ImmunoPET Imaging of Insulin-Like Growth Factor 1 Receptor in a Subcutaneous Mouse Model of Pancreatic Cancer

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• 作者：Christopher G. England ; Anyanee Kamkaew ; Hyung-Jun Im ; Hector F. Valdovinos ; Haiyan Sun ; Reinier Hernandez ; Steve Y. Cho ; Edward J. Dunphy ; Dong Soo Lee ; Todd E. Barnhart ; Weibo Cai
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：June 6, 2016
• 年：2016
• 卷：13
• 期：6
• 页码：1958-1966
• 全文大小：505K
• 年卷期：0
• ISSN：1543-8392

文摘

The role of insulin-like growth factor-1 receptor (IGF-1R) in cancer tumorigenesis was established decades ago, yet there are limited studies evaluating the imaging and therapeutic properties of anti-IGF-1R antibodies. Noninvasive imaging of IGF-1R may allow for optimized patient stratification and monitoring of therapeutic response in patients. Herein, this study reports the development of a Zirconium-89 (⁸⁹Zr)-labeled anti-IGF-1R antibody (⁸⁹Zr-Df-1A2G11) for PET imaging of pancreatic cancer. Successful chelation and radiolabeling of the antibody resulted in a highly stable construct that could be used for imaging IGF-1R expressing tumors in vivo. Western blot and flow cytometry studies showed that MIA PaCa-2, BxPC-3, and AsPC-1 pancreatic cancer cell lines expressed high, moderate, and low levels of IGF-1R, respectively. These three pancreatic cancer cell lines were subcutaneously implanted into mice. By employing the PET imaging technique, the tumor accumulation of ⁸⁹Zr-Df-1A2G11 was found to be dependent on the level of IGF-1R expression. Tumor accumulation of ⁸⁹Zr-Df-1A2G11 was 8.24 ± 0.51, 5.80 ± 0.54, and 4.30 ± 0.42 percentage of the injected dose (%ID/g) in MIA PaCa-2, BxPC-3, and AsPC-1-derived tumor models at 120 h postinjection, respectively (n = 4). Biodistribution studies and ex vivo immunohistochemistry confirmed these findings. In addition, ⁸⁹Zr-labeled nonspecific human IgG (⁸⁹Zr-Df-IgG) displayed minimal uptake in IGF-1R positive MIA PaCa-2 tumor xenografts (3.63 ± 0.95%ID/g at 120 h postinjection; n = 4), demonstrating that ⁸⁹Zr-Df-1A2G11 accumulation was highly specific. This study provides initial evidence that our ⁸⁹Zr-labeled IGF-1R-targeted antibody may be employed for imaging a wide range of malignancies. Antibodies may be tracked in vivo for several days to weeks with ⁸⁹Zr, which may enhance image contrast due to decreased background signal. In addition, the principles outlined in this study can be employed for identifying patients that may benefit from anti-IGF-1R therapy.