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Study for Interaction of Biological Milieu with Nano-drug Carrier system

Research Project

Project/Area Number 20390013
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Physical pharmacy
Research InstitutionThe University of Tokushima

Principal Investigator

KIWADA Hiroshi  The University of Tokushima, 大学院・ヘルスバイオサイエンス研究部, 教授 (50120184)

Co-Investigator(Kenkyū-buntansha) ISHIDA Tatsuhiro  徳島大学, 大学院・ヘルスバイオサイエンス研究部, 准教授 (50325271)
Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2010: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2009: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2008: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
Keywordsナノキャリア / 免疫系 / 抗PEG-IgM / B細胞 / ナノトキシコロジー / DDS / リポソーム / ポリエチレングリコール / 免疫反応
Research Abstract

PEG is considered as non-toxic and non-immunogenic material, and surface modification with it can improve the immunogenicity and pharmacokinetics of nanocarriers. However, we reported that PEGylated liposome (SL), which has been approved for clinical use, loses their long circulating properties when they are administered twice in same animal with certain interval (accelerated blood clearance (ABC) phenomenon). We elucidated that anti-PEG IgM, secreted in response to the first dose of SL, is responsible for the rapid clearance of the second dose via initiation of complement activation. We further elucidated that such anti-PEG IgM production is caused in nude mice (no T-cells), while it was not caused in SCID mice (no B and T cells) and splenectomized mice (no spleen). These suggest that spleen B cells produce the anti-PEG IgM in a T-cell independent manner. It appears that SL activates the immunity in spleen as T-cell independent antigens do. Our studies clearly demonstrate that any PEGylated formulations may display unexpected pharmacokinetic behavior upon repeated injection if such formulation induce anti-PEG IgM production and, as a consequence, may show less therapeutic efficacy or even cause undesirable side-effects. Therefore, a strategy to abrogate the immunogenicity of PEGylated formulations without significant compromising their in vivo performance would be highly desirable for the further development of promising PEGylated formulations.

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (56 results)

All 2011 2010 2009 2008 Other

All Journal Article (24 results) (of which Peer Reviewed: 24 results) Presentation (30 results) Book (1 results) Remarks (1 results)

  • [Journal Article] Anti-PEG IgM response against PEGylated liposomes in mice and rats.2011

    • Author(s)
      Ichihara M., Shimizu T., Imoto A., Hashiguchi Y., Uehara Y., Ishida T, Kiwada H.
    • Journal Title

      Pharmaceutics in press

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Anti-PEG IgM production by siRNA encapsulated in a PEGylated lipid nanocarrier is dependent on the sequence of the siRNA.2011

    • Author(s)
      Tagami T., Uehara Y., Moriyoshi N., Ishida T., Kiwada H.
    • Journal Title

      J.Control.Release in press

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Anti-PEG IgM response against PEGylated liposomes in mice and rats2011

    • Author(s)
      Ichihara M.
    • Journal Title

      Pharmaceutics

      Volume: (in press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Anti-PEG IgM production by siRNA encapsulated in a PEGylated lipid nanocarrier is dependent on the sequence of the siRNA.2011

    • Author(s)
      Tagami T.
    • Journal Title

      J.Control.Release

      Volume: (in press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evasion of the accelerated blood clearance phenomenon by coating of nanoparticles with various hydrophilic polymers.2010

    • Author(s)
      Ishihara T., Maeda T., Sakamoto H., Takasaki N., Shigyo M., Ishida T., Kiwada H., Mizushima Y., Mizushima T.
    • Journal Title

      Biomacromolecules 11

      Pages: 2700-2706

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Optimized PEGylated adenovirus vector reduces the anti-vector humoral immune response against adenovirus and induces a therapeutic effect against metastatic lung cancer.2010

    • Author(s)
      Eto Y., Yoshioka Y., Ishida T., Yao X., Morishige T., Narimatsu S., Mizuguchi H., Mukai Y., Okada N., Kiwada H., Nakagawa S.
    • Journal Title

