Development of new method of therapeutic angiogeneis using sustained-release of multiple growth factors.

开发使用缓释多种生长因子的治疗性血管生成新方法。

• 批准号: 16390395
• 负责人: IKEDA Tadashi
• 金额: $ 8.58万
• 依托单位: Kyoto University.
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390395/
• 关键词: therapeutic angiogenesis; growth factors; basic fibroblast growth factor; bFGF; drug delivery; b-FGF

We have reported so far that sustained-release of basic fibroblast growth factor (bFGF) augments tissue reperfusion and functional improvement both in animal models of myocardial infarction and hindlimb ischemia. However, sustained-release of bFGF alone is not sufficient to generate stable blood vessels. Moreover, in the clinical situations, presence of diabetus or hypercholesterolemia may hamper the angiogenic effect of bFGF. To overcome these problems, we investigated the effects of adjuvant thearapies combined with sustained-release of bFGF.In the present study, we have found that combined treatment with sustained-release bFGF and heparin synergistically enhances neovascularization in the hindlimb ischemia of hypercholesterolemic mice with impaired angiogenic responses to the ischemic stimulus. We are also reporting that 5HT receptor blocker, sarpogrerate has similar effect in diabetic rats. We also demonstrated that the sustained dual release of a lower dose of bFGF and hepatocyte growth factor (HGF) achieve equivalent tissue reperfusion and more mature vasculature in the ischemic limb than a higher dose of bFGF or HGF alone.Using a rat model of chronic myocardial infarction, we demonstrated the sustained-release of erythropoietin improved left ventricular function without inducing polycythemia. We also examined the effect of sustained-release of granulocyte colony stimulating factor (G-CSF), which revealed no significant improvement compared with control.From these results, we are designing clinical protocols of therapeutic angiogenesis to treat limb ischemia and choronic myocardial ischemia.

到目前为止，我们已经报道了持续释放的碱性成纤维细胞生长因子（bFGF）增强组织再灌注和功能改善，无论是在动物模型的心肌梗死和后肢缺血。然而，单独的bFGF的持续释放不足以产生稳定的血管。此外，在临床情况下，糖尿病或高胆固醇血症的存在可能会阻碍bFGF的血管生成作用。为了克服这些问题，我们调查的影响，辅助thearapies结合缓释bfGF.In目前的研究中，我们发现，联合治疗与缓释bFGF和肝素协同增强血管生成反应受损的高胆固醇血症小鼠后肢缺血缺血缺血。我们还报道了5-HT受体阻断剂沙格雷酯在糖尿病大鼠中具有类似的作用。我们还表明，持续的低剂量的bFGF和肝细胞生长因子（HGF）的双重释放实现等效的组织再灌注和更成熟的血管在缺血limb.Using慢性心肌梗死的大鼠模型，我们证明了持续释放的促红细胞生成素改善左心室功能，而不诱导红细胞增多症。我们还研究了粒细胞集落刺激因子（G-CSF）的缓释效果，与对照组相比，没有显着改善。从这些结果，我们正在设计治疗性血管生成治疗肢体缺血和脉络膜心肌缺血的临床方案。

项目成果

Combined treatment with sustained-release basic fibroblast growth factor and heparin enhances neovascularization in hypercholesterolemic mouse hindlimb ischemia

• DOI: 10.1253/circj.71.412
• 发表时间: 2007-03-01
• 期刊: CIRCULATION JOURNAL
• 影响因子: 3.3
• 作者: Arai, Yoshio;Fujita, Masatoshi;Komeda, Masashi
• 通讯作者: Komeda, Masashi

Therapeutic angiogenesis by the controlled release of basic fibroblast growth factor for ischemic limb and heart injury : toward safety and minimal invasiveness.

通过控制释放碱性成纤维细胞生长因子治疗缺血性肢体和心脏损伤的治疗性血管生成：走向安全和微创。

• 发表时间: 2004
• 期刊: J Artif Organs 7
• 作者: Nakajima H;Sakakibara Y;Tambara K;Iwakura A;Doi K;Marui A;Ueyama K;Ikeda T;Tabata Y;Komeda M
• 通讯作者: Komeda M

ASO治療の現在・未来bFGFを用いた血管新生治療実験の結果より

ASO治疗的现状和未来 从bFGF的血管生成治疗实验结果来看

• 发表时间: 2004
• 期刊: Cardiovascular Med-Surg 6
• 作者: 廣瀬圭一;丸井晃;新井善雄;洞井和彦;池田義;米田正始
• 通讯作者: 米田正始

A novel approach to therapeutic angiogenesis for patients with critical limb ischemia by sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel ---- Initial report of the phase I-IIa study.

通过使用可生物降解的明胶水凝胶持续释放碱性成纤维细胞生长因子来治疗严重肢体缺血患者的血管生成的新方法---- I-IIa 期研究的初步报告。

• 发表时间: 2007
• 期刊: Circulation J. (in press)
• 作者: Marui A;Tabata Y;Kojima S;Yamamoto M;Tambara K;Nishina T;Saji Y;Inui K;Hashida T;Yokoyama S;Onodera R;Ikeda T;Fukushima M;Komeda M.
• 通讯作者: Komeda M.

Simultaneous application of basic fibroblast growth factor and hepatocyte growth factor to enhance the blood vessels formation.

同时应用碱性成纤维细胞生长因子和肝细胞生长因子，增强血管形成。

• 发表时间: 2005
• 期刊: J Vasc Surg. 41
• 作者: Marui A;Kanematsu A;Yamahara K;Doi K;Kushibiki T;Yamamoto M;Itoh H;Ikeda T;Tabata Y;Komeda M.
• 通讯作者: Komeda M.