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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Cyr, Erika M. Bonab, Ali A. Huston, James S. Smith, Suzanne V. Voss, Stephan D. Mcintosh, Lacey J. Packard, Alan B. Gillies, Stephen D. Dibartolo, Nadine Fischman, Alan J. Carter, Edward A. Treves, S. Ted Sargeson, Alan M. Dearling, Jason L. J. |
| Description | Author Affiliation: Voss SD ( Department of Radiology and Division of Nuclear Medicine, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. stephan.voss@childrens.harvard.edu); |
| Abstract | The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement (18)F-FDG. Copper-64 ((64)Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability of conventional chelates has limited its clinical application. The objective of this work was to evaluate the novel chelating agent SarAr (1-N-(4-aminobenzyl)-3, 6,10,13,16,19-hexaazabicyclo[6.6.6] eicosane-1,8-diamine) for use in developing a new class of tumor-specific (64)Cu radiopharmaceuticals for imaging neuroblastoma and melanoma. The anti-GD2 monoclonal antibody (mAb) 14.G2a, and its chimeric derivative, ch14.18, target disialogangliosides that are overexpressed on neuroblastoma and melanoma. Both mAbs were conjugated to SarAr using carbodiimide coupling. Radiolabeling with (64)Cu resulted in >95% of the (64)Cu being chelated by the immunoconjugate. Specific activities of at least 10 microCi/microg (1 Ci = 37 GBq) were routinely achieved, and no additional purification was required after (64)Cu labeling. Solid-phase radioimmunoassays and intact cell-binding assays confirmed retention of bioactivity. Biodistribution studies in athymic nude mice bearing s.c. neuroblastoma (IMR-6, NMB-7) and melanoma (M21) xenografts showed that 15-20% of the injected dose per gram accumulated in the tumor at 24 hours after injection, and only 5-10% of the injected dose accumulated in the liver, a lower value than typically seen with other chelators. Uptake by a GD2-negative tumor xenograft was significantly lower (<5% injected dose per gram). MicroPET imaging confirmed significant uptake of the tracer in GD-2-positive tumors, with minimal uptake in GD-2-negative tumors and nontarget tissues such as liver. The (64)Cu-SarAr-mAb system described here is potentially applicable to (64)Cu-PET imaging with a broad range of antibody or peptide-based imaging agents. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 44 |
| Volume Number | 104 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2007-11-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Aniline Compounds Chemistry Bicyclo Compounds, Heterocyclic Immunoconjugates Immunology Melanoma Diagnosis Neuroblastoma Positron-Emission Tomography Animals Cell Line, Tumor Copper Radioisotopes Mice Molecular Structure Neoplasm Transplantation Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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