Improvement of tumor-targeting therapy with nanocarrier system by changing the tumor microenvironment.

• Project/Area Number: 24390010
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: The University of Tokushima
• Principal Investigator: ISHIDA Tatsuhiro 徳島大学, ヘルスバイオサイエンス研究部, 教授 (50325271)
• Co-Investigator(Kenkyū-buntansha): 際田 弘志 徳島大学, ヘルスバイオサイエンス研究部, 非常勤講師 (50120184)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2012: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: ドラッグデリバリー / リポソーム / がん治療 / がん微小環境

Outline of Final Research Achievements

Efficient systemic delivery　of anticancer drug to tumor tissue is a current critical challenge. Several studies have demonstrated that nanoparticles enhance the systemic delivery of anticancer drug to tumor via EPR effect. However, the disordered tumor microenvironment still poses a potential impediment with respect to the efficient delivery. Metronomic chemotherapy successfully improved the accumulation of PEG-coated liposome in solid tumor and improved therapeutic efficacy of oxaliplatin (l-OHP) encapsulated in the liposome. We also showed that repeated injection of l-OHP containing PEGylated liposome enhanced the accumulation of subsequently injected liposome and improved their therapeutic effect compared to the treatment with longer intervals between doses. The methodology (regimen) we proposed in this study may be applicable for clinical setting.

