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Ratiometric Activatable Cell-Penetrating Peptides Label Pancreatic Cancer, Enabling Fluorescence-Guided Surgery, Which Reduces Metastases and Recurrence in Orthotopic Mouse Models

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The aim of this study was to evaluate the efficacy of using matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9)-cleavable ratiometric activatable cell-penetrating peptides (RACPPs) conjugated to Cy5 and Cy7 fluorophores to accurately label pancreatic cancer for fluorescence-guided surgery (FGS) in an orthotopic mouse model.

Methods

Orthotopic mouse models were established using MiaPaCa-2-GFP human pancreatic cancer cells. Two weeks after implantation, tumor-bearing mice were randomized to conventional white light reflectance (WLR) surgery or FGS. FGS was performed at far-red and infrared wavelengths with a customized fluorescence-dissecting microscope 2 h after injection of MMP-2 and MMP-9-cleavable RACPPs. Green fluorescence imaging of the GFP-labeled cancer cells was used to assess the effectiveness of surgical resection and monitor recurrence. At 8 weeks, mice were sacrificed to evaluate tumor burden and metastases.

Results

Mice in the WLR group had larger primary tumors than mice in the FGS group at termination [1.72 g ± standard error (SE) 0.58 vs. 0.25 g ± SE 0.14; respectively, p = 0.026). Mean disease-free survival was significantly lengthened from 5.33 weeks in the WLR group to 7.38 weeks in the FGS group (p = 0.02). Recurrence rates were lower in the FGS group than in the WLR group (38 vs. 73 %; p = 0.049). This translated into lower local and distant recurrence rates for FGS compared to WLR (31 vs. 67 for local recurrence, respectively, and 25 vs. 60 % for distant recurrence, respectively). Metastatic tumor burden was significantly greater in the WLR group than in the FGS group (96.92 mm2 ± SE 52.03 vs. 2.20 mm2 ± SE 1.43; respectively, χ 2 = 5.455; p = 0.02).

Conclusions

RACPPs can accurately and effectively label pancreatic cancer for effective FGS, resulting in better postresection outcomes than for WLR surgery.

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Acknowledgment

This work was supported in part by grants CA132971 and CA142669 from the National Cancer Institute (to M.B. and AntiCancer, Inc.), T32 training grant CA121938 (to C.A.M.), training grant 5R25CA153915 and fellowship grant 1F30HL118998-01 (to C.N.F.), Burrough-Wellcome Fund CAMS and 5K08EB008122 from the National Institutes of Health (to Q.T.N.), and CA158448 from the National Cancer Institute (to R.Y.T.). The authors would also like to thank Elamprakash Savariar for synthesizing the ratiometric imaging agents and Paul Steinbach for surgical imaging support.

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Authors and Affiliations

  1. Department of Surgery, University of California San Diego, San Diego, CA, USA

    Cristina A. Metildi MD, Quyen T. Nguyen MD, PhD, Robert M. Hoffman PhD & Michael Bouvet MD

  2. Department of Pharmacology, University of California San Diego, San Diego, CA, USA

    Csilla N. Felsen BS, Elamprakash N. Savariar PhD & Roger Y. Tsien PhD

  3. Moores Cancer Center, University of California San Diego, San Diego, CA, USA

    Quyen T. Nguyen MD, PhD, Sharmeela Kaushal PhD, Robert M. Hoffman PhD, Roger Y. Tsien PhD & Michael Bouvet MD

  4. AntiCancer, Inc, San Diego, CA, USA

    Robert M. Hoffman PhD

  5. Howard Hughes Medical Institute, University of California San Diego, San Diego, CA, USA

    Roger Y. Tsien PhD

Authors
  1. Cristina A. Metildi MD
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  2. Csilla N. Felsen BS
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  3. Elamprakash N. Savariar PhD
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  8. Michael Bouvet MD
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Correspondence to Michael Bouvet MD.

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Metildi, C.A., Felsen, C.N., Savariar, E.N. et al. Ratiometric Activatable Cell-Penetrating Peptides Label Pancreatic Cancer, Enabling Fluorescence-Guided Surgery, Which Reduces Metastases and Recurrence in Orthotopic Mouse Models. Ann Surg Oncol 22, 2082–2087 (2015). https://doi.org/10.1245/s10434-014-4144-1

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