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Establishment of Antineovascular Therapy by use of Structure-recognizing targeting probes

结构识别靶向探针抗血管治疗的建立

基本信息

批准号：
15390050
负责人：
OKU Naoto
金额：
$ 9.66万
依托单位：
UNIVERSITY OF SHIZUOKA
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

We previously developed a new modality of cancer treatment by use of DDS technology, in which anticancer drugs are effectively delivered to the angiogenic endothelial cells of a solid tumor. Antineovascular therapy (ANET) may cause indirect lethal damage of tumor cells through the damage of newly formed blood vessels with reduced side effects. At first, we isolated peptides specific for tumor angiogenic vasculature using a phage-displayed peptide library. Thus obtained pentapeptide APRPG was used for the modification of liposomes. In the present study, we firstly synthesized APRPG-polyethyleneglycol (PEG)-lipid for the purpose of improving ANET. Positron Emission Tomography (PET) study indicated that APRPG-PEG-modified liposomes had long-circulating characteristics and accumulated in tumor in tumor-bearing mice. APRPG-PEG-modified liposomes encapsulating adriamycin caused strong tumor growth suppression through possible damaging of angiogenic endothelial cells. The accumulation of APRP … More G-PEG-liposomes was quite similar to that of control PEG-liposomes. However, intratumoral distribution of APRPG-PEG-liposomes was quite different from the control liposomes : The former colocalized with endothelial cells, and the latter accumulated the surrounding of the blood vessels when the intratumoral distribution of fluorescence-labeled liposomes was examined by confocal laser scanning microscopy. We also observed that the APRPG-PEG-liposomes were quite useful for antiangiogenic photodynamic therapy. To clarify the molecular mechanism of angiogenesis, and to provide novel targets for antineovascular therapy, we performed proteomic analysis of HUVEC treated with VEGF or cancer cells-conditioned medium by two-dimensional difference in-gel electrophoresis (2D-DIGE) and identified differentially expressed proteins by MALDI-TOF-MS. Proteomic analysis of HUVEC treated with VEGF detected >3500 protein spot and identified a number of differentially expressed proteins. This proteomic approach may improve ANET through providing structure-recognizing targeting probes to angiogenic site. Less

我们以前开发了一种新的癌症治疗模式，通过使用DDS技术，其中抗癌药物被有效地递送到实体瘤的血管生成内皮细胞。抗肿瘤血管治疗（ANET）可以通过损伤新生血管对肿瘤细胞造成间接致命性损伤，同时减少副作用。首先，我们使用噬菌体展示肽库分离肿瘤血管生成血管特异性肽。由此获得的五肽APRPG用于脂质体的修饰。本研究首次合成了APRPG-聚乙二醇（PEG）-脂质，以改善ANET。正电子发射断层扫描（PET）研究表明，APRPG-PEG修饰的脂质体具有长循环特性，并在荷瘤小鼠体内蓄积。APRPG-PEG修饰的脂质体包裹阿霉素通过可能的血管生成内皮细胞损伤引起强烈的肿瘤生长抑制。APRP的积累 ...更多信息 G-PEG-脂质体与对照PEG-脂质体非常相似。然而，肿瘤内分布的APRPG-PEG-脂质体是完全不同的对照脂质体：前者与内皮细胞共定位，后者积累的血管周围时，肿瘤内分布的荧光标记的脂质体的共聚焦激光扫描显微镜检查。我们还观察到，APRPG-PEG-脂质体是相当有用的抗血管生成的光动力疗法。为了阐明血管生成的分子机制，为抗血管生成治疗提供新的靶点，我们用双向差异凝胶电泳（2D-DIGE）对经VEGF或癌细胞条件培养基处理的HUVEC进行蛋白质组学分析，并用MALDI-TOF-MS鉴定差异表达的蛋白质。3500个蛋白点，鉴定出一批差异表达蛋白。这种蛋白质组学方法可能通过提供结构识别的靶向探针到血管生成位点来改善ANET。少