Study of immunological response to nucleic acid delivery system

• Project/Area Number: 15H04639
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: The University of Tokushima
• Principal Investigator: ISHIDA Tatsuhiro 徳島大学, 大学院医歯薬学研究部(薬学系), 教授 (50325271)
• Co-Investigator(Kenkyū-buntansha): 南川 典昭 徳島大学, 大学院医歯薬学研究部(薬学系), 教授 (40209820) ; 異島 優 徳島大学, 大学院医歯薬学研究部(薬学系), 准教授 (00457590) ; 清水 太郎 徳島大学, 大学院医歯薬学研究部(薬学系), 特任助教 (30749388) ; 安藤 英紀 徳島大学, 大学院医歯薬学研究部(薬学系), 特任助教 (00735524) ; 鵜川 真実 徳島大学, 大学院医歯薬学研究部(薬学系), 特任助教 (50735511)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2015: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: 核酸 / 免疫 / Anti-PEG IgM / リポソーム / DDS / 核酸デリバリー / 自然免疫活性化

Outline of Final Research Achievements

In this study, we reported that immunostimulatory siRNA/pDAN-containing PEGylated lipoplex (PEGylated siRNAlipoplex) activates the immune system, resulting in the enhanced production of anti-PEG IgM. We revealed the contribution of toll-like receptor 7/9 to activate the innate immune system, respectively. A strategy to evade B cell-intrinsic TLR7/9 activation by siRNA/pDNA, such as chemical modification, may overcome immunological barriers to PEGylated liposome-based nucleic acid therapeutics. In addition, we showed PEG in the cosmetics may trigger anti-PEG IgM production in human. Our study gives the researchers valuable information which is useful to develop PEGylated nucleic acid based therapeutics.

