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Novel antiangiogenic therapy targeting biglycan using tumor endothelial cell-specific liposomal siRNA delivery system

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Title: Novel antiangiogenic therapy targeting biglycan using tumor endothelial cell-specific liposomal siRNA delivery system
Authors: Maishi, Nako Browse this author →KAKEN DB
Sakurai, Yu Browse this author →KAKEN DB
Hatakeyama, Hiroto Browse this author →KAKEN DB
Umeyama, Yui Browse this author →KAKEN DB
Nakamura, Takashi Browse this author →KAKEN DB
Endo, Rikito Browse this author
Alam, Mohammad Towfik Browse this author →KAKEN DB
Li, Cong Browse this author
Annan, Dorcas Akuba-Muhyia Browse this author →KAKEN DB
Kikuchi, Hiroshi Browse this author →KAKEN DB
Morimoto, Hirofumi Browse this author
Morimoto, Masahiro Browse this author
Akiyama, Kosuke Browse this author →KAKEN DB
Ohga, Noritaka Browse this author →KAKEN DB
Hida, Yasuhiro Browse this author →KAKEN DB
Harashima, Hideyoshi Browse this author →KAKEN DB
Hida, Kyoko Browse this author →KAKEN DB
Keywords: biglycan
drug delivery system
tumor angiogenesis
tumor endothelial cell
tumor microenvironment
Issue Date: 9-Mar-2022
Publisher: John Wiley & Sons
Journal Title: Cancer science
Publisher DOI: 10.1111/cas.15323
PMID: 35266253
Abstract: Tumor blood vessels play important roles in tumor progression and metastasis. Targeting tumor endothelial cells (TECs) is one of the strategies for cancer therapy. We previously reported that biglycan, a small leucine-rich proteoglycan, is highly expressed in TECs. TECs utilize biglycan in an autocrine manner for migration and angiogenesis. Furthermore, TEC-derived biglycan stimulates tumor cell migration in a paracrine manner leading to tumor cell intravasation and metastasis. In this study, we explored the therapeutic effect of biglycan inhibition in the TECs of renal cell carcinoma using an in vivo siRNA delivery system known as a multifunctional envelope-type nanodevice (MEND), which contains a unique pH-sensitive cationic lipid. To specifically deliver MEND into TECs, we incorporated cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) into MEND because alpha(V)beta(3) integrin, a receptor for cRGD, is selective and highly expressed in TECs. We developed RGD-MEND-encapsulating siRNA against biglycan. First, we confirmed that MEND was delivered into OS-RC-2 tumor-derived TECs and induced in vitro RNAi-mediated gene silencing. MEND was then injected intravenously into OS-RC-2 tumor-bearing mice. Flow cytometry analysis demonstrated that MEND was specifically delivered into TECs. Quantitative RT-PCR indicated that biglycan was knocked down by biglycan siRNA-containing MEND. Finally, we analyzed the therapeutic effect of biglycan silencing by MEND in TECs. Tumor growth was inhibited by biglycan siRNA-containing MEND. Tumor microenvironmental factors such as fibrosis were also normalized using biglycan inhibition in TECs. Biglycan in TECs can be a novel target for cancer treatment.
Type: article
Appears in Collections:歯学院・歯学研究院 (Graduate School of Dental Medicine / Faculty of Dental Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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