Development of a new miRNA delivery system for targeting cancer stem cells

• Project/Area Number: 23659626
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Tokyo Medical University
• Principal Investigator: UEDA Shinobu 東京医科大学, 医学部, 助手 (00521874)
• Co-Investigator(Kenkyū-buntansha): KURODA Masahiko 東京医科大学, 医学部, 教授 (80251304) ; TAKANASHI Masakatsu 東京医科大学, 医学部, 講師 (80312007) ; OHNO Shinichiro 東京医科大学, 医学部, 助教 (90513680)
• Co-Investigator(Renkei-kenkyūsha): TSUCHIDA Akihiko 東京医科大学, 医学部, 教授 (50207396)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 乳がん / miRNA / エキソソーム / がん / microRNA / 癌

Research Abstract

It is known to dysregulation of microRNAs contribution to the development and progression of cancers. MiRNAs in serum correlate with the cancer, cardiovascular disorders and the various types of diseases. In addition, extracellular miRNAs have been detected in exosomes isolated from numerous body fluids including serum. In this study, we examined whether exosomes were a new useful tools for gene delivery in a model of cancer. Modified exosomes with the GE11 peptide that binds to EGFR including let-7a were prepared (let-7a/GE11 exosomes). let-7a/GE11 exosomes were intravenously injected into Rag2-/- mice transplanted breast cancer cells (HCC-70). After four injections, let-7a/GE11 exosomes markedly suppressed tumor growth. These results suggest that exosomes may provide an effective miRNA delivery system for cancer therapy.

Research Products

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• [Journal Article] Development of Severe Pathology in Immunized Pregnant Mice Challenged with Lethal Malaria Parasites. (2013)
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• [Journal Article] Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes (2013)
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• [Journal Article] Intracaval and intracardiac extension of invasive thymoma complicated by superior and inferior vena cava syndrome. (2013)
  • Author(s): Atsushi Kurata
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• [Journal Article] Systemically injected exosomes targeted to EGFR deliver anti-tumor microRNA to breast cancer cells (2012)
  • Author(s): 後藤 典子
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• [Journal Article] TLS-CHOP represses miR-486 expression, inducing upregulation of a metastasis regulator PAI-1 in human myxoid liposarcoma (2012)
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• [Journal Article] LGR5-positive colon cancer stem cells interconvert with drug-resistant LGR5-negative cells and are capable of tumor reconstitution (2012)
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  • Journal Title: Stem Cells Volume: 30(12) Issue: 12 Pages: 2631-44
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• [Journal Article] Efficacy of a novel class of RNA interference therapeutic agents (2012)
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  • Journal Title: PLoS One Volume: 7 Issue: 8 Pages: 1-15
  • DOI: 10.1371/journal.pone.0042655
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• [Journal Article] Isolation of miRNAs that target EGFR mRNA in human lung cancer (2012)
  • Author(s): Yamaguchi G, Takanashi M, Tanaka M, Fujita K, Ohira T, Kuroda M, Ikeda N
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• [Journal Article] Identification of a novel role of Septin 10 in Paclitaxel-resistance in cancers through a functional genomics screen (2012)
  • Author(s): Xu M, Takanashi M, Oikawa K, Nishi H, Isaka K, Yoshimoto T, Ohyashiki J, Kuroda M
  • Journal Title: Cancer Sci Volume: 103 Issue: 4 Pages: 821-827
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• [Journal Article] Mitotic figure recognition : agreement among pathologists and computerized detector (2012)
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• [Journal Article] Visual functional and histopathological correlation in experimental autoimmune optic neuritis (2012)
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• [Journal Article] A novel oncogenic pathway by TLS-CHOP involving repression of MDA-7/IL-24 expression (2012)
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• [Journal Article] Mitotic figure recognition: agreement among pathologists and computerized detector. (2012)
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• [Journal Article] Mitotic figure recognition: agreement among pathologists and computerized detector. (2012)
  • Author(s): Malon C, Brachtel E, Cosatto E, Graf HP, Kurata A, Kuroda M, Meyer JS, Saito A, Wu S, Yagi Y.