      Biol.Pharm.Bull. 25

      Pages: 149-154

    • NAID

      130000322353

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes.2010

    • Author(s)
      Koide H., Asai, T., Hatanaka, K., Akai, S., Ishii, T., Kenjo, E., Ishida, T., Kiwada, H., Tsukada, H., Oku, N.
    • Journal Title

      Int.J.Pharm. 392

      Pages: 218-223

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] CpG motifs in pDNA-sequences increase anti-PEG IgM production induced by PEG-coated pDNA-lipoplexes.2010

    • Author(s)
      Tagami, T., Nakamura, K., Shimizu, T., Yamazaki, N., Ishida, T., Kiwada, H.
    • Journal Title

      J.Control.Release 142

      Pages: 160-166

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Evasion of the accelerated blood clearance phenomenon by coating of nanoparticles with various hydrophilic polymers.2010

    • Author(s)
      Ishihara T.
    • Journal Title

      Biomacromolecules

      Volume: 11 Pages: 2700-2706

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Optimized PEGylated adenovirus vector reduces the anti-vector humoral immune response against adenovirus and induces a therapeutic effect against metastatic lung cancer.2010

    • Author(s)
      Eto Y.
    • Journal Title

      Biol.Pharm.Bull.

      Volume: 25 Pages: 149-154

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes.2010

    • Author(s)
      Koide H.
    • Journal Title

      Int.J.Pharm.

      Volume: 392 Pages: 218-223

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CpG motifs in pDNA-sequences increase anti-PEG IgM production induced by PEG-coated pDNA-lipoplexes.2010

    • Author(s)
      Tagami, T.
    • Journal Title

      J.Control.Release

      Volume: 142 Pages: 160-166

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes.2010

    • Author(s)
      Koide H.
    • Journal Title

      Int.J.Pharm. (In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles.2009

    • Author(s)
      Ishihara, T., Takeda, M., Sakamoto, H., Kimoto, A., Kobayashi, C., Takasaki, N., Yuki, K., Tanaka, K., Takenaga, M., Igarashi, R., Maeda, T., Yamakawa, N., Okamoto, Y., Otsuka, M., Ishida, T., Kiwada, H.
    • Journal Title

      Pharm.Res. 26

      Pages: 2270-2279

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles.2009

    • Author(s)
      Mizushima, Y., Mizushima, T.
    • Journal Title

      Pharm.Res. 26

      Pages: 2270-2279

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Effect of siRNA in PEG-coated siRNA-lipoplex on anti-PEG IgM production.2009

    • Author(s)
      Tagami, T., Nakamura, K., Shimizu, T., Ishida, T., Kiwada, H.
    • Journal Title

      J.Control.Release 137

      Pages: 234-240

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] CpG motifs in pDNA-sequences increase anti-PEG IgM production induced by PEG-coated pDNA-lipoplexes.2009

    • Author(s)
      Tagami, T.
    • Journal Title

      J.Control.Release 142

      Pages: 160-166

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles.2009

    • Author(s)
      Ishihara, T.
    • Journal Title

      Pharm.Res. 26

      Pages: 2270-2279

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Particle size-dependent triggering of accelerated blood clearance phenomenon.2008

    • Author(s)
      Koide H., Asai, T., Hatanaka, K., Urakami, T., Ishii, T., Kenjo, E., Nishihara, M., Yokoyama, M., Ishida, T., Kiwada, H., Oku, N.
    • Journal Title

      Int.J.Pharm. 362

      Pages: 197-200

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats.2008

    • Author(s)
      Ishida, T., Kashima, S., Kiwada, H.
    • Journal Title

      J.Control.Release 126

      Pages: 162-165

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes.2008

    • Author(s)
      Ishida, T., Kiwada, H.
    • Journal Title

      Int.J.Pharm. 354

      Pages: 56-62

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Global gene expression profiling in cultured cells is strongly influenced by treatment with siRNA-cationic liposome complexes.2008

    • Author(s)
      Tagami, T., et al.
    • Journal Title

      Pharm. Res. 25

      Pages: 2497-2504

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Particle size-dependent triggering of accelerated blood clearance phenomenon.2008

