Evaluation on EPR effect and active control of EPR effect for achieving efficient tumor accumulation of nanocarrier delivery system

• Project/Area Number: 21689002
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Physical pharmacy
• Research Institution: The University of Tokushima
• Principal Investigator: 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)
• Co-Investigator(Renkei-kenkyūsha): KIWADA Hiroshi 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 教授 (50120184)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥26,780,000 (Direct Cost: ¥20,600,000、Indirect Cost: ¥6,180,000); Fiscal Year 2011: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2010: ¥11,440,000 (Direct Cost: ¥8,800,000、Indirect Cost: ¥2,640,000); Fiscal Year 2009: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
• Keywords: DDS / ナノキャリア / 腫瘍 / EPR効果 / がん治療 / 抗がん剤 / リポソーム / 腫瘍内微小環境 / メトロノミック・ケモセラピー / 抗がく剤

Research Abstract

Chemotherapy delivered in nanocarriers has been developed to improve the clinical treatment of solid tumors by achieving high accumulation of chemotherapeutic agents in tumor tissues but limited accumulation in healthy organs via due to the so-called" enhanced permeability and retention(EPR) effect". We showed that low dose metronomic chemotherapy given the damage in endothelial cells of growing tumor vasculature and tumor cells, increased tumor accumulation of nanocarriers as a result of vascular normalization and enlargement of intratumoral space in solid tumors. This strategy may be breakthrough in anti-cancer chemotherapy with nanocarrier-based anticancer drugs against intractable tumors which have lower vascular density and permeability.

Research Products

• [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., Okada, T., Doi, Y., Ichihara, M., Ishida, T., Kiwada, H.
  • Journal Title: Int. J. Pharm. Volume: 426 Pages: 263-270
  • Peer Reviewed
• [Journal Article] Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model (2012)
  • Author(s): Tagami, T., Abu Lila, A. S., Matsunaga, M., Moriyoshi, N., Nakamura, H., Nakamura, K., Suzuki, T., Doi, Y., Ishida, T., Kiwada, H.
  • Journal Title: Drug Deliv. Transl. Res. Volume: 2 Pages: 77-86
  • 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.
  • Journal Title: Int.J.Pharm. Volume: 426 Pages: 263-270
  • Peer Reviewed
• [Journal Article] Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model (2012)
  • Author(s): Tagami, T.
  • Journal Title: Drug Deliv.Transl.Res. Volume: 2 Pages: 77-86
  • Peer Reviewed
• [Journal Article] i-angiogenic therapy via cationic liposome-mediated systemic siRNA delive (2012)
  • Author(s): Tagami, T
  • Journal Title: Int.J.Pharm. Volume: 422 Pages: 280-289
  • Peer Reviewed
• [Journal Article] A double-modulation strategy in cancer treatment with a chemotherapeutic agent and siRNA (2011)
  • Author(s): Nakamura, K, Abu Lila A., Matsunaga, M., Doi, Y., Ishida, T., Kiwada, H.
  • Journal Title: Mol. Ther. Volume: 19 Pages: 2040-2047
  • Peer Reviewed
• [Journal Article] A double-modulation strategy in cancer treatment with a chemotherapeutic agent and siRNA (2011)
  • Author(s): Nakamura, K
  • Journal Title: Mor.Ther. Volume: 19 Pages: 2040-2047
  • Peer Reviewed
• [Journal Article] Argonaute2 is a potential target for siRNA-based cancer therapy for HT1080 human fibrosarcoma (2011)
  • Author(s): Tagami, T.
  • Journal Title: Drug Deliv.Transl.Res. Volume: 1 Pages: 277-288
  • Peer Reviewed
• [Journal Article] Combination therapy of metronomic S-1 dosing with oxaliplatin-containing PEG-coated liposome improves antitumor activity in a murine colorectal tumor model (2010)
  • Author(s): Doi Y., Okada T., Matsumoto H., Ichihara M., Ishida T., Kiwada, H.