  • Journal Title: Anal Cell Pathol (Amst). Volume: 35(2) Pages: 97-100
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• [Journal Article] miR-92 is a key oncogenic component of the miR-17-92 cluster in colon cancer (2011)
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• [Journal Article] Regulation of the development of acute hepatitis by IL-23 through IL-22 and IL-17 production (2011)
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• [Journal Article] Dysregulation of IFN system can lead to poor response to pegylated interferon and ribavirin therapy in chronic hepatitis C (2011)
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  • Journal Title: PLoS ONE Volume: 6 Issue: 5 Pages: e19799-e19799
  • DOI: 10.1371/journal.pone.0019799
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• [Journal Article] Clinical impact of down-regulated plasma miR-92a levels in non-Hodgkin's lymphoma (2011)
  • Author(s): Ohyashiki K, Umezu T, Yoshizawa S, Ito Y, Ohyashiki M, Kawashima H, Tanaka M, Kuroda M, Ohyashiki JH
  • Journal Title: PLoS One Volume: 6(2) Issue: 2 Pages: 16408-16408
  • DOI: 10.1371/journal.pone.0016408
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• [Journal Article] The progression of liver fibrosis is related with overexpression of the miR-199 and 200 families (2011)
  • Author(s): Murakami Y, Toyoda H, Tanaka M, Kuroda M, Harada Y, Matsuda F, Tajima A, Kosaka N, Ochiya T, Shimotohno K
  • Journal Title: PLoS One Volume: 6(1) Issue: 1 Pages: e16081-e16081
  • DOI: 10.1371/journal.pone.0016081
  • NAID: 120002871278
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• [Journal Article] Dysregulation of IFN system can lead to poor response to pegylated interferon and ribavirin therapy in chronic hepatitis C. (2011)
  • Author(s): Onomoto K, Morimoto S, Kawaguchi T, Toyoda H, Tanaka M, Kuroda M, Uno K, Kumada T, Matsuda F, Shimotohno K, Fujita T, Murakami Y.
  • Journal Title: PLoS One. Volume: 6(5)
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• [Journal Article] Anthocyanidins-enriched bilberry extracts inhibit 3T3-L1 adipocyte differentiation via the insulin pathway. (2011)
  • Author(s): Suzuki R, Tanaka M, Takanashi M, Hussain A, Yuan B, Toyoda H, Kuroda M.
  • Journal Title: Nutr Metab (Lond). Volume: 8 Pages: 14-14
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• [Journal Article] Clinical impact of down-regulated plasma miR-92a levels in non-Hodgkin's lymphoma. (2011)
  • Author(s): Ohyashiki K, Umezu T, Yoshizawa S, Ito Y, Ohyashiki M, Kawashima H, Tanaka M, Kuroda M, Ohyashiki JH.
  • Journal Title: PLoS One. Volume: 6(2)
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• [Journal Article] The progression of liver fibrosis is related with overexpression of the miR-199 and 200 families. (2011)
  • Author(s): Murakami Y, Toyoda H, Tanaka M, Kuroda M, Harada Y, Matsuda F, Tajima A, Kosaka N, Ochiya T, Shimotohno K.
  • Journal Title: PLoS One. Volume: 6(1)
  • NAID: 120002871278
  • Peer Reviewed
• [Presentation] microRNA の病理研究・治療への応用 (2013)
  • Author(s): 黒田雅彦、村上善基、上田しのぶ、藤田浩司