    • Author(s)
      Koide H., et al.
    • Journal Title

      Int. J. Pharm. 362

      Pages: 197-200

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats.2008

    • Author(s)
      Ishida, T., et al.
    • Journal Title

      J. Control. Release 126

      Pages: 162-165

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation] PEG on nanocarriers induces anti PEG IgM production as a result of activation of immune system.2011

    • Author(s)
      Hashiguchi, Y.
    • Organizer
      Nano in Cancer : Linking chemistry, biology and clinical application in vivo
    • Place of Presentation
      Miami, USA
    • Year and Date
      2011-01-14
    • Related Report
      2010 Annual Research Report
  • [Presentation] PEG on nanocarriers induces anti PEG IgM production as a result of activation of immune system., Nano in Cancer : Linking Chemistry2011

    • Author(s)
      Hashiguchi Y., Shimizu T., Ichihara M., Ishida T., Kiwada H.
    • Organizer
      Biology and Clinical Applications in vivo
    • Place of Presentation
      Miami USA, Jan.
    • Related Report
      2010 Final Research Report
  • [Presentation] 正常マウス脾臓細胞移入SCIDマウスにおけるABC現象の再現2010

    • Author(s)
      井本亜美
    • Organizer
      第49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
      鳥取市
    • Year and Date
      2010-11-07
    • Related Report
      2010 Annual Research Report
  • [Presentation] 抗PEG IgM抗体誘導におけるS-1と1-OHP封入PEG修飾リポソーム併用条件が与える影響の検討2010

    • Author(s)
      長尾愛
    • Organizer
      第49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
      鳥取市
    • Year and Date
      2010-11-07
    • Related Report
      2010 Annual Research Report
  • [Presentation] PEG修飾ナノキャリア生体内投与後に生ずる免疫活性化(ABC現象)機構解明に関する検討2010

    • Author(s)
      市原理子、石田竜弘、際田弘志
    • Organizer
      第19回DDSカンファランス
    • Place of Presentation
      (静岡)
    • Year and Date
      2010-09-04
    • Related Report
      2010 Final Research Report
  • [Presentation] Immunostimulatory properties of liposomes containing PEG.2010

    • Author(s)
      Ishida, T., Kiwada, H.
    • Organizer
      International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      2010-08-06
    • Related Report
      2010 Final Research Report
  • [Presentation] Immunostimulatory properties of liposomes containing PEG2010

    • Author(s)
      Ishida, T.
    • Organizer
      International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      2010-08-06
    • Related Report
      2010 Annual Research Report
  • [Presentation] PEG修飾リポソームに対する抗PEG-IgM分泌における脾臓辺縁帯B細胞の関与について2010

    • Author(s)
      橋口優紀
    • Organizer
      第26回日本DDS学会
    • Place of Presentation
      大阪市
    • Year and Date
      2010-06-18
    • Related Report
      2010 Annual Research Report
  • [Presentation] PEG修飾リポソーム投与により誘導される抗PEG IgM分泌における脾臓の役割に関する検討2010

    • Author(s)
      市原理子
    • Organizer
      第26回日本DDS学会
    • Place of Presentation
      大阪市
    • Year and Date
      2010-06-18
    • Related Report
      2010 Annual Research Report
  • [Presentation] 核酸デリバリーにおけるABC現象、遺伝子・デリバリー研究会2010

    • Author(s)
      石田竜弘、際田弘志
    • Organizer
      第10回シンポジウム
    • Place of Presentation
      (札幌)
    • Year and Date
      2010-06-03
    • Related Report
      2010 Final Research Report
  • [Presentation] 核酸デリバリーにおけるABC現象2010

    • Author(s)
      石田竜弘
    • Organizer
      遺伝子・デリバリー研究会第10回シンポジウム
    • Place of Presentation
      札幌市
    • Year and Date
      2010-06-03
    • Related Report
      2010 Annual Research Report
  • [Presentation] 核酸デリバリーにおける修飾剤種が与えるポリマー特異性IgM分泌への影響2010