  • Journal Title: Cancer Sci. Volume: 101 Pages: 2470-2475
  • Peer Reviewed
• [Journal Article] Sequential administration with oxaliplatin-containing PEG-coated cationic liposomes promotes a significant delivery of subsequent dose into murine solid tumor (2010)
  • Author(s): Abu Lila, A., Doi, Y., Nakamura, K., Ishida, T., Kiwada, H.
  • Journal Title: J. Control. Release Volume: 142 Pages: 167-173
  • Peer Reviewed
• [Journal Article] Targeting anticancer drugs to tumor vasculature using cationic liposomes (2010)
  • Author(s): Abu Lila, A., Ishida, T., Kiwada, H.
  • Journal Title: Pharm. Res. Volume: 27 Pages: 1171-1183
  • Peer Reviewed
• [Journal Article] Combination therapy of metronomic S-1 dosing with oxaliplatin-containing PEG-coated liposome improves antitumor activity in a murine colorectal tumor model. (2010)
  • Author(s): Doi Y.
  • Journal Title: Cancer Sci. Volume: 101 Pages: 2470-2475
  • Peer Reviewed
• [Journal Article] Co-administration of tacrolimus suppresses pharmacokinetic modulation of multiple subcutaneously administrated human interferon-alpha in beagle dogs. (2010)
  • Author(s): Yamazaki, H.
  • Journal Title: Drug Metab.Pharmacokinet. Volume: 25 Pages: 149-154
  • Peer Reviewed
• [Journal Article] Sequential administration with oxaliplatin-containing PEG-coated cationic liposomes promotes a significant delivery of subsequent dose into murine solid tumor. (2010)
  • Author(s): Abu Lila, A.
  • Journal Title: J.Control.Release Volume: 142 Pages: 167-173
  • Peer Reviewed
• [Journal Article] Sequential administration with oxaliplatin-containing PEG-coated cationic 1 iposomes promotes a significant delivery of subsequent dose into murine solid tumor. (2010)
  • Author(s): Abu Lila, A.
  • Journal Title: J.Control. Release 142 Pages: 167-173
  • Peer Reviewed
• [Journal Article] Targeting anticancer drugs to tumor vasculature using cationic liposomes. (2010)
  • Author(s): Abu Lila, A.
  • Journal Title: Pharm.Res. (In press)
  • Peer Reviewed
• [Journal Article] Oxaliplatin encapsulated in PEG-coated cationic liposomes induces significant tumor growth suppression via a dual-targeting approach in a murine solid tumor model (2009)
  • Author(s): Abu Lila, A., Kizuki, S., Doi, Y., Suzuki, T., Ishida, T., Kiwada, H.
  • Journal Title: J. Control. Release Volume: 137 Pages: 8-14
  • Peer Reviewed
• [Journal Article] Synergistic antitumor activity of metronomic dosing of cyclophosphamide in combination with doxorubicin-containing PEGylated liposomes in a murine solid tumor model (2009)
  • Author(s): Ishida, T., Shiraga, E., Kiwada, H.
  • Journal Title: J. Control. Release Volume: 134 Pages: 194-200
  • Peer Reviewed
• [Journal Article] Oxaliplatin targeting to angiogenic vessels by PEGylated cationic liposomes suppresses the angiogenesis in a dorsal air sac mouse model (2009)
  • Author(s): Abu-Lila, A, Suzuki, T., Doi, Y., Ishida, T., Kiwada, H.
  • Journal Title: J. Control. Release Volume: 134 Pages: 18-25
  • Peer Reviewed
• [Journal Article] Recent advances in tumor vasculature targeting using liposomal drug delivery systems (2009)
  • Author(s): Abu Lila, A., Ishida, T., Kiwada, H.
  • Journal Title: Expert Opin. Drug Deliv. Volume: 6 Pages: 1297-1309
  • Peer Reviewed
• [Journal Article] Synergistic antitumor activity of metronomic dosing of cyclophosphamide in combination with doxorubicin-containing PEGylated liposomes in a murine solid tumor model. (2009)
  • Author(s): Ishida, T.