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 新規核酸を用いた血管新生網膜症に対する分子標的治療法の開発 (2013)
  • Author(s): 高梨正勝、須藤カツ子、松永芳径、石川章夫、大木忠明、濱崎智洋、後藤浩、黒田雅彦
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 前立腺癌におけるmicroRNA-200c の発現解析 (2013)
  • Author(s): 山田正俊、大野慎一郎、藤田浩司、倉田厚、黒田雅彦
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 新規のlipid conjugate RNA を用いたがん治療法の開発 (2013)
  • Author(s): 黒田雅彦、高梨正勝、須藤カツ子
  • Organizer: 第72回日本癌学会総会
• [Presentation] Systemically injected exosomes targeted to EGFR deliver anti-tumor microRNA to breast cancer cells (2013)
  • Author(s): Ohno S, Takanashi M, Ohgi T, Mizutani T, Murakami Y, Kuroda M
  • Organizer: Keystone Symposia Conference - Noncoding RNAs in Development and Cancer(A7)
  • Place of Presentation: Vancouver, British Columbia, CANADA
• [Presentation] microRNAの病理研究・治療への応用 (2013)
  • Author(s): 黒田雅彦、村上善基、上田しのぶ、藤田浩司
  • Organizer: 第102回 日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 剖検症例の冠動脈を用いた肥厚内膜の免疫組織化学的検討 (2013)
  • Author(s): 堀田綾子、倉田厚、齋藤生朗、黒田雅彦
  • Organizer: 第102回 日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 胃癌細胞株における上皮間葉移行に関与するマイクロRNAとその標的の検出 (2013)
  • Author(s): 倉田厚、山田正俊、橋本浩次、呉偉紅、那日蘇、藤田浩司、大野慎一郎、高梨正勝、黒田雅彦
  • Organizer: 第102回 日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 新規核酸を用いた血管新生網膜症に対する分子標的治療法の開発 (2013)
  • Author(s): 高梨正勝、須藤カツ子、松永芳径、石川章夫、大木忠明、濱崎智洋、後藤浩、黒田雅彦
  • Organizer: 第102回 日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 前立腺癌におけるmicroRNA-200cの発現解析 (2013)
  • Author(s): 山田正俊、大野慎一郎、藤田浩司、倉田厚、黒田雅彦
  • Organizer: 第102回 日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 細気管支肺胞上皮癌におけるRASとlet-7の発現の特徴 (2013)
  • Author(s): 藤田浩司、仲矢丈雄、池田徳彦、黒田雅彦
  • Organizer: 第102回 日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] Lung cancer miRNA replacement therapy using novel class of miRNA (2013)
  • Author(s): S Ohno, K Itano, Y Harada, M Takanashi, K Sudo, T Mizutani, M Kuroda.
  • Organizer: アメリカ癌学会 国際会議 分子標的とがん治療
  • Place of Presentation: Boston､ MA, USA
• [Presentation] 高効率にがん抑制効果を発揮するmiR-34aの新規形状の探索 (2013)
  • Author(s): 大野慎一郎、板野華連、柏迫幹絵、大木忠明、水谷隆之、須藤カツ子、高梨正勝、黒田雅彦
  • Organizer: 第５回 日本RNA研究会
  • Place of Presentation: 広島
• [Presentation] ユーイング肉腫における新規構成RNAによるキメラがん遺伝子ノックダウン効果の検証 (2013)
  • Author(s): 原田裕一郎、大野慎一郎、大木忠明、水谷隆之、須藤カツ子、高梨正勝、黒田雅彦
  • Organizer: 第５回 日本RNA研究会
  • Place of Presentation: 広島
• [Presentation] 新規のlipid conjugate RNAを用いたがん治療法の開発 (2013)
  • Author(s): 黒田雅彦、高梨正勝、須藤カツ子
  • Organizer: 第72回 日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Systemically injected exosomes targeted to EGFR deliver anti-tumor microRNA to breast cancer cells. (2013)
  • Author(s): Shinichiro Ohno, Masakatsu Takanashi, Tadaaki Ohgi, Takayuki Mizutani, Yoshiki Murakami, Masahiko Kuroda.
  • Organizer: Keystone Symposia Conference
  • Place of Presentation: Vancouver, British Columbia, CANADA
• [Presentation] Delivery of miRNA to the EGFR-expressed tumor by systemic injection of target exosomes (2012)
  • Author(s): Ohno S, Takanashi M, Sudo K, Mizutani T, Ochiya T, Kuroda M
  • Organizer: International Society for the EGFR-extracellular Vesicled (ISEV)