    • Author(s)
      上原友美
    • Organizer
      遺伝子・デリバリー研究会第10回シンポジウム
    • Place of Presentation
      札幌市
    • Year and Date
      2010-06-02
    • Related Report
      2010 Annual Research Report
  • [Presentation] PEG修飾リポソーム投与マウス脾臓の抗PEG IgM分泌における役割2010

    • Author(s)
      市原理子
    • Organizer
      日本薬剤学会第25年会
    • Place of Presentation
      徳島市
    • Year and Date
      2010-05-14
    • Related Report
      2010 Annual Research Report
  • [Presentation] ABC現象における抗PEG-IgM分泌とMZ-B細胞の活性化について2010

    • Author(s)
      橋口優紀
    • Organizer
      日本薬学会第130年会
    • Place of Presentation
      岡山市
    • Year and Date
      2010-03-29
    • Related Report
      2009 Annual Research Report
  • [Presentation] Sequential treatment, pre-dose with empty PEGylated liposome (SL) and second dose antigen-encapsulating SL, promotes activation in a primary immune response.2010

    • Author(s)
      Hashiguchi, Y., Shimizu, T., Ishida T., Kiwada H.
    • Organizer
      International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics
    • Place of Presentation
      Vancouver, Canada
    • Related Report
      2010 Final Research Report
  • [Presentation] Spleen cells secret anti-PEG IgM following intravenous injection of PEGylated liposome.2010

    • Author(s)
      Ichihara, M., Imoto, A., Hashiguchi, Y., Uehara, Y., Ishida T., Kiwada H.
    • Organizer
      International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics
    • Place of Presentation
      Vancouver, Canada
    • Related Report
      2010 Final Research Report
  • [Presentation] Elucidation of ABC phenomenon caused by repeat injection of PEGylated nanocarrier.2009

    • Author(s)
      Koide, H., Asai, T., Yokoyama, M., Ishida T., Kiwada H., Oku, N.
    • Organizer
      4th International Liposome Society Conference. Liposome advances : Progress in Drug and Vaccine Delivery
    • Place of Presentation
      London, UK
    • Year and Date
      2009-12-14
    • Related Report
      2010 Final Research Report
  • [Presentation] PEGを用いた核酸送達システムにおいて核酸がanti-PEG IgM分泌に与える影響2009

    • Author(s)
      田上辰秋
    • Organizer
      第18回DDSカンファレンス
    • Place of Presentation
      静岡市
    • Year and Date
      2009-09-12
    • Related Report
      2009 Annual Research Report
  • [Presentation] siRNA封入PEG修飾リポソーム投与時におけるsiRNA配列のanti-PEG IgM分泌に与える影響2009

    • Author(s)
      田上辰秋
    • Organizer
      遺伝子・デリバリー研究会第9回シンポジウム
    • Place of Presentation
      大阪市
    • Year and Date
      2009-07-11
    • Related Report
      2009 Annual Research Report
  • [Presentation] 核酸デリバリーにおけるaccelerated blood clearance (ABC)現象2009

    • Author(s)
      石田竜弘、際田弘志
    • Organizer
      第25回日本DDS学会
    • Place of Presentation
      (東京)
    • Year and Date
      2009-07-03
    • Related Report
      2010 Final Research Report
  • [Presentation] 核酸デリバリーにおける accelerated blood clearance (ABC)現象2009

    • Author(s)
      石田竜弘
    • Organizer
      第25回日本DDS学会
    • Place of Presentation
      東京都
    • Year and Date
      2009-07-03
    • Related Report
      2009 Annual Research Report
  • [Presentation] ポリエチレングリコール(PEG)を利用した核酸送達システムにおいてプラスミドDNA配列内のCpG除去が抗PEG抗体産生に与える影響2009

    • Author(s)
      田上辰秋
    • Organizer
      第25回日本DDS学会
    • Place of Presentation
      東京都
    • Year and Date
      2009-07-03
    • Related Report
      2009 Annual Research Report
  • [Presentation] CpG-free pDNAを使用したPEG修飾リポプレックス投与がABC現象に与える影響2009

