Journal article
Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for Zr-89(4+) and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice
Theranostics, Vol.6(4), pp.511-521
01/01/2016
DOI: 10.7150/thno.14261
PMCID: PMC4775861
PMID: 26941844
Abstract
A novel octadentate 3-hydroxypyridin-2-one (2,3-HOPO) based di-macrocyclic ligand was evaluated for chelation of Zr-89; subsequently, it was used as a bi-functional chelator for preparation of Zr-89-labeled antibodies. Quantitative chelation of Zr-89(4+) with the octadentate ligand forming (ZrL)-Zr-89 complex was achieved under mild conditions within 15 minutes. The Zr-89-complex was stable in vitro in presence of DTPA, but a slow degradation was observed in serum. In vivo, the hydrophilic Zr-89-complex showed prevalently renal excretion; and an elevated bone uptake of radioactivity suggested a partial release of Zr-89(4+) from the complex.
The 2,3-HOPO based ligand was conjugated to the monoclonal antibodies, HER2-specific trastuzumab and an isotypic anti-gD antibody, using a p-phenylene bis-isothiocyanate linker to yield products with an average loading of less than 2 chelates per antibody. Conjugated antibodies were labeled with Zr-89 under mild conditions providing the PET tracers in 60-69% yield. Despite the limited stability in mouse serum; the PET tracers performed very well in vivo. The PET imaging in mouse model of HER2 positive ovarian carcinoma showed tumor uptake of Zr-89-trastuzumab (29.2 +/- 12.9 % ID/g) indistinguishable (p = 0.488) from the uptake of positive control Zr-89-DFO-trastuzumab (26.1 +/- 3.3 % ID/g).
In conclusion, the newly developed 3-hydroxypyridin-2-one based di-macrocyclic chelator provides a viable alternative to DFO-based heterobifunctional ligands for preparation of Zr-89-labeled monoclonal antibodies for immunoPET studies.
Details
- Title: Subtitle
- Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for Zr-89(4+) and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice
- Creators
- Jeff N. Tinianow - GenentechDarpan N. Pandya - Wake Forest UniversitySylvie L. Pailloux - LumiphoreAnnie Ogasawara - GenentechAlexander N. Vanderbilt - GenentechHerman S. Gill - GenentechSimon-P. Williams - GenentechThaddeus J. Wadas - Wake Forest UniversityDarren Magda - LumiphoreJan Marik - Genentech
- Resource Type
- Journal article
- Publication Details
- Theranostics, Vol.6(4), pp.511-521
- DOI
- 10.7150/thno.14261
- PMID
- 26941844
- PMCID
- PMC4775861
- NLM abbreviation
- Theranostics
- ISSN
- 1838-7640
- eISSN
- 1838-7640
- Publisher
- Ivyspring Int Publ
- Number of pages
- 11
- Grant note
- IIP-1215462 / NSF SBIR Phase I grant; National Science Foundation (NSF); NSF - Directorate for Engineering (ENG)
- Language
- English
- Date published
- 01/01/2016
- Academic Unit
- Radiology; Radiation Oncology
- Record Identifier
- 9984313079002771
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