Ratiometric activatable cell-penetrating peptides label pancreatic cancer, enabling fluorescence-guided surgery, which reduces metastases and recurrence in orthotopic mouse models.

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 mm(2) ± SE 52.03 vs. 2.20 mm(2) ± 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.

• Authors: Cristina A Metildi, Csilla N Felsen, Elamprakash N Savariar, Quyen T Nguyen, Sharmeela Kaushal, Robert M Hoffman, Roger Y Tsien, Michael Bouvet
• Journal: Annals of surgical oncology (Ann Surg Oncol) Vol. 22 Issue 6 Pg. 2082-7 ( 2015) ISSN: 1534-4681 [Electronic] United States
• PMID: 25319581 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cell-Penetrating Peptides
• Green Fluorescent Proteins
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Animals
• Cell-Penetrating Peptides (administration & dosage, metabolism)
• Female
• Fluorescence
• Green Fluorescent Proteins (metabolism)
• Humans
• Matrix Metalloproteinase 2 (chemistry, metabolism)
• Matrix Metalloproteinase 9 (chemistry, metabolism)
• Mice
• Mice, Nude
• Microscopy, Fluorescence
• Neoplasm Metastasis
• Neoplasm Recurrence, Local (prevention & control)
• Optical Imaging (methods)
• Pancreatic Neoplasms (pathology, surgery)
• Surgery, Computer-Assisted
• Tumor Burden