2010 Fiscal Year Final Research Report
Study for Interaction of Biological Milieu with Nano-drug Carrier system
| Project/Area Number |
20390013
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | The University of Tokushima |
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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)
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| 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)
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| Project Period (FY) |
2008 – 2010
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| 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 |
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| 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.
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[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.
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Journal Title
Biol.Pharm.Bull. 25
Pages: 149-154
Peer Reviewed
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[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.
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Journal Title
Int.J.Pharm. 392
Pages: 218-223
Peer Reviewed
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[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.
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Journal Title
J.Control.Release 142
Pages: 160-166
Peer Reviewed
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[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.
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Journal Title
Pharm.Res. 26
Pages: 2270-2279
Peer Reviewed
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[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.
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Journal Title
Int.J.Pharm. 362
Pages: 197-200
Peer Reviewed
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[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
Year and Date
20100805-20100807
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[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
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