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

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.

• Authors: Julius Chapiro, Surojit Sur, Lynn Jeanette Savic, Shanmugasundaram Ganapathy-Kanniappan, Juvenal Reyes, Rafael Duran, Sivarajan Chettiar Thiruganasambandam, Cassandra Rae Moats, MingDe Lin, Weibo Luo, Phuoc T Tran, Joseph M Herman, Gregg L Semenza, Andrew J Ewald, Bert Vogelstein, Jean-François Geschwind
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 24 Pg. 6406-17 (Dec 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 25326230 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Pyruvates
• beta-Cyclodextrins
• bromopyruvate
• betadex

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Compounding
• Humans
• Male
• Mice
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Pyruvates (administration & dosage, chemistry)
• Spheroids, Cellular
• Tumor Burden (drug effects)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• beta-Cyclodextrins (chemistry)