PMID- 25456837
OWN - NLM
STAT- MEDLINE
DCOM- 20150908
LR  - 20191210
IS  - 1872-9614 (Electronic)
IS  - 0969-8051 (Linking)
VI  - 42
IP  - 2
DP  - 2015 Feb
TI  - MicroPET/CT imaging of patient-derived pancreatic cancer xenografts implanted 
      subcutaneously or orthotopically in NOD-scid mice using (64)Cu-NOTA-panitumumab 
      F(ab')2 fragments.
PG  - 71-7
LID - S0969-8051(14)00524-1 [pii]
LID - 10.1016/j.nucmedbio.2014.10.009 [doi]
AB  - INTRODUCTION: Our objective was to study microPET/CT imaging of patient-derived 
      pancreatic cancer xenografts in NOD-scid mice using F(ab')2 fragments of the 
      fully-human anti-EGFR monoclonal antibody, panitumumab (Vectibix) labeled with 
      (64)Cu. More than 90% of pancreatic cancers are EGFR-positive. METHODS: F(ab')2 
      fragments were produced by proteolytic digestion of panitumumab IgG or 
      non-specific human IgG, purified by ultrafiltration then modified with NOTA 
      chelators for complexing (64)Cu. Panitumumab IgG and Fab fragments were similarly 
      labeled with (64)Cu. EGFR immunoreactivity was determined in competition and 
      direct (saturation) cell binding assays. The biodistribution of (64)Cu-labeled 
      panitumumab IgG, F(ab')2 and Fab was compared in non-tumor-bearing Balb/c mice. 
      MicroPET/CT and biodistribution studies were performed in NOD-scid mice engrafted 
      subcutaneously (s.c.) or orthotopically with patient-derived OCIP23 pancreatic 
      tumors, or in NOD-scid with s.c. PANC-1 human pancreatic cancer xenografts. 
      RESULTS: Panitumumab F(ab')2 fragments were produced in high purity (>90%), 
      derivitized with 3.2+/-0.7 NOTA/F(ab')2, and labeled with (64)Cu (0.3-3.6MBq/mug). 
      The binding of (64)Cu-NOTA-panitumumab F(ab')2 to OCIP23 or PANC-1 cells was 
      decreased significantly by an excess of panitumumab IgG. The Kd for binding of 
      (64)Cu-NOTA-panitumumab F(ab')2 to EGFR on PANC-1 cells was 0.14+/-0.05nmol/L. 
      F(ab')2 fragments exhibited more suitable normal tissue distribution for tumor 
      imaging with (64)Cu than panitumumab IgG or Fab. Tumor uptake at 48h post 
      injection (p.i.) of (64)Cu-NOTA-panitumumab F(ab')2 was 12.0+/-0.9% injected dose/g 
      (ID/g) in s.c. and 11.8+/-0.9% ID/g in orthotopic OCIP23 tumors vs. 6.1+/-1.1% ID/g 
      in s.c. PANC-1 xenografts. Tumor/Blood (T/B) ratios were 5:1 to 9:1 for OCIP23 
      and 2.4:1 for PANC-1 tumors. Tumor uptake of (64)Cu-NOTA-non-specific F(ab')2 in 
      OCIP23 xenografts was 5-fold lower than (64)Cu-panitumumab F(ab')2. All tumor 
      xenografts were clearly imaged by microPET/CT at 24 or 48h p.i. of 
      (64)Cu-NOTA-panitumumab F(ab')2. CONCLUSIONS: (64)Cu-panitumumab F(ab')2 
      fragments bound with high affinity to EGFR on pancreatic cancer cells in vitro 
      and localized specifically in patient-derived pancreatic cancer xenografts in 
      mice in vivo, allowing tumor visualization by microPET/CT at 24 or 48h p.i.
CI  - Copyright (c) 2014 Elsevier Inc. All rights reserved.
FAU - Boyle, Amanda J
AU  - Boyle AJ
AD  - Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, 
      Canada.
FAU - Cao, Ping-Jiang
AU  - Cao PJ
AD  - Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health 
      Network, Toronto, ON, Canada.
FAU - Hedley, David W
AU  - Hedley DW
AD  - Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health 
      Network, Toronto, ON, Canada.
FAU - Sidhu, Sachdev S
AU  - Sidhu SS
AD  - Banting and Best Department of Medical Research, Donnelly Centre for Cellular and 
      Biomolecular Research, University of Toronto, Toronto, ON, Canada.
FAU - Winnik, Mitchell A
AU  - Winnik MA
AD  - Department of Chemistry, University of Toronto, Toronto, ON, Canada.
FAU - Reilly, Raymond M
AU  - Reilly RM
AD  - Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, 
      Canada; Department of Medical Imaging, University of Toronto, Toronto, ON, 
      Canada; Toronto General Research Institute, University Health Network, Toronto, 
      ON, Canada. Electronic address: raymond.reilly@utoronto.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141022
PL  - United States
TA  - Nucl Med Biol
JT  - Nuclear medicine and biology
JID - 9304420
RN  - 0 (Copper Radioisotopes)
RN  - 0 (Heterocyclic Compounds)
RN  - 0 (Heterocyclic Compounds, 1-Ring)
RN  - 0 (Immunoglobulin Fab Fragments)
RN  - 56491-86-2 (1,4,7-triazacyclononane-N,N',N''-triacetic acid)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Animals
MH  - Biological Transport
MH  - *Cell Transformation, Neoplastic
MH  - *Copper Radioisotopes
MH  - ErbB Receptors/metabolism
MH  - Heterocyclic Compounds/*chemistry
MH  - Heterocyclic Compounds, 1-Ring
MH  - Humans
MH  - *Immunoglobulin Fab Fragments/chemistry/metabolism
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Pancreatic Neoplasms/diagnostic imaging/*pathology
MH  - Positron-Emission Tomography/*methods
MH  - Radiation Dosage
MH  - Tissue Distribution
MH  - X-Ray Microtomography/*methods
OTO - NOTNLM
OT  - Copper-64
OT  - Epidermal growth factor receptor (EGFR)
OT  - Pancreatic cancer
OT  - Panitumumab
OT  - Positron emission tomography (PET)
OT  - Tumor models
EDAT- 2014/12/03 06:00
MHDA- 2015/09/09 06:00
CRDT- 2014/12/03 06:00
PHST- 2014/08/15 00:00 [received]
PHST- 2014/10/12 00:00 [revised]
PHST- 2014/10/15 00:00 [accepted]
PHST- 2014/12/03 06:00 [entrez]
PHST- 2014/12/03 06:00 [pubmed]
PHST- 2015/09/09 06:00 [medline]
AID - S0969-8051(14)00524-1 [pii]
AID - 10.1016/j.nucmedbio.2014.10.009 [doi]
PST - ppublish
SO  - Nucl Med Biol. 2015 Feb;42(2):71-7. doi: 10.1016/j.nucmedbio.2014.10.009. Epub 
      2014 Oct 22.