  • Place of Presentation: Gothenburg, Sweden
  • Year and Date: 2012-04-18
• [Presentation] マウスに経口投与したエクソソームの生体内での安定性と分布 (2012)
  • Author(s): 髙梨 正勝、須藤 カツ子、大野 慎一郎、上田 しのぶ、石川 章夫、黒田 雅彦
  • Organizer: 第71回日 本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 大腸癌発生における形態異常とmiRNA (2012)
  • Author(s): 黒田 雅彦
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 血管新生網膜症に対する分子標的治療法を目指した核酸薬の開発 (2012)
  • Author(s): 髙梨 正勝、須藤 カツ子、松永 芳径、大木 忠明、濱崎 智洋、谷口 維紹、仲矢 丈雄、臼井 嘉彦、後藤 浩、黒田 雅彦
  • Organizer: 第32回日本眼薬理学会
  • Place of Presentation: 滋賀
• [Presentation] EGFR リガンド発現エクソソームを用いた新規ドラッグデリバリーシステムの開発 (2012)
  • Author(s): 大野 慎一郎、上田 しのぶ、石川 章夫、松山 永久、藤田 浩司、高梨 正勝、黒田雅彦
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] Selective target delivery of miRNA using EGF expressing exosomes (2012)
  • Author(s): Ohno S, Takanashi M, Ueda S, Ohgi T, Mizutani T, Kuroda M
  • Organizer: Keystone symposia Nucleic Acid Therapeutics : From Base Pairs to Bedsides (A2)
  • Place of Presentation: Santa Fe, New Mexico
• [Presentation] KLF5 is essential for oncogenesis of intestinal tumors and control of intestinal stem cells. (2012)
  • Author(s): Takeo Nakaya, Seishi Ogawa, Ichiro Manabe, Masami Tanaka, Masashi Sanada, Toshiro Sato, Motoki Goto, Makoto Taketo, Kazuki Nakao, Masashi Fukayama, Masahiko Kuroda, Ryozo Nagai
  • Organizer: 第35回分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] Wapl regulates HP1 expression and levels of various histone H3 tail modifications. (2012)
  • Author(s): Kosuke Oikawa, Masakatsu Takanashi, Mayako Niwa, Yujing Sun, Ting Gui, Aiko Shimokado, Shunji Itoh, Takashi Ozaki, Masahiko Kuroda, Yasuteru Muragaki.
  • Organizer: 第35回分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] IgG4関連疾患による下垂体性甲状腺機能低下症－ステロイド投与による回復についての考察 (2012)
  • Author(s): 橋本 浩次、堀内 鳩子、鈴木 純子、稲垣 聡子、久間 里紗、岸本 正彦、山田 正俊、倉田 厚、黒田 雅彦.
  • Organizer: 第55回日本甲状腺学会学術集会
  • Place of Presentation: 福岡
• [Presentation] マウスに経口投与したエクソソームの生体内での安定性と分布． (2012)
  • Author(s): 髙梨 正勝、須藤 カツ子、大野 慎一郎、上田 しのぶ、石川 章夫、黒田 雅彦．
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] KLF5は腸管腫瘍形成に必須である (2012)
  • Author(s): 仲矢 丈雄、眞田 昌、眞鍋 一郎、深山 正久、小川 誠司、黒田 雅彦、永井 良三
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 粘液型脂肪肉腫においてTLS-CHOPは抗がん性サイトカインMDA-7/IL24の発現を抑制する (2012)
  • Author(s): 及川 恒輔、髙梨 正勝、黒田 雅彦、村垣 泰光
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Caveolin-1の発現低下は孤立性繊維性腫瘍の特徴である (2012)
  • Author(s): 元井 亨、加藤 生真、福田 由美子、船田 信顕、林 幸子、小川 真澄、立石 陽子、堀口 慎一郎、黒田 雅彦、五嶋 孝博、比島 恒和．
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] 胃低分化癌におけるin situ hybridization法を用いたmiRNA-92aおよび200cの発現低下の意義 (2012)
  • Author(s): 倉田 厚、呉 偉紅、山田 正俊、那 日蘇、藤田 浩司、大野 慎一郎、高梨 正勝、黒田 雅彦
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] TLS-CHOPがん遺伝子が発現制御するmiRNAの解析 (2012)
  • Author(s): ボルジゲン 那日蘇、大野 慎一郎、田中 正視、呉 偉紅、田中 理英子、藤田 浩司、高梨 正勝、黒田 雅彦
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] 剖検における腹部大動脈径の増大と腎嚢胞数の相関 (2012)
  • Author(s): 倉田 厚、井上 茂、黒田 雅彦．
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] EGFRリガンド発現エクソソームを用いた新規ドラッグデリバリーシステムの開発 (2012)
  • Author(s): 大野 慎一郎、上田 しのぶ、石川 章夫、松山 永久、藤田 浩司、高梨 正勝、黒田 雅彦
