Development of an antioxidative nano-particle for redox sensoring and reno-protection

• Project/Area Number: 21591018
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Tsukuba University of Technology
• Principal Investigator: HIRAYAMA Aki 筑波技術大学, 保健科学部, 教授 (20323298)
• Co-Investigator(Kenkyū-buntansha): NAGASAKI Yukio 筑波大学, 数理物質科学研究科, 教授 (90198309)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 急性腎障害 / ナノ粒子 / 酸化ストレス / ドラッグデリバリーシステム / 腎保護薬 / 電子スピン共鳴 / TEMPO / DDS(Drug Delivery System)

Research Abstract

A TEMPO radical containing nano-particle (RNP) which possessed high in vivo stability and antioxidative effects was synthesized and applied to a treatment of acute kidney injury (AKI) model. RNP was synthesized as a micelle containing TEMPO in the core and poly(ethelenglycol)-poly(chloromethylstyrene) as its outer shell (PEG-PCTEMPO). Controlling the amino group of the repeating units of PCTEMPO, we synthesized pH-sensitive RNP (N-RNP) which release the inner TEMPO in acidic circumstance. RNP showed significant reno-protection through its high in vivo stability and target-specificity against tissue with high oxidative stress.

Research Products

• [Journal Article] The ROS scavenging and renal protective effects of pH-responsive nitroxide radical-containing nanoparticles (2011)
  • Author(s): Toru Yoshitomi, Aki Hirayama, Yukio Nagasaki
  • Journal Title: Biomaterials Volume: 32 Issue: 31 Pages: 8021-8028
  • DOI: 10.1016/j.biomaterials.2011.07.014
  • NAID: 120007137437
  • Peer Reviewed
• [Journal Article] Newly Synthesized Radical-containing Nanoparticles (RNP)Enhance Neuroprotection after Cerebral Ischemia-reperfusion Injury (2011)
  • Author(s): Aiki Marushima, Hideo Tsurusima, Toru Yoshitomi, Kazuko Toh, Aki Hirayama, Yukio Nagasaki, Akira Matumura
  • Journal Title: Neurosurgery Volume: 68 Issue: 5 Pages: 1418-1426
  • DOI: 10.1227/neu.0b013e31820c02d9
  • Peer Reviewed
• [Journal Article] Gastric acid induces mitochondrial superoxide production and lipid peroxidation in gastric evithelial cells (2011)
  • Author(s): Matsui H.
  • Journal Title: J Gastroenterology Volume: 46 Issue: 10 Pages: 1167-1176
  • DOI: 10.1007/s00535-011-0434-6
  • Peer Reviewed
• [Journal Article] Newly synthesized radical-containing nanoparticles (rnp) enhance neuroprotection after cerebral ischemia-reperfusion injury. (2011)
  • Author(s): Marushima A
  • Journal Title: Neurosurgery Volume: Epub Jan 26
  • Peer Reviewed
• [Journal Article] Spherical carbon adsorbent (AST-120) protects deterioration of renal function in chronic kidney disease rats through inhibition of reactive oxygen species production from mitochondria and reduction of serum livid peroxidation. (2011)
  • Author(s): Owada S
  • Journal Title: Nephron Experimental Nephrology Volume: 115
  • Peer Reviewed
• [Journal Article] Spherical carbon adsorbent (AST-120) protects deterioration of renal function in chronic kidney disease rats through inhibition of reactive oxygen species production from mitochondria and reduction of serum lipid peroxidation (2010)
  • Author(s): Owada S, Maeba T, Sugano Y, Hirayama A, Ueda A, Nagase S, Goto S, Nishijima F, Bannai K, Yamato H
  • Journal Title: Nephron Exp Nephrol Volume: 115(4)
• [Journal Article] Development of a pH-Sensitive Reno-Protective Nano-Particle for Relief of Ischemia-Reperfusion Acute Kidney Injury. (2010)
  • Author(s): Hirayama A
  • Journal Title: Journal of American Society of Nephrology Volume: 21
  • Peer Reviewed
• [Journal Article] 脳虚血再灌流における酸化ストレス障害と脳保護療法-pH応答性ラジカル含有ナノ粒子(radical-containing nanoparticle : RNP)の可能性- (2010)
  • Author(s): 丸島愛樹
  • Journal Title: 脳卒中 Volume: 32 Pages: 552-558
  • Peer Reviewed
• [Journal Article] pH-Sensitive Radical.Containing-Nanoparticle (RNP) for theL-Band-EPR Imaging of Low pH Circumstances (2009)
  • Author(s): Yoshitomi T, Suzuki R, Mamiya T, Matsui H, Hirayama A, Nagasaki Y.