    • Author(s)
      田上辰秋
    • Organizer
      日本薬学会第129年会
    • Place of Presentation
      国際会議湯(京都)
    • Year and Date
      2009-03-27
    • Related Report
      2008 Annual Research Report
  • [Presentation] PEG修飾リポソーム投与による脾臓辺縁帯B細胞の活性化2009

    • Author(s)
      清水太郎
    • Organizer
      日本薬学会第129年会
    • Place of Presentation
      国際会議場(京都)
    • Year and Date
      2009-03-27
    • Related Report
      2008 Annual Research Report
  • [Presentation] PEG修飾微粒子キャリアー投与時の免疫反応2008

    • Author(s)
      石田竜弘
    • Organizer
      Frontier's Nanomedicine -Summer Workshop2008-
    • Place of Presentation
      北海道大学大学院薬学研究院(札幌)
    • Year and Date
      2008-08-05
    • Related Report
      2008 Annual Research Report
  • [Presentation] Unexpected immunological response against sterically stabilized, PEGylated, liposome after intravenous injection.2008

    • Author(s)
      Ishida, T.
    • Organizer
      International Symposium on“Nanotoxicology Assessment and Biomedical, Environmental Application of Fine Particles and Nanotubes"(ISNT2008)
    • Place of Presentation
      Sapporo
    • Year and Date
      2008-06-17
    • Related Report
      2008 Annual Research Report
  • [Presentation] Interaction of PEGylated liposomes with splenic marginal zone B cells may trigger production of anti-PEG IgM in the ABC phenomenon.2008

    • Author(s)
      Shimizu, T., Ishida T., Kiwada H.
    • Organizer
      11^<th> Liposome Research Days conference
    • Place of Presentation
      Yokohama (Japan)
    • Related Report
      2010 Final Research Report
  • [Presentation] Effect of siRNA on anti-PEG IgM production in the accelerated blood clearance (ABC) phenomenon when formulated with PEGylated cationic liposome.2008

    • Author(s)
      Tagami, T., Nakamura, K., Shimizu, T., Ishida T., Kiwada H.
    • Organizer
      11^<th> Liposome Research Days conference
    • Place of Presentation
      Yokohama (Japan)
    • Related Report
      2010 Final Research Report
  • [Presentation] Unexpected immunological response against sterically stabilized, PEGylated, liposome after intravenous injection.2008

    • Author(s)
      石田竜弘, 際田弘志
    • Organizer
      International Symposium on "Nanotoxicology Assessment and Biomedical, Environmental Application of Fine Particles and Nanotubes" ISNT2008
    • Place of Presentation
      Sapporo, Japan
    • Related Report
      2010 Final Research Report
  • [Presentation] Accelerated blood clearance (ABC) phenomenon on PEGylated nanocarrier : Unexpected immune-reaction against PEGylated liposome.2008

    • Author(s)
      Shimizu, T., Ishida T., Kiwada H.
    • Organizer
      International Symposium on "Nanotoxicology Assessment and Biomedical, Environmental Application of Fine Particles and Nanotubes" (ISNT2008)
    • Place of Presentation
      Sapporo, Japan
    • Related Report
      2010 Final Research Report
  • [Book] Unexpected reactions by in vivo application of PEGylated liposomes. "(Safety of Nanoparticles : From Manufacturing to Clinical Applications (A volume in the Nanostructure Science and Technology series))(T.J.Webster (Ed.)), Chapter 6, p111-1302009

    • Author(s)
      Ishida, T., Kiwada, H.
    • Publisher
      Springer Science + Business Media, New York, USA
    • Related Report
      2010 Final Research Report
  • [Remarks] ホームページ等

    • URL

      http://www.ph.tokushima-u.ac.jp/article/0015027.html

    • Related Report
      2010 Final Research Report

URL: 

Published: 2008-04-01   Modified: 2016-04-21  

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