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] 子宮頸部扁平上皮病変におけるhWAPLの発現検討 (2012)
  • Author(s): 山田 正俊、倉田 厚、菅間 博、宇野 枢、黒田 雅彦
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
• [Presentation] 神経眼科の進歩 視神経炎 -免疫学的アプローチによる病態の解明と新規治療法の開発 (2012)
  • Author(s): 毛塚 剛司 他
  • Organizer: 第116回日本眼科学会総会 評議員会指名講演III
  • Place of Presentation: 東京
  • Invited
• [Presentation] Selective target delivery of miRNA using EGF expressing exosomes (2012)
  • Author(s): Shinichiro Ohno, Masakatsu Takanashi, Shinobu Ueda, Tadaaki Ohgi, Takayuki Mizutani, Masahiko Kuroda
  • Organizer: Keystone symposia Nucleic Acid Therapeutics: From Base Pairs to Bedsides (A2)
  • Place of Presentation: Santa Fe, New Mexico
• [Presentation] Delivery of antitumor molecules to the EGFR expressing cancer using EGF expressing exosomes (2011)
  • Author(s): 大野 慎一郎、上田 しのぶ、石川 章夫、藤田 浩司、高梨 正勝、黒田 雅彦
  • Organizer: 第37回分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] 乳がん幹細胞の維持に関与する microRNA の探索 (2011)
  • Author(s): 上田 しのぶ、高梨正勝、黒田 雅彦
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] リガンド修飾エクソソームによるEGFreceptor 発現細胞を標的としたドラッグデリバリーシステムの開発 (2011)
  • Author(s): 大野 慎一郎、上田 しのぶ、石川 章夫、松山永久、高梨 正勝、黒田 雅彦
  • Organizer: 第70回日 本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] CD63-GFP を発現したエクソソームのマウス生体内での安定性と分布について (2011)
  • Author(s): 高梨 正勝、須藤 カツ子、大野 慎一郎、上田 しのぶ、石川 章夫、黒田 雅彦
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 人工型exosome の生体内分布と安定性についての研究 (2011)
  • Author(s): 高梨 正勝、須藤 カツ子、大野 慎一郎、上田 しのぶ、石川章夫、黒田 雅彦
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 横浜
• [Presentation] 乳がん幹細胞の維持に関与するmicroRNAの探索 (2011)
  • Author(s): 上田 しのぶ、高梨 正勝、黒田 雅彦
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 人工型exosomeの生体内分布と安定性についての研究 (2011)
  • Author(s): 高梨 正勝、須藤 カツ子、大野 慎一郎、上田 しのぶ、石川 章夫、黒田 雅彦
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 横浜
• [Presentation] CD63-GFPを発現したエクソソームのマウス生体内での安定性と分布について (2011)
  • Author(s): 高梨 正勝、須藤 カツ子、大野 慎一郎、上田 しのぶ、石川 章夫、黒田 雅彦
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] リガンド修飾エクソソームによるEGF receptor発現細胞を標的としたドラッグデリバリーシステムの開発 (2011)
  • Author(s): 大野 慎一郎、上田 しのぶ、石川 章夫、松山 永久、高梨 正勝、黒田 雅彦
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Delivery of antitumor molecules to the EGFR expressing cancer using EGF expressing exosomes (2011)
  • Author(s): 大野 慎一郎、上田 しのぶ、石川 章夫、藤田 浩司、高梨 正勝、黒田 雅彦
  • Organizer: 第３７回分子生物学会年会
  • Place of Presentation: 横浜
• [Book] 新たなドラッグデリバリーシステムとしてのエクソソーム.細胞工学 (2013)
  • Author(s): 大野慎一郎、髙梨 正勝、黒田 雅彦
  • Publisher: 秀潤社, vol.32 No.1
• [Book] 臨床・創薬利用が見えてきたmicroRNA.遺伝子医学MOOK23 (2012)
  • Author(s): 落谷孝広/監修、黒田雅彦・尾崎充彦/編集
  • Publisher: メディカルドゥ
• [Book] 次世代に向けた核酸医薬品の新技術 -RNA 干渉法を用いた分子標的核酸医薬の開発.化学第67巻第9号 (2012)
  • Author(s): 仲矢丈雄・黒田雅彦・大木忠明
  • Publisher: 株式会社化学同人
• [Book] 病理画像診断これでスッキリ！ (2012)
  • Author(s): 梅澤明弘、黒田雅彦
  • Publisher: メジカルビュー社
• [Remarks]
  • URL: http://www.tokyo-med.ac.jp/molpathol/index.html
• [Remarks] Department of Molecular Pathology Kuroda's Lab
  • URL: http://www.tokyo-med.ac.jp/molpathol/
• [Remarks]
  • URL: http://www.tokyo-med.ac.jp/molpathol/index.html