  • Journal Title: Bioconjugate Chem Volume: 20 Pages: 1792-1798
• [Journal Article] pH-Sensitive Radical-Containing-Nanoparticle(RNP)for the L-Band-EPR Imaging of Low pH Circumstances. (2009)
  • Author(s): Yoshitomi T
  • Journal Title: Bioconjugate Chem. 20 Pages: 1792-1798
  • Peer Reviewed
• [Journal Article] Design of Core-Shell-Type Nanoparticles Carrying Stable Radicals in the Core (2009)
  • Author(s): Yoshitomi T
  • Journal Title: Biomacromolecules 10 Pages: 596-601
  • Peer Reviewed
• [Presentation] Application of ESR and Spin Technologies for the Control of Kidney Diseases (2011)
  • Author(s): Hirayama A, Ueda A, Nagase S, Aoyagi K, Owada S
  • Organizer: International Workshop"Advanced ESR Studies for New Frontiers in Biofunctional Spin Science and Technology"(AEBST 2011)
  • Place of Presentation: Kobe
  • Year and Date: 2011-11-13
• [Presentation] レドックス反応性ナノ粒子による腎虚血再灌流障害の治療第 (2011)
  • Author(s): 吉冨徹,平山暁,長崎幸夫
  • Organizer: 64回日本酸化ストレス学会学術集会
  • Place of Presentation: 北海道,ルスツ
• [Presentation] 急性腎障害に対するナノ粒子治療の開発シンポジウムJapan Kidney Week 2011 (2011)
  • Author(s): 平山暁,吉富徹,長崎幸夫
  • Organizer: 第55回(社)日本透析医学会学術集会・総会
  • Place of Presentation: 横浜
• [Presentation] Novel redox nanotherapy fof renal ischemia reperfusion injury (2011)
  • Author(s): Nagasaki Y, Yoshitomi T, Hirayama A
  • Organizer: XLVIII ERA-EDTA Congress
  • Place of Presentation: Prague, Czech Rep
• [Presentation] Novel redox nanotherapy fof renal ischemia reperfusion injury (2011)
  • Author(s): Nagasaki Y.
  • Organizer: XLVIII ERA-EDTA Congress
  • Place of Presentation: Prague
• [Presentation] Indoxyl sulfate and guanidino succinic acid directly induce mitochondrial superoxide production (2011)
  • Author(s): Hirayama A.
  • Organizer: XLVIII ERA-EDTA Congress
  • Place of Presentation: Prague
• [Presentation] pH応答性TEMPO含有ナノ粒子のマウス急性腎不全モデルに対する保護効果 (2010)
  • Author(s): 平山暁
  • Organizer: 第22回腎とフリーラジカル研究会
  • Place of Presentation: 町村会館(東京)
  • Year and Date: 2010-10-16
• [Presentation] Design of Ph-Sensitive Radical-Containing-Nanoparticle(Rnp)For The EPR Imaging Of Low Ph Environments (2010)
  • Author(s): Yoshitomi T.
  • Organizer: Symposium on Biomedical Polymers for Drug Delivery
  • Place of Presentation: University Of Utah, Salt Lake City, Utah, United States of America
  • Year and Date: 2010-03-26
• [Presentation] Design of pH-sensitive polymeric micelle possessing reduced forms of TEMPO for imaging of ROS (2010)
  • Author(s): Yoshitomi T
  • Organizer: Oxygen Club California World Conference 2010
  • Place of Presentation: Santa Barbara, California, United States of America
  • Year and Date: 2010-03-18
• [Presentation] Novel Nanosphere Theranostic for Anti-Oxidative Stress (2010)
  • Author(s): Nagasaki Y
  • Organizer: THE 1st INTERNATIONAL CONFERENCE FOR GREEN TECHNOLOGIES
  • Place of Presentation: Ajou University, Suwon, Korea
  • Year and Date: 2010-02-06
• [Presentation] 酸化ストレスをターゲットとした新しいナノ粒子セラノスティックス (2010)
  • Author(s): 長崎幸夫
  • Organizer: 第24回酸化ストレス学会関東支部会
  • Place of Presentation: つくば
  • Year and Date: 2010-01-09
• [Presentation] Development of a pH-Sensitive Reno-Protective Nano-Particle for Relief of Ischemia-Reperfusion Acute Kidney Injury (2010)
  • Author(s): Hirayama A, Yoshitomi T, Owada S, Ueda A, Matsui H, Aoyagi K, Nagasaki Y
  • Organizer: 43rd Annual meeting of the American Society of Nephrology (Renal Week 2010)
  • Place of Presentation: Denver (abstract in J Am Soc Nephrol)
• [Presentation] Design of redox imaging nanoprobe using nitroxyl radical containing nanoparticle (2010)
  • Author(s): Yoshitomi T, Mamiya T, Matsui H, Hirayama A ,Nagasaki Y
  • Organizer: SFRBM 2010-17th Annual Meeting of the Society for Free Radical Biology and Medicine
  • Place of Presentation: Orlando, Florida
• [Presentation] Design of nitroxyl radicals containing nanoparticle for MR imaging of tumor (2010)
  • Author(s): Yoshitomi T, Matsumoto S, Krishna MC, Matsumoto K, Anzai K, Matsui H, Hirayama A, Nagasaki Y
  • Organizer: The 37th Annual Meeting and Exposition of the Controlled Release Society
  • Place of Presentation: Oregon Convention Center, Portland, Oregon, USA.