  • Journal Title: J.Control. Release 134 Pages: 194-200
  • Peer Reviewed
• [Presentation] S-1とオキサリプラチン封入PEG修飾リポソームの併用療法におけるリポソームの体内動態の変化に関する研究 (2012)
  • Author(s): 中村浩之
  • Organizer: 日本薬学会第126年会
  • Place of Presentation: 北海道大学(北海道)
  • Year and Date: 2012-03-30
• [Presentation] 腫瘍内微小環境の能動的制御に基づくsiRNAデリバリー技術の開発とがん治療への展開 (2012)
  • Author(s): 石田竜弘
  • Organizer: 日本薬学会第126年会
  • Place of Presentation: 北海道大学(北海道)(招待講演)
  • Year and Date: 2012-03-30
• [Presentation] Development of new cancer treatment strategy that combines PEG-coated siRNA-lipoplex with metronomic S-1 dosing (2011)
  • Author(s): Moriyoshi, N.
  • Organizer: International Liposome Society 2011 meeting
  • Place of Presentation: University of London, London
  • Year and Date: 2011-12-11
• [Presentation] フッ化ピリミジン系経口抗癌剤(S-1)がPEG修飾カチオニックリポソームの腫瘍移行性に与える影響 (2011)
  • Author(s): 岡田知子
  • Organizer: 第20回DDSカンファランス
  • Place of Presentation: グランシップ(静岡)
  • Year and Date: 2011-09-16
• [Presentation] Tegaful製剤S-1とsiRNA含有liposomeの併用による新規がん治療法の開発 (2011)
  • Author(s): 森吉直人
  • Organizer: アンチセンス・遺伝子・デリバリーシンポジウム2011
  • Place of Presentation: 大阪大学(大阪)
  • Year and Date: 2011-09-01
• [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)(招待講演)
  • Year and Date: 2011-08-09
• [Presentation] PEG修飾リポソーム投与マウス脾臓中の抗PEG IgM分泌担当細胞の探索 (2011)
  • Author(s): 市原理子
  • Organizer: 第27回日本DDS学会学術集会
  • Place of Presentation: 東京大学(東京)
  • Year and Date: 2011-06-10
• [Presentation] 抗がん剤封入PEG修飾リポソームにおけるABC現象(第2報):サルにおける検討 (2011)
  • Author(s): 鈴木卓也
  • Organizer: 日本薬剤学会第26年会
  • Place of Presentation: タワーホール船堀(東京)
  • Year and Date: 2011-05-31
• [Presentation] Improvement of tumor-targeting therapy with nanocarrier system by changing the tumor microenviroment (2011)
  • Author(s): Ishida, T., Kiwada, H.
  • Organizer: 2011 RCAA International Symposium Endogenous Ligands Modulating Anticancer Agents
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2011-02-11
• [Presentation] A novel double modulation strategy in cancer treatment with chemothera peutic agent and siRNA : S-1 improves siRNA accumulation and then Bcl-2 knockdown by the siRNA increases chemosensitivity of 5-FU. (2011)
  • Author(s): Ishida, T.
  • Organizer: NANO IN CANCER : LINKING CHEMISTRY, BIOLOGY, AND CLINICAL APPLICATIONS IN VIVO
  • Place of Presentation: Miami, USA
  • Year and Date: 2011-01-13
• [Presentation] 腫瘍内微小環境変化を利用したsiRNAデリバリーシステムの開発 (2010)
  • Author(s): 石田竜弘、際田弘志
  • Organizer: 第32回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 富山
  • Year and Date: 2010-11-29
• [Presentation] 腫瘍内微小環境変化を利用したsiRNAデリバリーシステムの開発 (2010)
  • Author(s): 石田竜弘
  • Organizer: 第32回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 富山市
  • Year and Date: 2010-11-29
• [Presentation] Metronomic oral S-1, a fluoropyrimidine anticancer agent, dosing affects tumor accumulation of PEG-coated liposome. (2010)
  • Author(s): Okada, T.
