DEPARTMENT OF CARDIOVASCULAR MEDICINE KYUSHU UNIVERSITY GRADUATE SCHOOL OF MEDICAL SCIENCES

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Research Units

Vascular Molecular Pathophysiology & Translational Research Unit


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menu Research Outline Main Research Themes and Relevant Publications Principle Investigator of the group Staff and Research Focus Research Outline Main Research Themes and Relevant Publications Profile of Lead Researcher Staffs and the Research Focus 研究概要 主要なテーマと関連論文 主任研究者情報 研究室情報

Main Research Themes and Relevant Publications


  1. Translational research of anti-inflammatory (anti-MCP-1, anti-NF-κB) therapies for intractable cardiovascular diseases
  2. Creation and clinical application of advanced nanomedicine by integrated nano-biomedical engineering

2. Creation and clinical application of advanced nanomedicine by integrated nano-biomedical engineering


  1. Research and development of revolutionary medical devices (such as development of unique nanoparticle coating technology, invention of bioabsorbable polymer, development of bioabsorbable Mg stent, invention of nanoparticle coating stent, and production of nanotechnology-based DDS catheter).

  2. Creation of nanomedicine by the development of inhaled nano-DDS

  3. Prevention of arteriosclerotic plaque rupture using selective monocyte/macrophage nano-DDS
  4. Minimally invasive angiogenesis therapy by selective vascular endothelial nano-DDS


As basic research that integrates advanced technologies aiming to achieve innovations, we have succeeded to develop nanomedicine and are heading for its clinical application. Press release of this achievement attracted great attention from the industrial sector, leading to collaboration with a medical device company in conducting a joint project of practical application.
http://www.hosokawamicron.co.jp/news/pdf/news20070222.pdf

Through this industry-university collaboration, we have established the foundation for the development of world-standard treatment devices (completely bioabsorbable nano-DDS control stent) and other innovative nanotherapies (including molecule-targeted therapy and therapeutic angiogenetic treatment using nanoparticle DDS for arteriosclerotic disease, and nanotherapy for intractable lung diseases using inhaled nano-DDS), which will realize minimally invasive therapies. The top priority goal is to apply the research results to clinical treatment. We are making progress in translational research (from bench to bedside) in collaboration with the Department of Intellectual Property and the Center of Highly Advanced Medical Center.


未来を拓くナノ医療  ナノ医工学融合による名の医療の創製と低侵襲安心医療実現
Research project 1: Minimally invasive intravascular nanomedicine based on intelligent DDS stent development by integrated nano-biomedical engineering
未来医療を拓く炎症制御による  生体完全吸収性ナノテクDDSステントの創製

Synopsis:
[Needs and background]
Japan has entered the era of an unprecedented aging society. The increase of arteriosclerotic diseases (including myocardial infarction, angina pectoris, stroke, and arteriosclerosis obliterans of peripheral arteries) aggravates the already soaring medical expenditure and may soon reach a point that the society can longer sustain. Therefore, efforts to overcome this situation need to be undertaken at a national level.

Percutaneous catheter intervention has gained popularity in the world as a treatment for arteriosclerotic diseases, and the global market is thus very large. Although drug-eluting stent (DES) is widely used in this treatment approach, some important issues associated with the current DES remain to be resolved. These issues include the increase in acute myocardial infarction and death due to late-onset thrombosis (see reference below), “permanent retention type”, coating difficulty for molecule-targeted drugs, and no domestically manufactured products.

[Objective]
The objective of this study was to create and clinically apply global-standard minimally invasive intravascular medical systems equipped with nanotechnology-based DDS control mechanisms (molecule-targeted drug-eluting, completely bio-absorbable DDS stent and DDS catheter) as the next generation devices capable of solving all the issues encountered in the clinical setting.

The specific goal is to develop innovative minimally invasive intravascular medical systems (molecule-targeted drug-eluting, completely bioabsorbable DDS stent and DDS catheter) with global competitive power, through integrating nano-biomedical technology. For this purpose, we pursue the research and development of the following three components. First, we propose a completely bioabsorbable stent using domestically manufactured noncombustible magnesium (Mg). Second, we coat the Mg stent with bioabsorbable nanoparticles using a proprietary coating method. Third, we aim to put into practical use these medical devices with high efficiency and low adverse effect capable of effectively delivering molecule-targeted drugs to arteriosclerotic lesions.

[Expected achievement (generating new industries and strengthening competitiveness of Japanese industry), originality, features, etc.]
Realization of revolutionary, minimally invasive nanomedicine based on nanotechnology-based DDS: If a completely bioabsorbable molecule targeted drug-eluting stent based on the development of nano-DDS control technique can be commercialized, then revolutionary nanotherapies for arteriosclerotic diseases (restenosis, myocardial infarction, stroke) can be established.

