography / methods* Receptor, ErbB-2 / metabolism* Tissue Distribution Trastuzumab / chemistry Trastuzumab / metabolism* Urokinase-Type Plasminogen Activator / administration & dosage Urokinase-Type Plasminogen Activator / pharmacology* |
| IF | 4.396 |
| 引用数 | 1 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | A431(RCB1872) |