• [Presentation] 反応性イメージングを目指したニトロキシルラジカル含有ナノ粒子の設計と評価 (2010)
  • Author(s): 吉冨徹、間宮孝、松井裕史、平山暁、長崎幸夫
  • Organizer: 第26回日本DDS学会学術集会
  • Place of Presentation: 大阪国際交流センター
• [Presentation] Design of pH-sensitive polymeric micelle possessing reduced forms of TEMPO for imaging of ROS (2010)
  • Author(s): Yoshitomi T, Mamiya T, Matsui H, Hirayama A, Nagasaki Y
  • Organizer: Young Investigator's Award winning presentation
  • Place of Presentation: Oxygen Club California World Congress, Santa Barbara, CA, USA.
• [Presentation] 反応性イメージングを目指したニトロキシルラジカル含有ナノ粒子の設計と評価 (2010)
  • Author(s): 吉冨徹
  • Organizer: 第26回日本DDS学会学術集会
  • Place of Presentation: 大阪国際交流センター(大阪)
• [Presentation] 腫瘍集積性を有するニトロキシルラシカル含有ナノ粒子の設計と高分解能MRI評価 (2010)
  • Author(s): 吉冨徹
  • Organizer: 第63回日本酸化ストレス学会学術集会
  • Place of Presentation: 神奈川県民ホール(横浜)
• [Presentation] Development of a pH-Sensitive Reno-Protective Nano-Particle for Relief of Ischemia-Reperfusion Acute Kidney Injury. (2010)
  • Author(s): Hirayama A
  • Organizer: 43rd Annual meeting of the American Society of Nenhroloev (Renal Week 2010)
  • Place of Presentation: Colorado Convention Center (Denver, CO)
• [Presentation] Design ofnitroxyl radicals containing nanoparticle for MR imaging of tumor (2010)
  • Author(s): Yoshitomi T
  • Organizer: The 37th AnnualMeeting and Exposition of the Controlled Release Society
  • Place of Presentation: Oregon Convention Center (Portland, OR)
• [Presentation] Design of redox imaging nanoprobe using nitroxyl radical containing nanoparticle (2010)
  • Author(s): Yoshitomi T
  • Organizer: SFRBM 2010-17th Annual Meeting of the Society for Free Radical Biology and Medicine
  • Place of Presentation: Caribe Royale Hotel & Conference Center (Orlando, FL)
• [Presentation] Design of pH-sensitive radical-containing nanoparticle (RNP) as the EPR imaging of acidic pH environments (2010)
  • Author(s): Yoshitomi T
  • Organizer: 2010 International Chemical Congress of PacificBasinSocieties (PACIFICHEM 2010)
  • Place of Presentation: Hawaii Convention Center, 他 (Honolulu, HA)
• [Presentation] TEMPO含有ナノ粒子の開発と生体内動態 (2009)
  • Author(s): 吉冨徹、平山暁、間宮孝、松井裕史、長崎幸夫
  • Organizer: 第48回電子スピンサイエンス学会年会(SEST2009)
  • Place of Presentation: 神戸
  • Year and Date: 2009-11-12
• [Presentation] Development of TEMPOL-Containing Nano-Particle for Continuous Superoxide Scavenging and Antihypertension (2009)
  • Author(s): Hirayama A
  • Organizer: 42nd Annual meeting of the American Society of Nephrology(Renal Week 2009)
  • Place of Presentation: San Diego, California, United States of America
  • Year and Date: 2009-10-30
• [Presentation] Serum Multiple Free Radical Scavenging Activities in Dialysis Patients : Evaluated by Newly Developed Analytical Method Using EPR Spin Trapping. (2009)
  • Author(s): Owada S
  • Organizer: 42nd Annual meeting of the American Society of Nephrology(Renal Week 2009)
  • Place of Presentation: San Diego, California, United States of America