Benefits to the people, society and economy: If we succeed to develop this high-efficiency, low-adverse-effect minimally invasive medicine that improves patients’ QOL/survival and allows early social rehabilitation, this will lead to reduction and optimization of medical expenditures, which is a great contribution to the health, welfare and labor administration. In addition, the birth of nanomedicine with international completive power will generate new medical industries and contribute greatly to strengthen the competitive power of Japanese industries.

High originality through innovations by integration of advanced technologies: This research has extremely high originality because it is a challenge to develop global standard minimally invasive medical devices though integration of advanced technologies. Patents have been filed or obtained for all the techniques, materials and ideas. The technology is very difficult to imitate. Therefore, this product may become the Japanese developed global standard medical device with international competitive power.


Reference: The shock of late-onset thrombosis related to DES (PDF)

Research project 2: Creation of minimally invasive inhaled nanomedical system for severe pulmonary hypertension based on the development of inhaled DDS control technology

[Scientific background of research]
Pulmonary hypertension is classified into pulmonary arterial hypertension (idiopathic, collagen disorder, portal hypertension), pulmonary hypertension associated with left heart disease, pulmonary hypertension associated with lung disease and/or hypoxemia, pulmonary hypertension due to chronic thrombotic and/or embolic disease, and others (Venice 2003 revised classification). The prognosis of advanced severe pulmonary hypertension is usually very poor (5-year survival rate lower than 5%), and currently there is no effective treatment. Therefore, symptomatic and palliative treatments are the mainstay. Recently new therapies for severe pulmonary arterial hypertension have been established and attracted attention.

Continuous intravenous infusion of prostacyclin has gained popularity, and this treatment has improved survival. However, there are several issues related to continuous intravenous prostacyclin infusion: (1) the necessity of placing a central venous catheter, (2) the risk of infection, and (3) the need to carry the pump for intravenous infusion. These issues lower the patient’s QOL. Furthermore, oral medication is also increasingly being used, and treatment options have increased with the approval of endothelin antagonist (bosentan) and prostacyclin analogs (beraprost). However, even using these new therapies to their best advantages, the 5-year survival rate remains very low at 60%. Therefore research and development of a curative and minimally invasive therapy in accordance with the disease mechanisms for severe pulmonary hypertension has been long awaited.

For the past few years, we have collaborated with the industrial sector to develop an inhalation type drug delivery system (DDS) using a bioabsorbable high molecular weight polymer (poly-lactic-co-glycolic acid; PLGA). The world’s first “inhaled nano-DDS” preparation that we developed through integrating biomedical engineering is a proprietary product developed by our group. It has the following originality and features: (1) excellent intracellular delivery efficiency and intracellular stability, (2) the therapeutic factor delivered into cell is stable in the cell and released gradually (intracellular DDS), and (3) control technology with high-order structure by producing a composite form of nanoparticles with aerodynamic particle sizes (bronchioles: 2-7 μm, alveoli: 0.5-2 μm) optimal for inhalation (when nano-particles alone are inhaled, over 99% of the particles adhere to the oral cavity and tracheal wall, and do not reach the peripheral airway beyond the bronchioles. To deliver the factors to bronchioles and alveoli, the nanoparticles have to be made into a composite with aerodynamic particle size of 1-7 μm) (patent filed).

By developing this inhaled nano-DDS technology, therapeutic factors can be delivered stably into the cells of various lung tissues (including alveolar epithelium, bronchioles, arterioles and venules, alveolar macrophages). The major lesions in severe pulmonary hypertension are hyperproliferation, inflammation, contraction and thrombosis, leading to secondary damages of alveolar and airway. Therefore, direct delivery of therapeutic factors to lesions by the use of inhaled nano-DDS is the most appropriate treatment, and is an approach that may lead to the development of curative and minimally invasive treatment.

[Objective]
The objective of the present research is to conduct a feasibility study of whether the world’s first inhaled nano-DDS that we developed may become the breakthrough next generation treatment for severe pulmonary hypertension. Specifically, we seek to examine the following three points: (1) to demonstrate intracellular delivery of nanoparticles in cultured pulmonary arterial cells, (2) to administer nanoparticles intratracheally into animals and monitor their distribution and localization, and (3) to administer intratracheally molecule-targeted factors enclosed in nanoparticles into animal models of severe pulmonary hypertension, and evaluate its efficiency and safety.

Scientific features, originality, expected results and significance
[Scientific features and originality]
This research is a challenge to develop inhaled nano-DDS and therefore has high originality. This research is unique in proposing for the first time in the world the approach of delivering nanoparticles as far as the bronchiolar-alveolar level using composite nanoparticles as a powder inhalant. Technical features include the achievement of excellent intracellular delivery efficiency and intracellular stability. Using our technologies, breakthrough inhalation type nano-DDS with long-lasting action (at least 7 days) after one inhalation has been achieved.

