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

我们之前利用DDS技术开发了一种新的癌症治疗方法，即抗癌药物有效地输送到实体肿瘤的血管生成内皮细胞。抗血管治疗(ANET)可能通过损伤新生血管对肿瘤细胞造成间接致命性损伤，且副作用减少。首先，我们利用噬菌体展示的多肽库来分离肿瘤血管生成的特异性多肽。将得到的五肽APRPG用于脂质体的修饰。在本研究中，我们首次合成了APRPG-聚乙二醇脂类，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修饰的阿霉素脂质体可能通过破坏血管生成的内皮细胞而导致肿瘤生长受到强烈的抑制。碱性磷酸酶…的蓄积更多的G-聚乙二醇脂质体与对照的聚乙二醇脂质体相似。然而，APRPG-PEG-脂质体在肿瘤内的分布与对照组有很大不同：前者与内皮细胞共定位，后者在激光共聚焦扫描显微镜下观察到荧光标记的脂质体在瘤内的分布时，后者聚集在血管周围。我们还观察到APRPG-PEG-脂质体在抗血管生成光动力学治疗中非常有用。为了阐明血管生成的分子机制，并为抗血管治疗提供新的靶点，我们利用二维差示凝胶电泳法(2D-DGE)对经血管内皮生长因子(VEGF)或癌细胞条件培养液处理的人脐静脉内皮细胞(HUVEC)进行蛋白质组学分析，并用MALDI-TOF-MS鉴定差异表达蛋白质。蛋白质组学分析检测到&gt；3500蛋白斑点，鉴定出多个差异表达的蛋白质。这种蛋白质组学方法可能通过为血管生成部位提供结构识别靶向探针来改进ANET。较少

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