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

我们之前通过使用DDS技术开发了一种新的癌症治疗模式，其中抗癌药物有效地传递到实体瘤的血管生成内皮细胞。抗肿瘤血管治疗（ANET）可能通过损伤新生血管对肿瘤细胞造成间接致死性损伤，但副作用较小。首先，我们使用噬菌体展示肽库分离肿瘤血管生成的特异性肽。由此获得的五肽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(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，并在荷瘤小鼠的肿瘤中积累。aprpg - peg修饰的脂质体包裹阿霉素，通过可能破坏血管生成内皮细胞，对肿瘤生长产生强烈的抑制作用。g - peg -脂质体的APRP积累量与对照组相当。然而，当共聚焦激光扫描显微镜观察荧光标记脂质体在肿瘤内的分布时，aprpg - peg -脂质体在肿瘤内的分布与对照脂质体有很大不同：前者与内皮细胞共定位，后者积聚在血管周围。我们还观察到aprpg - peg -脂质体在抗血管生成光动力治疗中非常有用。为了阐明血管生成的分子机制，并为抗肿瘤治疗提供新的靶点，我们通过二维凝胶电泳（2D-DIGE）对VEGF或癌细胞条件培养基处理的HUVEC进行了蛋白质组学分析，并通过MALDI-TOF-MS鉴定了差异表达蛋白。对VEGF处理的HUVEC进行蛋白质组学分析，检测到>3500蛋白点，并鉴定出许多差异表达蛋白。这种蛋白质组学方法可以通过提供血管生成位点的结构识别靶向探针来改善ANET。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