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Clin Cancer Res. 2014 Dec 15;20(24):6406-17. doi: 10.1158/1078-0432.CCR-14-1271. Epub 2014 Oct 17.

Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer.

Author information

1
Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
2
Ludwig Center and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland.
3
Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Diagnostic and Interventional Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
4
Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
5
Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
6
Vascular Program, Institute for Cell Engineering and Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
7
Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
8
Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. jfg@jhmi.edu.

Abstract

PURPOSE:

This study characterized the therapeutic efficacy of a systemically administered formulation of 3-bromopyruvate (3-BrPA), microencapsulated in a complex with β-cyclodextrin (β-CD), using an orthotopic xenograft mouse model of pancreatic ductal adenocarcinoma (PDAC).

EXPERIMENTAL DESIGN:

The presence of the β-CD-3-BrPA complex was confirmed using nuclear magnetic resonance spectroscopy. Monolayer as well as three-dimensional organotypic cell culture was used to determine the half-maximal inhibitory concentrations (IC50) of β-CD-3-BrPA, free 3-BrPA, β-CD (control), and gemcitabine in MiaPaCa-2 and Suit-2 cell lines, both in normoxia and hypoxia. Phase-contrast microscopy, bioluminescence imaging (BLI), as well as zymography and Matrigel assays were used to characterize the effects of the drug in vitro. An orthotopic lucMiaPaCa-2 xenograft tumor model was used to investigate the in vivo efficacy.

RESULTS:

β-CD-3-BrPA and free 3-BrPA demonstrated an almost identical IC50 profile in both PDAC cell lines with higher sensitivity in hypoxia. Using the Matrigel invasion assay as well as zymography, 3-BrPA showed anti-invasive effects in sublethal drug concentrations. In vivo, animals treated with β-CD-3-BrPA demonstrated minimal or no tumor progression as evident by the BLI signal as opposed to animals treated with gemcitabine or the β-CD (60-fold and 140-fold signal increase, respectively). In contrast to animals treated with free 3-BrPA, no lethal toxicity was observed for β-CD-3-BrPA.

CONCLUSION:

The microencapsulation of 3-BrPA represents a promising step towards achieving the goal of systemically deliverable antiglycolytic tumor therapy. The strong anticancer effects of β-CD-3-BrPA combined with its favorable toxicity profile suggest that clinical trials, particularly in patients with PDAC, should be considered.

PMID:
25326230
PMCID:
PMC4300523
DOI:
10.1158/1078-0432.CCR-14-1271
[Indexed for MEDLINE]
Free PMC Article
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