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

Julius Chapiro, Surojit Sur, Lynn Jeanette Savic, Shanmugasundaram Ganapathy-Kanniappan, Juvenal Reyes, Rafael Duran, Sivarajan Chettiar Thiruganasambandam, Cassandra Rae Moats, Ming De Lin, Weibo Luo, Phuoc T. Tran, Joseph M. Herman, Gregg L. Semenza, Andrew J. Ewald, Bert Vogelstein, Jean François Geschwind

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

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.

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.

Original languageEnglish (US)
Pages (from-to)6406-6417
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number24
DOIs
StatePublished - Dec 15 2014

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Pancreatic Neoplasms
gemcitabine
Therapeutics
Adenocarcinoma
Heterografts
Inhibitory Concentration 50
bromopyruvate
Phase-Contrast Microscopy
Cell Line
Neoplasms
Drug Compounding
Cyclodextrins
Pharmaceutical Preparations
Research Design
Magnetic Resonance Spectroscopy
Cell Culture Techniques
Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Chapiro, J., Sur, S., Savic, L. J., Ganapathy-Kanniappan, S., Reyes, J., Duran, R., ... Geschwind, J. F. (2014). Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer. Clinical Cancer Research, 20(24), 6406-6417. https://doi.org/10.1158/1078-0432.CCR-14-1271

Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer. / Chapiro, Julius; Sur, Surojit; Savic, Lynn Jeanette; Ganapathy-Kanniappan, Shanmugasundaram; Reyes, Juvenal; Duran, Rafael; Thiruganasambandam, Sivarajan Chettiar; Moats, Cassandra Rae; Lin, Ming De; Luo, Weibo; Tran, Phuoc T.; Herman, Joseph M.; Semenza, Gregg L.; Ewald, Andrew J.; Vogelstein, Bert; Geschwind, Jean François.

In: Clinical Cancer Research, Vol. 20, No. 24, 15.12.2014, p. 6406-6417.

Research output: Contribution to journalArticle

Chapiro, J, Sur, S, Savic, LJ, Ganapathy-Kanniappan, S, Reyes, J, Duran, R, Thiruganasambandam, SC, Moats, CR, Lin, MD, Luo, W, Tran, PT, Herman, JM, Semenza, GL, Ewald, AJ, Vogelstein, B & Geschwind, JF 2014, 'Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer', Clinical Cancer Research, vol. 20, no. 24, pp. 6406-6417. https://doi.org/10.1158/1078-0432.CCR-14-1271
Chapiro J, Sur S, Savic LJ, Ganapathy-Kanniappan S, Reyes J, Duran R et al. Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer. Clinical Cancer Research. 2014 Dec 15;20(24):6406-6417. https://doi.org/10.1158/1078-0432.CCR-14-1271
Chapiro, Julius ; Sur, Surojit ; Savic, Lynn Jeanette ; Ganapathy-Kanniappan, Shanmugasundaram ; Reyes, Juvenal ; Duran, Rafael ; Thiruganasambandam, Sivarajan Chettiar ; Moats, Cassandra Rae ; Lin, Ming De ; Luo, Weibo ; Tran, Phuoc T. ; Herman, Joseph M. ; Semenza, Gregg L. ; Ewald, Andrew J. ; Vogelstein, Bert ; Geschwind, Jean François. / Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 24. pp. 6406-6417.
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abstract = "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.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.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.",
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AU - Chapiro, Julius

AU - Sur, Surojit

AU - Savic, Lynn Jeanette

AU - Ganapathy-Kanniappan, Shanmugasundaram

AU - Reyes, Juvenal

AU - Duran, Rafael

AU - Thiruganasambandam, Sivarajan Chettiar

AU - Moats, Cassandra Rae

AU - Lin, Ming De

AU - Luo, Weibo

AU - Tran, Phuoc T.

AU - Herman, Joseph M.

AU - Semenza, Gregg L.

AU - Ewald, Andrew J.

AU - Vogelstein, Bert

AU - Geschwind, Jean François

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Y1 - 2014/12/15

N2 - 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.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.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.

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