[Expected results and significance]
This research has great clinical significance because if therapeutic factors can be delivered selectively to lesions by the use of an inhalation form of nano-DDS, this will lead to the development of innovative minimally invasive therapies for severe pulmonary hypertension. This novel treatment is expected to be safe for two reasons: (1) bioabsorbable polymer is used, and (2) greater effectiveness can be obtained using a lower dose of therapeutic substance compared to system administration. Moreover the long-acting, sustained effect after one inhalation will contribute greatly to improve patients’ QOL.

Since multiple administrations and multi-drug administration can be given easily using this inhalation type nano-DDS, individual molecule-targeting approach is possible for multiple factors (such as proliferation, inflammation, contraction and thrombosis) responsible for pulmonary hypertension. Therefore tailor-made therapy may be realized by combined use with genetic diagnosis.

Relevant Publications and Presentations
  1. 船越公太、江頭健輔:ステント内再狭窄の分子機構と生体吸収性ナノ粒子電着による遺伝子溶出ステントがもたらす新たな治療戦略. 日本薬理学雑誌 社団法人日本薬理学会 2007;129(3):171-176
  2. 船越公太、江頭健輔:ナノDDS制御コーティング技術の創製による次世代ステント内再狭窄抑制対策の開発. Mebio メジカルビュー社 2007;24(4):106-117
  3. Nakano K, Egashira K, Masuda S, Funakoshi K, Kimura S, Tsujimoto H, Hara K, Kawashima Y, Tominaga R, Sunagawa K. Development of a novel bioabsorbable polymeric nanoparticle drug or gene eluting stent by electro-deposit nanoparticle-coating technology. Jpn J Intervent Cardiol. 2007:22(3):201-210

For translational research, due to the importance of patent application, top priority has been placed on application for patents. For this reason, presentation of research results in conferences has been delayed. The following topics were presented in 2007 at the annual meetings of the Japanese Circulation Society, the Japanese College of Cardiology and the American Heart Association.

[Japan Circulation Society Meeting (March 2007)]

  1. プレナリーセッション「新たなるナノテクノロジーとは?」 Development of a Novel Bioabsorbable Polymeric Nanoparticle-Eluting Stent by an Actively-Controlled Multilayer Coating Technology
  2. 一般演題
  1. Sustained Intracellular Delivery of Nanoparticles in Porcine Coronary Arteries from a Bioabsorbable Polymeric Nanoparticle-Eluting Stent
  2. Intracellular Delivery of Imatinib (PDGF Receptor Tyrosine Kinase Inhibitor) with Bioabsorbable Polymeric Nanoparticle Technology Effectively Suppresses Vein Graft Neointima Formation
  3. A Novel Nanotechnology-Based Strategy for Therapeutic Neovascularization: Local Delivery of Statin with Biodegradable-Polymeric-Nanoparticle Improves Therapeutic Efficacy of Ischemic Neovascularization

[Japanese College of Cardiology Meeting (September 2007)]
  1. 教育講演

    「薬剤溶出性ステントの問題点(遅発性血栓症、など)と新しい次世代アプローチ(分子細胞標的薬溶出・生体吸収性ナノDDSステント)」


[American Heart Association Meeting (November 2007)]

  1. 「A Novel Anti-Inflammatory Therapeutic Approach for Pulmonary Arterial Hypertension: Blockade of NF-kB by Nano-DDS of NF-kB decoy to the lung ameliorates monocrotaline-induced PAH」
  2. 「Blockade of PDGF Receptor Tyrosine Kinase by Ex Vivo Nano-DDS of Imatinib Mesylate into the Vein Suppresses Vein Graft Neointima Formation」
  3. 「Nanoparticle-Mediated Intracellular Delivery of Imatinib, a PDGF Receptor Tyrosine Kinase Inhibitor, in Porcine Coronary Arteries from Nanoparticle-Eluting Stent Attenuates Neointimal Formation」
  4. 「An Innovative Therapeutic Approach for Pulmonary Arterial Hypertension: Single Intratracheal Administration of Bioabsorbable Nanoparticle Incorporated with Statin Ameliorates Monocrotaline-induced Pulmonary Artery Hypertension and Survival」
  5. 「Vascular Endothelial Growth Factor Accelerates Neointima Formation Through Flk-1 After Wire Injury In Flt-1 Tyrosine Kinase-deficient Mice」

  1. Translational research of anti-inflammatory (anti-MCP-1, anti-NF-κB) therapies for intractable cardiovascular diseases
  2. Creation and clinical application of advanced nanomedicine by integrated nano-biomedical engineering

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