  • Organizer: International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2010-08-06
• [Presentation] 腫瘍へのsiRNAデリバリーシステムの開発～効果と安全性の観点から～ (2010)
  • Author(s): 石田竜弘
  • Organizer: 第47回薬剤学懇談会研究討論会
  • Place of Presentation: 高山
  • Year and Date: 2010-06-24
• [Presentation] 腫瘍へのsiRNAデリバリーシステムの開発～効果と安全性の観点から～ (2010)
  • Author(s): 石田竜弘
  • Organizer: 第47回薬剤学懇談会研究討論会
  • Place of Presentation: 高山市
  • Year and Date: 2010-06-24
• [Presentation] 生体内動態検討を基盤としたリポソームDDSの開発 (2010)
  • Author(s): 石田竜弘
  • Organizer: 第26回日本DDS学会
  • Place of Presentation: 大阪市
  • Year and Date: 2010-06-18
• [Presentation] ナノキャリアに対するEPR効果に寄与する腫瘍内微小環境変化に関する研究:S-1の低用量頻回投与(metronomic chemotherapy)から得られた知見 (2010)
  • Author(s): 土井祐輔
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山市
  • Year and Date: 2010-03-29
• [Presentation] がん細胞種が及ぼす抗がん剤封入リボソームの腫瘍移行性とその治療効果への影響 (2010)
  • Author(s): 松本春菜
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山市
  • Year and Date: 2010-03-28
• [Presentation] フッ化ピリミジン系経口抗癌剤とOxaliplatin封入PEG修飾カチオニックリポソーム併用による抗腫瘍効果の検討 (2009)
  • Author(s): 岡田知子
  • Organizer: 第48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: 徳島市
  • Year and Date: 2009-11-07
• [Presentation] S-1のmetronomic chemotherapyがもたらすナノキャリア腫瘍集積性向上に関わる腫瘍内微小環境変化 (2009)
  • Author(s): 土井祐輔
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2009-10-03
• [Presentation] ナノキャリアに対するEPR効果に寄与する腫瘍内微小環境変化に関する検討.S-1の低用量頻回投与(metronomlc chemothera)から得られた知見 (2009)
  • Author(s): 土井祐輔
  • 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] Argonaute2標的siRNAリポプレックスを用いたがん治療戦略、学術シンポジウム4 RNAi医薬の展望. From Bench to Bedside- (2009)
  • Author(s): 石田竜弘、浅井知浩、奥直人、際田弘志
  • Organizer: 日本薬剤学会第24年会
  • Place of Presentation: 静岡
  • Year and Date: 2009-05-23
• [Presentation] Improvement of tumor-targeting therapy with nanocarriers by changing the tumor microenvironment (2009)
  • Author(s): Ishida, T., Kiwada, H.
  • Organizer: 2009 International Symposium of the Intelligent Drug Delivery System.
  • Place of Presentation: Korea
  • Year and Date: 2009-04-30
• [Book] Cationic liposomes and tumour vasculature targeting : a therapeutic approach that has potential for solid tumours (2011)
  • Author(s): Abu Lila A. S., Ishida T., Kiwada, H.
  • Publisher: i-Smithers-Creative Publishing Solutions
• [Book] Breaking the barriers to tumor-targeting via nanocarrier-based drug delivery to the tumor microenvironment (2010)
  • Author(s): Doi, Y., Ishida, T., Kiwada, H.
  • Publisher: Nova Science Publishers
• [Book] A book chaper in Cancer Targeted Therapy ; Breaking the barriers to tumor-targeting via nanocarrier-based drug delivery to the tumor microenvironment. (2010)
  • Author(s): Doi, Y.
  • Publisher: Nova Science Publishers(In Press)
• [Remarks]
  • URL: http://www.tokushima-u.ac.jp/ph/faculty/labo/ykz/