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Research ArticleOncology

Predicting Gemcitabine Delivery by 18F-FAC PET in Murine Models of Pancreatic Cancer

James Russell, Milan Grkovski, Isabella J. O’Donoghue, Teja M. Kalidindi, Nagavarakishore Pillarsetty, Eva M. Burnazi, Amanda Kulick, Amber Bahr, Qing Chang, H. Carl LeKaye, Elisa de Stanchina, Kenneth H. Yu and John L. Humm
Journal of Nuclear Medicine February 2021, 62 (2) 195-200; DOI: https://doi.org/10.2967/jnumed.120.246926
James Russell
1Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
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Milan Grkovski
1Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
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Isabella J. O’Donoghue
1Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
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Teja M. Kalidindi
2Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
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Nagavarakishore Pillarsetty
2Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
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Eva M. Burnazi
3Radiochemistry and Molecular Imaging Probe Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York
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Amanda Kulick
4Anti-Tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York; and
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Amber Bahr
4Anti-Tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York; and
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Qing Chang
4Anti-Tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York; and
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H. Carl LeKaye
1Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
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Elisa de Stanchina
4Anti-Tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York; and
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Kenneth H. Yu
5Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
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John L. Humm
1Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
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Abstract

18F-FAC (2′-deoxy-2′-18F-fluoro-β-d-arabinofuranosylcytosine) has close structural similarity to gemcitabine and thus offers the potential to image drug delivery to tumors. We compared tumor 18F-FAC PET images with 14C-gemcitabine levels, established ex vivo, in 3 mouse models of pancreatic cancer. We further modified tumor gemcitabine levels with injectable PEGylated recombinant human hyaluronidase (PEGPH20) to test whether changes in gemcitabine would be tracked by 18F-FAC. Methods: 18F-FAC was synthesized as described previously. Three patient-derived xenograft (PDX) models were grown in the flanks of NSG mice. Mice were given PEGPH20 or vehicle intravenously 24 h before coinjection of 18F-FAC and 14C-gemcitabine. Animals were euthanized and imaged 1 h after tracer administration. Tumor and muscle uptake of both 18F-FAC and 14C-gemcitabine was obtained ex vivo. The efficacy of PEPGPH20 was validated through staining with hyaluronic acid binding protein. Additionally, an organoid culture, initiated from a KPC (Pdx-1 Cre LSL-KrasG12D LSL-p53R172H) tumor, was used to generate orthotopically growing tumors in C57BL/6J mice, and these tumors were then serially transplanted. Animals were injected with PEGPH20 and 14C-gemcitabine as described above to validate increased drug uptake by ex vivo assay. PET/MR images were obtained using a PET insert on a 7-T MR scanner. Animals were imaged immediately before injection with PEGPH20 and again 24 h later. Results: Tumor-to-muscle ratios of 14C-gemcitabine and 18F-FAC correlated well across all PDX models and treatments (R2 = 0.78). There was a significant increase in the tumor PET signal in PEGPH20-treated PDX animals, and this signal was matched in ex vivo counts for 2 of 3 models. In KPC-derived tumors, PEGPH20 raised 14C-gemcitabine levels (tumor-to-muscle ratio of 1.9 vs. 2.4, control vs. treated, P = 0.013). PET/MR 18F-FAC images showed a 12% increase in tumor 18F-FAC uptake after PEGPH20 treatment (P = 0.023). PEGPH20-treated animals uniformly displayed clear reductions in hyaluronic acid staining. Conclusion: 18F-FAC PET was shown to be a good surrogate for gemcitabine uptake and, when combined with MR, to successfully determine drug uptake in tumors growing in the pancreas. PEGPH20 had moderate effects on tumor uptake of gemcitabine.

  • 18F-FAC
  • gemcitabine
  • drug delivery
  • hyaluronic acid
  • pancreatic cancer
  • PET/MRI

Footnotes

  • Published online Jul. 9, 2020.

  • © 2021 by the Society of Nuclear Medicine and Molecular Imaging.
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Journal of Nuclear Medicine: 62 (2)
Journal of Nuclear Medicine
Vol. 62, Issue 2
February 1, 2021
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Predicting Gemcitabine Delivery by 18F-FAC PET in Murine Models of Pancreatic Cancer
James Russell, Milan Grkovski, Isabella J. O’Donoghue, Teja M. Kalidindi, Nagavarakishore Pillarsetty, Eva M. Burnazi, Amanda Kulick, Amber Bahr, Qing Chang, H. Carl LeKaye, Elisa de Stanchina, Kenneth H. Yu, John L. Humm
Journal of Nuclear Medicine Feb 2021, 62 (2) 195-200; DOI: 10.2967/jnumed.120.246926

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Predicting Gemcitabine Delivery by 18F-FAC PET in Murine Models of Pancreatic Cancer
James Russell, Milan Grkovski, Isabella J. O’Donoghue, Teja M. Kalidindi, Nagavarakishore Pillarsetty, Eva M. Burnazi, Amanda Kulick, Amber Bahr, Qing Chang, H. Carl LeKaye, Elisa de Stanchina, Kenneth H. Yu, John L. Humm
Journal of Nuclear Medicine Feb 2021, 62 (2) 195-200; DOI: 10.2967/jnumed.120.246926
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Keywords

  • 18F-FAC
  • gemcitabine
  • drug delivery
  • hyaluronic acid
  • pancreatic cancer
  • PET/MRI
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