Journal article
ImmunoPET and Near-Infrared Fluorescence Imaging of Pancreatic Cancer with a Dual-Labeled Bispecific Antibody Fragment
Molecular pharmaceutics, Vol.14(5), pp.1646-1655
05/01/2017
DOI: 10.1021/acs.molpharmaceut.6b01123
PMCID: PMC5473618
PMID: 28292180
Abstract
Dual-targeted imaging agents have shown improved targeting efficiencies in comparison to single-targeted entities. The purpose of this study was to quantitatively assess the tumor accumulation of a dual-labeled heterobifunctional imaging agent, targeting two overexpressed biomarkers in pancreatic cancer, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging modalities. A bispecific immunoconjugate (heterodimer) of CD105 and tissue factor (TF) Fab' antibody fragments was developed using click chemistry. The heterodimer was dual-labeled with a radionuclide (
Cu) and fluorescent dye. PET/NIRF imaging and biodistribution studies were performed in four-to-five week old nude athymic mice bearing BxPC-3 (CD105/TF
) or PANC-1 (CD105/TF
) tumor xenografts. A blocking study was conducted to investigate the specificity of the tracer. Ex vivo tissue staining was performed to compare TF/CD105 expression in tissues with PET tracer uptake to validate in vivo results. PET imaging of
Cu-NOTA-heterodimer-ZW800 in BxPC-3 tumor xenografts revealed enhanced tumor uptake (21.0 ± 3.4%ID/g; n = 4) compared to the homodimer of TRC-105 (9.6 ± 2.0%ID/g; n = 4; p < 0.01) and ALT-836 (7.6 ± 3.7%ID/g; n = 4; p < 0.01) at 24 h postinjection. Blocking studies revealed that tracer uptake in BxPC-3 tumors could be decreased by 4-fold with TF blocking and 2-fold with CD105 blocking. In the negative model (PANC-1), heterodimer uptake was significantly lower than that found in the BxPC-3 model (3.5 ± 1.1%ID/g; n = 4; p < 0.01). The specificity was confirmed by the successful blocking of CD105 or TF, which demonstrated that the dual targeting with
Cu-NOTA-heterodimer-ZW800 provided an improvement in overall tumor accumulation. Also, fluorescence imaging validated the PET imaging, allowing for clear delineation of the xenograft tumors. Dual-labeled heterodimeric imaging agents, like
Cu-NOTA-heterodimer-ZW800, may increase the overall tumor accumulation in comparison to single-targeted homodimers, leading to improved imaging of cancer and other related diseases.
Details
- Title: Subtitle
- ImmunoPET and Near-Infrared Fluorescence Imaging of Pancreatic Cancer with a Dual-Labeled Bispecific Antibody Fragment
- Creators
- Haiming Luo - University of Wisconsin–MadisonChristopher G England - University of Wisconsin–MadisonShreya Goel - University of Wisconsin–MadisonStephen A Graves - University of Wisconsin–MadisonFanrong Ai - University of Wisconsin–MadisonBai Liu - Altor BioScienceCharles P Theuer - Tracon PharmaceuticalsHing C Wong - Altor BioScienceRobert J Nickles - University of Wisconsin–MadisonWeibo Cai - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Molecular pharmaceutics, Vol.14(5), pp.1646-1655
- DOI
- 10.1021/acs.molpharmaceut.6b01123
- PMID
- 28292180
- PMCID
- PMC5473618
- ISSN
- 1543-8384
- eISSN
- 1543-8392
- Grant note
- R01 EB021336 / NIBIB NIH HHS T32 CA009206 / NCI NIH HHS R01 CA169365 / NCI NIH HHS P30 CA014520 / NCI NIH HHS
- Language
- English
- Date published
- 05/01/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Radiation Oncology
- Record Identifier
- 9984383277202771
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