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

Détails

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_E756F5BCDE47
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer.
Périodique
Clinical Cancer Research
Auteur(s)
Chapiro J., Sur S., Savic L.J., Ganapathy-Kanniappan S., Reyes J., Duran R., Thiruganasambandam S.C., Moats C.R., Lin M., Luo W., Tran P.T., Herman J.M., Semenza G.L., Ewald A.J., Vogelstein B., Geschwind J.F.
ISSN
1078-0432 (Print)
ISSN-L
1078-0432
Statut éditorial
Publié
Date de publication
2014
Peer-reviewed
Oui
Volume
20
Numéro
24
Pages
6406-6417
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Résumé
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.
Mots-clé
Animals, Antineoplastic Agents/administration & dosage, Antineoplastic Agents/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, Pancreatic Neoplasms/metabolism, Pyruvates/administration & dosage, Pyruvates/chemistry, Spheroids, Cellular, Tumor Burden/drug effects, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, beta-Cyclodextrins/chemistry
Pubmed
Open Access
Oui
Création de la notice
03/09/2015 10:05
Dernière modification de la notice
20/08/2019 16:10
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