  • Year and Date: 2009-10-30
• [Presentation] ラジカル含有型ナノ粒子によるラット一過性脳虚血モデルにおける脳梗塞抑制効果 (2009)
  • Author(s): 丸島愛樹
  • Organizer: 第25回日本DDS学会
  • Place of Presentation: 東京
  • Year and Date: 2009-07-21
• [Presentation] Healing of Oxidative Stress in Brain on the Occasion of Cerebral Ischemia-Reperfusion. (2009)
  • Author(s): Yoshitomi T
  • Organizer: 2009 Gordon Research Conference on Biomaterials : Biocompatibility and Tissue Engineering
  • Place of Presentation: Plymouth, United States of America
  • Year and Date: 2009-07-19
• [Presentation] ジカル含有ナノ粒子を用いた脳虚血-再潅流モデルラットにおける脳梗塞の抑制 (2009)
  • Author(s): 藤加珠子
  • Organizer: 第62回日本酸化ストレス学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2009-06-21
• [Presentation] 生体内ROSの可視化を目指したEPRナノプローブの創製 (2009)
  • Author(s): 吉冨徹、間宮孝、松井裕史、平山暁、長崎幸夫
  • Organizer: 第62回日本酸化ストレス学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2009-06-11
• [Presentation] 安定した抗酸化・降圧効果を発揮するナノ粒子化TEMPOの開発 (2009)
  • Author(s): 平山暁,吉冨徹,植田敦志,青柳一正,長崎幸夫
  • Organizer: 第52回日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-06-03
• [Presentation] Stable Radical-containing Nanoparticles for Anti-oxydative Stress Disease (2009)
  • Author(s): Nagasaki Y
  • Organizer: FBPS2009
  • Place of Presentation: Mishima
  • Year and Date: 2009-05-20
• [Presentation] 酸化ストレスの検出を目指した還元型TEMPO内包pH応答性ナノ粒子(RNP-H)の設計と評価 (2009)
  • Author(s): 吉冨徹
  • Organizer: 第58回高分子学会年次大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-05-20
• [Presentation] Development of TEMPOL-Containing Nano-Particle for Continuous Superoxide Scavenging and Antihypertension. (2009)
  • Author(s): Hirayama A, Yoshitomi T, Ueda A, Matsui H, Owada S, Aoyagi K, Nagasaki Y
  • Organizer: 42nd Annual meeting of the American Society of Nephrology (Renal Week 2009)
  • Place of Presentation: San Diego
• [Presentation] Healing of Oxidative Stress in Brain on the Occasion of Cerebral Ischemia-Reperfusion. (2009)
  • Author(s): Yoshitomi T, Toh K, Marushima A, Suzuki K, Tsurushima H, Hirayama A, Matsumura A, Nagasaki Y
  • Organizer: 2009 Gordon Research Conference on Biomaterials: Biocompatibility and Tissue Engineering
  • Place of Presentation: Plymouth (USA)
• [Presentation] ラジカル含有ナノ粒子を用いた脳虚血-再潅流モデルラットにおける脳梗塞の抑制 (2009)
  • Author(s): 藤加珠子、吉冨徹、丸島愛樹、鈴木謙介、鶴嶋英夫、平山暁、松村明、長崎幸夫
  • Organizer: 第62回日本酸化ストレス学会学術集会
  • Place of Presentation: 福岡ポスターアワード(優秀演題賞)受賞演題)
• [Remarks]
  • URL: http://www.ims.tsukuba.ac.jp/~nagasaki_lab/index.htm
• [Patent(Industrial Property Rights)] 高分子環状ニトロキシドラジカル化合物とシリカの有機.無機ハイブリッド複合体 (2012)
  • Inventor(s): 長崎幸夫,吉冨徹,池田豊,植田敦志,平山暁,矢口達也,山下真代
  • Industrial Property Rights Holder: 国立大学法人筑波大学,国立大学法人筑波技術大学
  • Industrial Property Number: 2012-024460
  • Filing Date: 2012-02-07
• [Patent(Industrial Property Rights)] 高分子環状ニトロキシドラジカル化合物とシリカの有機-無機ハイブリッド複合体 (2012)
  • Inventor(s): 長崎幸夫, 吉冨徹, 池田豊, 植田敦志, 平山暁, 矢口達也, 山下真代
