Anti-PEG Immunity upon nucleic acid delivery

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390012
• 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 徳島大学, ヘルスバイオサイエンス研究部, 非常勤講師 (50120184)
• Co-Investigator(Kenkyū-buntansha): ISHIDA Tatsuhiro 徳島大学, 大学院・へルスバイオサイエンス研究部, 教授 (50325271)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: ＤＤＳ / ＰＥＧ / リポソーム / ABC現象 / Anti-PEG IgM / 免疫活性化

Research Abstract

For in vivo use of pDNA and siRNA, surface modification of the liposome with PEG is frequently applied to achieve gene-expression or suppression in the targeted tissue. However, PEG-coated liposomes induce anti-PEG IgM immunity. Here, we investigated how a Toll-like receptor (TLR) might enhance anti-PEG IgM production. Attenuated anti-PEG IgM production for pDNA-PEG liposome was observed in TLR9 KO mice, the attenuated IgM production for siRNA-PEG liposome was in TLR7 KO mice. In addition, the modification of pDNA-PEG liposome with PG attenuated the production of anti-polymer IgM. In vivo experiment, a second dose of pDNA-PG liposome restored the accumulation level in the tumor tissue, comparable to that of the first dose, whereas the tumor accumulation level of a second dose of pDNA-PEG liposome was significantly compromised. These results may have important implications for the design and development of an efficient PEG-coated non-viral nucleic acid delivery nanocarrier system.

Research Products

• [Journal Article] B cell-intrinsic toll-like receptor 7 is responsible for the enhanced anti-PEG IgM production following injection of siRNA-containing PEGylated lipoplex in mice (2014)
  • Author(s): Hashimoto, Y., Abu Lila A., Shimizu, T., Ishida, T., Kiwada, H
  • Journal Title: J. Control. Release Volume: 184C Pages: 1-8
  • DOI: 10.1016/j.jconrel.2014.04.003
  • Peer Reviewed
• [Journal Article] Generation, characterization and in vivo biological activity of two distinct monoclonal anti-PEG IgMs (2014)
  • Author(s): Hashimoto Y., Shimizu T., Mima Y., Abu Lila A., Ishida T., Kiwada H
  • Journal Title: Toxicol. Appl. Pharmacol Volume: 277 Pages: 30-38
  • DOI: 10.1016/j.taap.2014.03.002
  • Peer Reviewed
• [Journal Article] Application of polyglycerol-coating to pDNA lipoplex for the evasion of the accelerated blood clearance (ABC) phenomenon in nucleic acid delivery (2014)
  • Author(s): Abu Lila, A.S., Uehara, Y., Ishida, T., Kiwada, H
  • Journal Title: J. Pharm. Sci Volume: 103 Pages: 557-566
  • DOI: 10.1002/jps.23823
  • Peer Reviewed
• [Journal Article] Abrogation of the accelerated blood clearance phenomenon by SOXL regimen : Promise for clinical application (2013)
  • Author(s): Nagao, A., Abu Lila, A.S., Ishida, T, Kiwada, H
  • Journal Title: Int. J. Pharm Volume: 441 Pages: 395-401
  • DOI: 10.1016/j.ijpharm.2012.11.015.11
• [Journal Article] The co-delivery of oxaliplatin abrogates the immunogenic response to PEGylated siRNA-lipoplex (2013)
  • Author(s): Alaaeldin, E.,, Abu Lila, A.S., Moriyoshi, N., Sarahan, H.A., Ishida, T., Khaled A. Khale, Kiwada, H
  • Journal Title: Pharm. Res Volume: 30 Pages: 2344-2354
  • DOI: 10.1007/s11095-013-1078-4
  • Peer Reviewed
• [Journal Article] Accelerated blood clearance of PEGylated liposomes containing doxorubicin upon repeated administration to dogs (2012)
  • Author(s): Suzuki, T., Ichihara, M., Hyodo, K., Yamamoto, E., Ishida, T., Kiwada, H., Ishihara, H., Kikuchi, H
  • Journal Title: Int. J. Pharm Volume: 436 Pages: 636-643
  • DOI: 10.1016/j.ijpharm.2012.07.049
  • 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 Volume: 151 Pages: 149-154
  • DOI: 10.1016/j.jconrel.2010.12.013
  • Peer Reviewed
• [Presentation] 抗がん剤による腫瘍内微小環境変化を利用した新規DDSの開発 (2013)
  • Author(s): 石田竜弘, 際田弘志
  • Organizer: 第29回日本DDS学会学術集会
  • Place of Presentation: 京都テルサ(京都府京都市)
  • Year and Date: 2013-07-04
• [Presentation] PEG 修飾ナノキャリア投与時に惹起される免疫応答~抗PEG-IgM 分泌誘導とナノキャリアの体内動態への影響~ (2011)
  • Author(s): 石田竜弘
  • Organizer: 広島臓器移植セミナー
  • Place of Presentation: 広島大学医学部(広島県広島市)
  • Year and Date: 2011-08-10
• [Presentation] 腫瘍内微小環境変化を利用した核酸デリバリー戦略 (2011)
  • Author(s): 石田竜弘
  • Organizer: 遺伝子・デリバリー研究会第11回夏期セミナー
  • Place of Presentation: 三翠園ホテル(高知県高知市)
  • Year and Date: 2011-08-09
• [Presentation] Biological responses against lipid membrane containing PEG (2011)
  • Author(s): Ishida, T., Kiwada, H
  • Organizer: 3rd International Symposium on Surface and Interface of Biomaterials (SIB2011)
  • Place of Presentation: 北海道大学学術交流会館(北海道札幌市)
  • Year and Date: 2011-07-14