Research Products

• [Int'l Joint Research] Zagazig University(エジプト)
• [Int'l Joint Research] Hail University(サウジアラビア)
• [Int'l Joint Research] University of British Columbia(カナダ)
• [Int'l Joint Research] Semmelweis University(ハンガリー)
• [Journal Article] Reactivity of IgM antibodies elicited by PEGylated liposomes or PEGylated lipoplexes against auto and foreign antigens. (2018)
  • Author(s): 8.Ando, H., Abu Lila, A.S., Kawanishi, M., Shimizu, T., Okuhira, K., Ishima, Y., Ishida, T.
  • Journal Title: J. Control Release Volume: 270 Pages: 114-119
  • DOI: 10.1016/j.jconrel.2017.12.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intratumoral visualization of oxaliplatin within a liposomal formulation using X-ray fluorescence spectrometry. (2018)
  • Author(s): 5.Ando, H., Abu Lila, A.S., Tanaka, M., Doi, Y., Terada, Y., Yagi, N., Shimizu, T., Okuhira, K., Ishima, Y., Ishida, T.,
  • Journal Title: Mol Pharm. Volume: 15 Issue: 2 Pages: 403-409
  • DOI: 10.1021/acs.molpharmaceut.7b00762
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Metronomic S-1 dosing and thymidylate synthase silencing have synergistic antitumor efficacy in a colorectal cancer xenograft model. (2017)
  • Author(s): 17.Abu Lila, A.S., Moriyoshi, N., Fukushima, M., Huang, C., Wada, H., Ishida, T.
  • Journal Title: Cancer Letters Volume: 400 Pages: 223-231
  • DOI: 10.1016/j.canlet.2016.11.005
  • NAID: 120006894605
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ganglioside inserted into PEGylated liposome attenuates anti-PEG immunity. (2017)
  • Author(s): Mima, Y., Abu Lila, A.S., Shimizu, T., Ukawa, M., Ando, H., Kurata, Y., Ishida, T.
  • Journal Title: J. Control. Release Volume: 250 Pages: 20-26
  • DOI: 10.1016/j.jconrel.2017.01.040
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Co-administration of liposomal l-OHP and PEGylated TS shRNA-lipoplex: A novel approach to enhance anti-tumor efficacy and reduce the immunogenic response to RNAi molecules. (2017)
  • Author(s): 12.Alaaeldin, E., Abu Lila, A.S., Ando, H., Fukushima, M., Huang, C., Wada, H., Sarhan, H.A., Khaled, K.A., Ishida, T.
  • Journal Title: J. Control Release Volume: 255 Pages: 210-217
  • DOI: 10.1016/j.jconrel.2017.04.040
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Modulation of antitumor immunity contributes to the enhanced therapeutic efficacy of liposomal oxaliplatin in mouse model. (2017)
  • Author(s): 11.Shimizu, T., Abu Lila, A.S., Nishio, M., Doi, Y., Ando, H., Ukawa, M., Ishima, Y., Ishida, T.
  • Journal Title: Cancer Sci. Volume: 108 Issue: 9 Pages: 1864-1869
  • DOI: 10.1111/cas.13305
  • NAID: 120006535002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model. (2016)
  • Author(s): Abu Lila, A.S., Kato, C., Fukushima, M., Huang, C., Wada, H., Ishida, T.
  • Journal Title: Int. J. Oncol. Volume: 48 Issue: 4 Pages: 1399-1407
  • DOI: 10.3892/ijo.2016.3367
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] PEG修飾リポソームに対する免疫反応（ABC現象）の解明とワクチンへの応用 (2018)
  • Author(s): 石田竜弘
  • Organizer: 日本薬学会北海道支部・特別講演会
  • Invited
• [Presentation] Immunological response to PEGylated nanoparticles: Anti-PEG antibody issues. (2017)
  • Author(s): Ishida, T.
  • Organizer: ILS Liposome Advances and Liposome Research Days Combined Conference.
  • Int'l Joint Research / Invited
• [Presentation] 補体活性化能を持つポリマー修飾リポソームによる脾臓辺縁帯B細胞標的化に関する検討 (2017)
  • Author(s): 清水太郎、粟田瑞月、吉岡千尋、異島優、石田竜弘
  • Organizer: 日本薬剤学会第32年会
• [Presentation] ポリエチレングリコール修飾タンパク製剤Pegasysに対する抗PEG IgM応答 (2016)
  • Author(s): 本藤栄里、美馬優、清水太郎、石田竜弘
  • Organizer: 日本薬学会第１３６年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-27
• [Presentation] リポソーム化抗がん剤投与が引き起こす腫瘍免疫細胞の影響 (2016)
  • Author(s): 高山拓磨、清水太郎、鵜川真実、石田竜弘
  • Organizer: 日本薬剤学会第31年会
  • Place of Presentation: 長良川国際会議場・岐阜都ホテル（岐阜県・岐阜市）
• [Presentation] ヒトにおける抗PEG抗体保有率の調査 (2016)
  • Author(s): 清水太郎、久保幸代、石田竜弘
  • Organizer: 日本薬剤学会第31年会
  • Place of Presentation: 長良川国際会議場・岐阜都ホテル（岐阜県・岐阜市）
• [Presentation] Anti-PEG immunity against PEGylated materials. (2016)
  • Author(s): Ishida, T.
  • Organizer: International Workshop for Immune Effects of Nanomedicines: Clinical and Experimental Evidence, Prediction and Prevention.
  • Place of Presentation: Budapest, Hungary
  • Int'l Joint Research / Invited
• [Presentation] Development of a RNAi-based anticancer drug. (2016)
  • Author(s): Ishida, T.
  • Organizer: 12th France-Japan Drug Delivery Systems Symposium
  • Place of Presentation: Paris, France
  • Int'l Joint Research / Invited
• [Presentation] PEG化製剤に対するanti-PEG IgM結合特性に関する検討 (2015)
  • Author(s): 久保幸代、本藤栄里、阿部遼、美馬優、清水太郎、石田竜弘
  • Organizer: 第５４回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
  • Place of Presentation: 高知テルサ（高知県高知市）
  • Year and Date: 2015-10-31
• [Presentation] オキサリプラチン封入PEG修飾リポソーム製剤投与ラットの後肢皮膚組織における手足症候群様症状の評価 (2015)
  • Author(s): 西田健太朗、柏木美咲、室木究、柴俊輔、池田理沙、石田竜弘、長澤一樹
  • Organizer: 第５３回日本癌治療学会学術集会
  • Place of Presentation: 京都国際会館（京都府京都市）
  • Year and Date: 2015-10-29
• [Presentation] 胃がん腹膜播種モデルにおけるオキサリプラチン封入リポソーム静脈内投与による腫瘍増殖抑制効果 (2015)
  • Author(s): 渡邉奈美、安藤英紀、石田竜弘
  • Organizer: 第３１回日本DDS学会学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2015-07-03
• [Presentation] PEG修飾タンパク質Pegasys®投与によるABC現象誘導 (2015)
  • Author(s): 本藤栄里、美馬優、際田弘志、石田竜弘
  • Organizer: 日本薬剤学会第３０年会
  • Place of Presentation: 長崎ブリックホール（長崎県長崎市）
  • Year and Date: 2015-05-21
• [Presentation] IV 投与PEGリポソームに対するanti-PEG IgM応答への腹腔内免疫細胞の関与 (2015)
  • Author(s): 阿部遼、清水太郎、石田竜弘
  • Organizer: 日本薬剤学会第３０年会
  • Place of Presentation: 長崎ブリックホール（長崎県長崎市）
  • Year and Date: 2015-05-21