  • Industrial Property Rights Holder: 長崎幸夫, 吉冨徹, 池田豊, 植田敦志, 平山暁, 矢口達也, 山下真代および国立大学法人筑波大学国立大学法人筑波技術大学
  • Industrial Property Number: 2012-024460
  • Filing Date: 2012-02-07
• [Patent(Industrial Property Rights)] Polymerized cyclic nitro-xide radical compound, and use thereof (2010)
  • Inventor(s): NAGASAKI, Yukio. YOSHITOMI, Toru. MATSUI, Hirofumi. HIRAYAMA, Aki. MAMIYA, Takashi. MATSUMUR A, Akira. SUZUKI, Kensuke. TSURUSHIM A, Hideo. MARUSHIMA, Aiki. TOH, Kazuko MIYAMOTO, Daisuke
  • Industrial Property Rights Holder: NAGASAKI, Yukio. YOSHITOMI, Toru. MATSUI, Hirofumi. HIRAYAMA, Aki. MAMIYA, Takashi. MATSUMUR A, Akira. SUZUKI, Kensuke. TSURUSHIM A, Hideo. MARUSHIMA, Aiki. TOH, Kazuko MIYAMOTO, DaisukeおよびUniversity of Tsukuba
  • Filing Date: 2010-11-02
• [Patent(Industrial Property Rights)] Polymerized cyclic nitro-xide radical compound, and use thereof (2010)
  • Inventor(s): NAGASAKI, Yukio. YOSHITOMI, Toru. MATSUI, Hirofumi. HIRAYAMA, Aki. MAMIYA, Takashi. MATSUMUR A, Akira. SUZUKI, Kensuke. TSURUSHIM A, Hideo. MARUSHIMA, Aiki. TOH, Kazuko MIYAMOTO, Daisuke
  • Industrial Property Rights Holder: NAGASAKI, Yukio. YOSHITOMI, Toru. MATSUI, Hirofumi. HIRAYAMA, Aki. MAMIYA, Takashi. MATSUMUR A, Akira. SUZUKI, Kensuke. TSURUSHIM A, Hideo. MARUSHIMA, Aiki. TOH, Kazuko MIYAMOTO, DaisukeおよびUniversity of Tsukuba
  • Filing Date: 2010-11-02
  • Overseas
• [Patent(Industrial Property Rights)] Polymerized cyclic nitroxide radical compound, and use thereof (2009)
  • Inventor(s): NAGASAKI Yukio, YOSHITOMI Toru, MATSUI Hirofumi, HIRAYAMA Aki,MAMIYA Takashi, MATSUMURA Akira, SUZUKI Kensuke, TSURUSHIMA Hideo,MARUSHIMA Aiki, TOH Kazuko, MIYAMOTO Daisuke
  • Industrial Property Rights Holder: NAGASAKI Yukio, YOSHITOMI Toru, MATSUI Hirofumi, HIRAYAMA Aki, MAMIYA Takashi, MATSUMURA Akira, SUZUKI Kensuke, TSURUSHIMA Hideo, MARUSHIMA Aiki, TOH Kazuko, MIYAMOTO Daisuke, University of Tsukuba
  • Filing Date: 2009-05-11
  • Overseas
• [Patent(Industrial Property Rights)] Polymerized cyclic nitroxide radical compound, and use thereof (2009)
  • Inventor(s): NAGASAKI, Yukio. YOSHITOMI, Toru. MATSUI, Hirofumi. HIRAYAMA, Aki. MAMIYA, Takashi. MATSU-MURA, ra. SUZUKI, Kensuke. TSURUSHI-MA, Hideo. MARUSHI-MA, AiKi. TOH, Kazuko. MIYAMOTO, Daisuke
  • Industrial Property Rights Holder: NAGASAKI, Yukio. YOSHITOMI, Toru. MATSUI, Hirofumi. HIRAYAMA, Aki. MAMIYA, Takashi. MATSU-MURA, ra. SUZUKI, Kensuke. TSURUSHI-MA, Hideo. MARUSHI-MA, AiKi. TOH, Kazuko. MIYAMOTO, Daisukeおよび University of Tsukuba
  • Filing Date: 2009-05-11
  • Overseas
• [Patent(Industrial Property Rights)] Polymerized cyclic nitroxide radical compound, and use thereof (2009)
  • Inventor(s): NAGASAKI, Yukio. YOSHITOMI, Toru. MATSUI, Hirofumi. HIRAYAMA, Aki. MAMIYA, Takashi. MATSUMURA, Akira. SUZUKI, Kensuke. TSURUSHIMA, Hideo. MARUSHIMA, Aiki. TOH, Kazuko. MIYAMOTO, Daisuke
  • Industrial Property Rights Holder: 同左およびUniversity of Tsukuba
  • Filing Date: 2009-05-11
  • Overseas