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ID 59944
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Author
Sakai, Satoshi Graduate School of Medicine, The University of Tokyo
Iwata, Caname Graduate School of Medicine, The University of Tokyo
Tanaka, Hiroyoshi Y. Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Cabral, Horacio Graduate School of Engineering, The University of Tokyo
Morishita, Yasuyuki Graduate School of Medicine, The University of Tokyo
Miyazon, Kohei Graduate School of Medicine, The University of Tokyo
Kano, Mitsunobu R. Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University ORCID Kaken ID researchmap
Abstract
Pancreatic cancer is notorious for its poor prognosis. The histopathologic characteristic of pancreatic ductal adenocarcinoma (PDAC), which is the most common type of pancreatic cancer, is fibrosis within tumor tissue. Although fibrosis within tumor tissue is thought to impede drug therapy by interfering with the intratumoral accumulation of anti-tumor drugs, this hypothesis has yet to be proven directly in preclinical models. Here, we evaluated the effect of enhanced fibrosis on intratumoral accumulation of macromolecular drugs by increasing fibrosis in a murine tumor model of subcutaneously xenografted BxPC-3, a human PDAC cell line. When fibroblast growth factor-2 (FGF-2) was co-administered upon BxPC-3 inoculation, stromal fibrotic area was increased and was characterized by augmented murine collagen accumulation compared to inoculation of BxPC-3 alone, which correlated with increased monocyte/macrophage contents in the tumor tissues. We further discovered that the intratumoral accumulation of intravenously administrated fluorescein isothiocyanate-dextran of 2,000,000 Da (2 MDa) was significantly reduced in the FGF-2 co-administered tumors despite unaltered hyaluronan accumulation and pericyte coverage of the tumor neovasculature and increased lymphangiogenesis. Finally, we found that FGF-2 co-administered tumors are more refractory to macromolecular drug therapy using nab-paclitaxel (Abraxane). The model established and analyzed in this study, characterized by increased fibrotic component, provides a preclinical animal model suited to predict the intratumoral accumulation of macromolecular drugs and to evaluate the efficacy of drugs targeting the tumor stroma.
Keywords
Macromolecular drugs
Drug distribution
Pancreatic ductal adenocarcinoma
Fibrosis
FGF-2
Published Date
2016-05-28
Publication Title
Journal of Controlled Release
Volume
volume230
Publisher
Elsevier
Start Page
109
End Page
115
ISSN
0168-3659
NCID
AA10458678
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
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author
PubMed ID
DOI
Web of Science KeyUT
Related Url
isVersionOf https://doi.org/10.1016/j.jconrel.2016.04.007
License
https://creativecommons.org/licenses/by-nc-nd/4.0/
Funder Name
Ministry of Education, Culture, Sports, Science and Technology
助成番号
23790433
26293119