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

• Project/Area Number: 20390013
• 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: 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: ¥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.

Research Products

• [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
  • 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
  • Peer Reviewed
• [Journal Article] Anti-PEG IgM response against PEGylated liposomes in mice and rats (2011)
  • Author(s): Ichihara M.
  • Journal Title: Pharmaceutics Volume: (in press)
  • 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)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
• [Presentation] PEG on nanocarriers induces anti PEG IgM production as a result of activation of immune system., Nano in Cancer : Linking Chemistry (2011)
  • 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.
• [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
• [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
• [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
• [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
• [Presentation] Immunostimulatory properties of liposomes containing PEG (2010)
  • Author(s): Ishida, T.
  • Organizer: International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2010-08-06
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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)
• [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)
• [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
• [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
• [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, p111-130 (2009)
  • Author(s): Ishida, T., Kiwada, H.
  • Publisher: Springer Science + Business Media, New York, USA
• [Remarks] ホームページ等
  • URL: http://www.ph.tokushima-u.ac.jp/article/0015027.html