Research Products

• [Journal Article] Sequential treatment of oxaliplatin-containing PEGylated liposome together with S-1 improves intratumor distribution of subsequent doses of oxaliplatin-containing PEGylated liposome. (2014)
  • Author(s): Nakamura, H., Doi, Y., Abu Lila, A.S., Nagao, A., Ishida, T., Kiwada, H
  • Journal Title: Eur. J. Pharm. Biopharm. Volume: 87 Issue: 1 Pages: 142-151
  • DOI: 10.1016/j.ejpb.2013.12.007
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Influence of dose and animal species on accelerated blood clearance of PEGylated liposomal doxorubicin. (2014)
  • Author(s): Suzuki, T., Ichihara, M., Hyodo, K., Yamamoto, E., Ishida, T., Kiwada, H., Kikuchi, H., Ishihara, H.
  • Journal Title: Int. J. Pharm Volume: 476 Issue: 1-2 Pages: 205-212
  • DOI: 10.1016/j.ijpharm.2014.09.047
  • Peer Reviewed
• [Journal Article] Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy : a possible mechanism and the potential for clinical applicatio. (2012)
  • Author(s): Abu Lila, A.S., et al.
  • Journal Title: Int. J. Pharm. Volume: 438 Issue: 1-2 Pages: 176-183
  • DOI: 10.1016/j.ijpharm.2012.08.030
  • Peer Reviewed
• [Journal Article] Tumor type dependent vascular permeability constitutes a potential impediment to the therapeutic efficacy of liposomal oxaliplatin. (2012)
  • Author(s): Abu Lila, A.S., et al.
  • Journal Title: Eur. J. Pharm. Biopharm. Volume: 81 Issue: 3 Pages: 524-531
  • DOI: 10.1016/j.ejpb.2012.04.010
  • Peer Reviewed
• [Journal Article] Combination therapy with metronomic S-1 dosing and oxaliplatin-containing PEG-coated cationic liposomes in a murine colorectal tumor model: Synergy or antagonism? (2012)
  • Author(s): Abu Lila, A.S., et al.
  • Journal Title: Int. J. Pharm. Volume: 426 Issue: 1-2 Pages: 263-270
  • DOI: 10.1016/j.ijpharm.2012.01.046
  • Peer Reviewed
• [Presentation] Anti-PEG immunity against PEGylated materials. (2014)
  • Author(s): Ishida, T
  • Organizer: 11th DDS Symposium France-Japan
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県淡路市）
  • Year and Date: 2014-10-06
  • Invited
• [Presentation] In vivo imaging systemによる胸腔内投与リポプレックスの動態評価 (2014)
  • Author(s): 加藤千尋、石田竜弘、際田弘志
  • Organizer: 第３０回日本DDS学会学術集会
  • Place of Presentation: 慶應義塾大学薬学部（東京都港区）
  • Year and Date: 2014-07-30
• [Presentation] マウス肺癌細胞に対するFTY720とドキシルとの併用効果に関する検討 (2014)
  • Author(s): 清水太郎、高橋孝典、石田竜弘、際田弘志
  • Organizer: 第３０回日本DDS学会学術集会
  • Place of Presentation: 慶應義塾大学薬学部（東京都港区）
  • Year and Date: 2014-07-30
• [Presentation] 脾臓辺縁帯B細胞による抗原封入PEG修飾リポソームの濾胞への輸送現象を利用した抗腫瘍免疫誘導効果 (2014)
  • Author(s): 清水太郎、渡辺優希、美馬優、石田竜弘、際田弘志
  • Organizer: 日本薬剤学会第２９年会
  • Place of Presentation: 大宮ソニックシティビル（埼玉県さいたま市）
  • Year and Date: 2014-05-20
• [Presentation] In vivo imaging systemによる胸腔内投与リポプレックスの動態評価 (2014)
  • Author(s): 加藤千尋、石田竜弘、際田弘志
  • Organizer: 日本薬剤学会第２９年会
  • Place of Presentation: 大宮ソニックシティビル（埼玉県さいたま市）
  • Year and Date: 2014-05-20
• [Presentation] Improvement of tumor-targeting therapy with nanocarrier system by changing the tumor microenvironment. (2014)
  • Author(s): Ishida, T.
  • Organizer: Synchrotron Radiation in Nano-medicine and Advanced Health Care (SRNAHC)
  • Place of Presentation: KONAN University (兵庫県)
  • Invited
• [Presentation] ナノテクノロジーを用いた薬物動態制御の可視化 (2014)
  • Author(s): 石田竜弘
  • Organizer: 高分子学会九州支部・九州有機材料研究グループ研究会
  • Place of Presentation: 北九州市立大学（福岡県）
  • Invited
• [Presentation] リポソームからのPemetrexedの放出性が胸腔内移植腫瘍の増殖に与える影響 (2014)
  • Author(s): 小林早紀子、Amr Abu-Lila、石田竜弘、際田弘志
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本大学（熊本県）
• [Presentation] 転移性肝臓がんの存在がオキサリプラチン封入PEG修飾リポソームの肝移行性へ与える影響 (2014)
  • Author(s): 藤原由佳子、中村浩之、石田竜弘、際田弘志
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本大学（熊本県）
• [Presentation] 腫瘍内微小環境の能動的制御に基づく腫瘍選択的デリバリーシステムの開発 (2013)
  • Author(s): 石田竜弘
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: パシフィコ横浜(神奈川県)(招待講演)
  • Year and Date: 2013-03-30
• [Presentation] S-1と1-OHP封入PEG修飾リポソーム併用療法における腫瘍内血管系の変化 (2013)
  • Author(s): 中村浩之
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2013-03-28
• [Presentation] PEG修飾リポソームの腫瘍内移行に血管系の経時的変化が与える影響 (2013)
  • Author(s): 西尾美穂
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2013-03-28
• [Presentation] Potentiation of specific antibody response against antigen encapsulated in PEGylated liposomes via active transport of the liposomes from marginal zone into follicle. (2013)
  • Author(s): Shimizu, T., Ishida, T., Kiwada, H.
  • Organizer: 5th Asian Arden Conference
  • Place of Presentation: 愛知学院大学（愛知県）
• [Presentation] 腫瘍内血管系の動的変化がPEG修飾リポソームの腫瘍内分布に及ぼす影響 (2013)
  • Author(s): 西尾美穂、中村浩之、石田竜弘、際田弘志
  • Organizer: 第22回DDSカンファランス
  • Place of Presentation: グランシップ静岡（静岡県）
• [Presentation] PEG修飾剤末端構造が与えるABC現象誘導への影響に関する検討 (2013)
  • Author(s): 藤田理紗子、橋本洋佑、清水太郎、石田竜弘、際田弘志
  • Organizer: 第22回DDSカンファランス
  • Place of Presentation: グランシップ静岡（静岡県）
• [Presentation] In vivo imaging systemを用いたリポソーム胸腔内投与後の体内動態の評価 (2013)
  • Author(s): 加藤千尋、Amr Abu-Lila、石田竜弘、際田弘志
  • Organizer: 第５２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: 松山大学（愛媛県）
• [Presentation] 固形がんにおける抗がん剤封入PEG修飾リポソームとshRNA含有lipoplexによるがん治療法の確立 (2013)
  • Author(s): 田中真生、中村浩之、森吉直人、石田竜弘、際田弘志
  • Organizer: 第５２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: 松山大学（愛媛県）
• [Presentation] 腫瘍内微小環境の能動的制御による新規DDSの開発と治療への応用 (2012)
  • Author(s): 石田竜弘
  • Organizer: 創剤フォーラム第18回若手研究会
  • Place of Presentation: 長井記念ホール(徳島県)(招待講演)
  • Year and Date: 2012-11-17
• [Presentation] S-1と1-OHP封入SL併用療法におけるSLの体内動態および腫瘍内環境の変化 (2012)
  • Author(s): 中村浩之
  • Organizer: 創剤フォーラム第18回若手研究会
  • Place of Presentation: 長井記念ホール(徳島県)
  • Year and Date: 2012-11-17
• [Presentation] Improvement of tumor-targeting therapy with nanocarrier system by changing the tumor microenvironment. (2012)
  • Author(s): Ishida, T.
  • Organizer: 10th DDS Symposium France-Japan
  • Place of Presentation: Grand Hotel de Bordeaux(フランス)(招待講演)
  • Year and Date: 2012-10-13
• [Presentation] Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in murine solid tumor model. (2012)
  • Author(s): Ishida, T.
  • Organizer: Oligonucleotide Delivery : Biology, Engineering and Development
  • Place of Presentation: Hernstein (オーストリア)(招待講演)
  • Year and Date: 2012-10-08
• [Presentation] Sequential dose of 1-OHP containing PEGylated liposome improve the intratumor delivery and efficacy of PEGylated liposomal anticancer agents. (2012)
  • Author(s): Nakamura, H.
  • Organizer: 39th Annual Meeting & Exposition of the Controlled Release Society
  • Place of Presentation: Centre des congres de Quebec(カナダ)
  • Year and Date: 2012-07-16
• [Presentation] S-1と1-OHP封入PEG修飾リポゾーム併用療法がaccelerated blood clearance(ABC)現象に与える影響の検討 (2012)
  • Author(s): 長尾愛
  • Organizer: 第28回日本DDS学会学術集会
  • Place of Presentation: 札幌コンベンションセンター(北海道)
  • Year and Date: 2012-07-05