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A new adjuvant delivery system 'cyclic di-GMP/YSK05 liposome' for cancer immunotherapy

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Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/57443

Title: A new adjuvant delivery system 'cyclic di-GMP/YSK05 liposome' for cancer immunotherapy
Authors: Miyabe, Hiroko Browse this author
Hyodo, Mamoru Browse this author →KAKEN DB
Nakamura, Takashi Browse this author
Sato, Yusuke Browse this author
Hayakawa, Yoshihiro Browse this author →KAKEN DB
Harashima, Hideyoshi Browse this author →KAKEN DB
Keywords: C-di-GMP
Liposome
Adjuvant
Anti-tumor activity
Issue Date: 28-Jun-2014
Publisher: Elsevier
Journal Title: Journal of Controlled Release
Volume: 184
Start Page: 20
End Page: 27
Publisher DOI: 10.1016/j.jconrel.2014.04.004
PMID: 24727060
Abstract: Cyclic dinucleotides are of importance in the field of microbiology and immunology. They function as second messengers and are thought to participate in the signal transduction of cytosolic DNA immune responses. One such dinucleotide, cyclic di-GMP (c-di-GMP), stimulates the immune system. It is thought that c-di-GMP is recognized by ATP dependent RNA helicase (DDX41) in the cytosol, forms a complex with the Stimulator of interferon genes protein (STING), triggers a signal via the tank binding kinase 1-interferon regulatory factor 3 (TBK1-IRF3) pathway and induces the production of type I interferons. Therefore c-di-GMP can be thought of as a new class of adjuvant. However, because c-di-GMP contains two phosphate groups, this prevents its use as an adjuvant because it cannot pass through the cell membrane, even though the target molecule of c-di-GMP is located in the cytoplasm. Our group has been developing a series of liposomal drug delivery systems and recently investigated YSK05 which is a synthetic, pH sensitive lipid that has a high fusogenicity. We utilized this lipid as a carrier to transport c-di-GMP into the cytosol to then use c-di-GMP as an adjuvant. Based on screening experiments, YSK05/POPE/cholesterol = 40/25/35 was found to induce IFN-beta in Raw264.7 cells. The induction of IFN-beta from c-di-GMP liposomes was inhibited by adding BX795, a TBK1 inhibitor, indicating that the production of IFN-beta caused the activation of the STING-TBK1 pathway. C-di-GMP liposomes also showed significantly higher levels of expression of CD80, CD86 and MHC class I. The c-di-GMP/YSK05 liposome facilitated antigen specific cytotoxic T cell activity and the inhibition of tumor growth in a mouse model. These findings indicate that c-di-GMP/YSK05 liposomes could be used, not only to transfer c-di-GMP to the cytosol and induce an innate immune system but also as a platform for investigating the mechanism of immune sensing with cyclic dinucleotides in vitro and in vivo. (C) 2014 Elsevier B.V. All rights reserved.
Type: article (author version)
URI: http://hdl.handle.net/2115/57443
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 中村 孝司

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