PET imaging of insulin-like growth factor type 1 receptor expression with a 64Cu-labeled Affibody molecule
- 509 Downloads
The insulin-like growth factor 1 receptor (IGF-1R) serves as an attractive target for cancer molecular imaging and therapy. Previous single photon emission computerized tomography (SPECT) studies showed that the IGF-1R-targeting Affibody molecules 99mTc-ZIGF1R:4551-GGGC, [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 and 111In-DOTA-ZIGF1R:4551 can discriminate between high and low IGF-1R-expression tumors and have the potential for patient selection for IGF-1R-targeted therapy. Compared with SPECT, positron emission tomography (PET) may improve imaging of IGF-1R-expression, because of its high sensitivity, high spatial resolution, strong quantification ability. The aim of the present study was to develop the 64Cu-labeled NOTA-conjugated Affibody molecule ZIGF-1R:4:40 as a PET probe for imaging of IGF-1R-positive tumor. An Affibody analogue (Ac-Cys-ZIGF-1R:4:40) binding to IGF-1R was site-specifically conjugated with NOTA and labeled with 64Cu. Binding affinity and specificity of 64Cu-NOTA-ZIGF-1R:4:40 to IGF-1R were evaluated using human glioblastoma U87MG cells. Small-animal PET, biodistribution, and metabolic stability studies were conducted on mice bearing U87MG xenografts after the injection of 64Cu-NOTA-ZIGF-1R:4:40 with or without co-injection of unlabeled Affibody proteins. The radiosynthesis of 64Cu-NOTA-ZIGF-1R:4:40 was completed successfully within 60 min with a decay-corrected yield of 75 %. 64Cu-NOTA-ZIGF-1R:4:40 bound to IGF-1R with low nanomolar affinity (K D = 28.55 ± 3.95 nM) in U87MG cells. 64Cu-NOTA-ZIGF-1R:4:40 also displayed excellent in vitro and in vivo stability. In vivo biodistribution and PET studies demonstrated targeting of U87MG gliomas xenografts was IGF-1R specific. The tumor uptake was 5.08 ± 1.07 %ID/g, and the tumor to muscle ratio was 11.89 ± 2.16 at 24 h after injection. Small animal PET imaging studies revealed that 64Cu-NOTA-ZIGF-1R:4:40 could clearly identify U87MG tumors with good contrast at 1–24 h after injection. This study demonstrates that 64Cu-NOTA-ZIGF-1R:4:40 is a promising PET probe for imaging IGF-1R positive tumor.
KeywordsAffibody IGF-1R PET 64Cu NOTA
This work was supported in part by the Office of Science (BER), US Department of Energy (DE-SC0008397), National Natural Science Foundation of China (81071182) and Medical Innovation Foundation of Fujian, China (2009-CXB-46).
Conflict of interest
The authors declare that they have no conflict of interest.
The animal procedures were performed according to a protocol approved by the Stanford University Institutional Animal Care and Use Committee. This article does not contain any studies with human participants performed by any of the authors.
Not available since no human study was involved.
- Cornelissen B, McLarty K, Kersemans V, Reilly RM (2008) The level of insulin growth factor-1 receptor expression is directly correlated with the tumor uptake of 111In-IGF-1(E3R) in vivo and the clonogenic survival of breast cancer cells exposed in vitro to trastuzumab (Herceptin). Nucl Med Biol 35:645–653PubMedCrossRefGoogle Scholar
- Fleuren ED, Versleijen-Jonkers YM, van de Luijtgaarden AC, Molkenboer-Kuenen JD, Heskamp S, Roeffen MH, van Laarhoven HW, Houghton PJ, Oyen WJ, Boerman OC, van der Graaf WT (2011) Predicting IGF-1R therapy response in bone sarcomas: immuno-SPECT imaging with radiolabeled R1507. Clin Cancer Res 17:7693–7703PubMedCentralPubMedCrossRefGoogle Scholar
- Friedman M, Nordberg E, Höidén-Guthenberg I, Brismar H, Adams GP, Nilsson FY, Carlsson J, Stahl S (2007) Phage display selection of affibody molecules with specific binding to the extracellular domain of the epidermal growth factor receptor. Protein Eng Des Sel 20:189–199PubMedCrossRefGoogle Scholar
- Gong Y, Yao E, Shen R, Goel A, Arcila M, Teruya-Feldstein J, Zakowski MF, Frankel S, Peifer M, Thomas RK, Ladayi M, Pao W (2009) High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507). PLoS One 4:e7273PubMedCentralPubMedCrossRefGoogle Scholar
- Orlova A, Hofström C, Strand J, Varasteh Z, Sandstrom M, Andersson K, Tolmachev V, Gräslund T (2013) [99mTc(CO)3]+-(HE)3-ZIGF1R:4551, a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours. Eur J Nucl Med Mol Imaging 40:439–449PubMedCrossRefGoogle Scholar
- Prasanphanich AF, Nanda PK, Rold TL, Ma L, Lewis MR, Garrison JC, Hoffman TJ, Sieckman GL, Figueroa SD, Smith CJ (2007) [64Cu-NOTA-8-Aoc-BBN (7-14)NH2] targeting vector for positron-emission tomography imaging of gastrinreleasing peptide receptor-expressing tissues. Proc Natl Acad Sci USA 104:12462–12467PubMedCentralPubMedCrossRefGoogle Scholar
- Zha J, O’Brien C, Savage H, Huw LY, Zhong F, Berry L, Lewis Philips GD, Luis E, Cavet G, X H, Amler LC, Lackner MR (2009) Molecular predictors of response to a humanized anti-insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer. Mol Cancer Ther 8:2110–21121PubMedCrossRefGoogle Scholar