Predicting gemcitabine delivery by 18F-FAC PET in murine models of pancreatic cancer.

[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 to [14C]-gemcitabine levels, established ex vivo, in three mouse models of pancreatic cancer. We further modified tumor gemcitabine levels with injectable hyaluronidase (PEGPH20) to test whether changes in gemcitabine would be tracked by [18F]-FAC. Methods: [18F]-FAC was synthesized at MSKCC as described previously. Three patient derived xenografts (PDX) models were grown in the flanks of NSG mice. Mice were given PEGPH20 or vehicle i.v. 24 hours prior to co-injection of [18F]-FAC and [14C]-gemcitabine. Animals were euthanized and imaged one hour after tracer administration. Tumor and muscle uptake of both [18F]-FAC and [14C]-gemcitabine were 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-Kras G12D LSL-p53 R172H) tumor, was used to generate orthotopically growing tumors in C57BL/6J mice, which 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 7T Brucker MR scanner. Animals were imaged immediately before injection with PEGPH20, and again 24 hours later. Results: Tumor/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 which was matched in ex vivo counts for 2 out of 3 models. In KPC-derived tumors, PEGPH20 raised [14C]-gemcitabine levels (T/M 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 following 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.