Systemic Delivery of Microencapsulated 3-Bromopyruvate for the Therapy of Pancreatic Cancer

被引：53

作者：

Chapiro, Julius ^{[1
]}

Sur, Surojit ^{[2
,3
]}

Savic, Lynn Jeanette ^{[1
,4
]}

Ganapathy-Kanniappan, Shanmugasundaram ^{[1
]}

Reyes, Juvenal ^{[5
]}

Duran, Rafael ^{[1
]}

Thiruganasambandam, Sivarajan Chettiar ^{[5
]}

Moats, Cassandra Rae ^{[6
]}

Lin, MingDe ^{[1
]}

Luo, Weibo ^{[7
,8
]}

Tran, Phuoc T. ^{[5
]}

Herman, Joseph M. ^{[5
]}

Semenza, Gregg L. ^{[7
,8
]}

Ewald, Andrew J. ^{[9
]}

Vogelstein, Bert ^{[2
,3
]}

Geschwind, Jean-Francois ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Div Vasc & Intervent Radiol, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA

[2] Johns Hopkins Kimmel Canc Ctr, Ludwig Ctr, Baltimore, MD USA

[3] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD USA

[4] Charite, Dept Diagnost & Intervent Radiol, D-13353 Berlin, Germany

[5] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD 21287 USA

[6] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21287 USA

[7] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Vasc Program, Baltimore, MD 21287 USA

[8] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21287 USA

[9] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21287 USA

来源：

CLINICAL CANCER RESEARCH | 2014年 / 20卷 / 24期

关键词：

TUMOR-STROMA INTERACTIONS; MATRIX METALLOPROTEINASES; HSP90; INHIBITOR; GLYCOLYSIS; CARCINOMA; CELLS; GEMCITABINE; EXPRESSION; INVASION; MODEL;

D O I：

10.1158/1078-0432.CCR-14-1271

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Purpose: This study characterized the therapeutic efficacy of a systemically administered formulation of 3-bromopyruvate (3-BrPA), microencapsulated in a complex with beta-cyclodextrin (beta-CD), using an orthotopic xenograft mouse model of pancreatic ductal adenocarcinoma (PDAC). Experimental Design: The presence of the beta-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 beta-CD-3-BrPA, free 3-BrPA, beta-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: beta-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 beta-CD-3-BrPA demonstrated minimal or no tumor progression as evident by the BLI signal as opposed to animals treated with gemcitabine or the beta-CD (60-fold and 140-fold signal increase, respectively). In contrast to animals treated with free 3-BrPA, no lethal toxicity was observed for beta-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 beta-CD-3-BrPA combined with its favorable toxicity profile suggest that clinical trials, particularly in patients with PDAC, should be considered. (C)2014 AACR.

引用

页码：6406 / 6417

页数：12

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