Gonçalves Mario, Estieu-Gionnet Karine, Berthelot Thomas, Laïn Georges, Bayle Mireille, Canron Xavier, Betz Natacha, Bikfalvi Andreas, Déléris Gérard
CEA Saclay, DSM/DRECAM/LSI/LPI, 91191, Gif-sur-Yvette Cedex, France.
Pharm Res. 2005 Aug;22(8):1411-21. doi: 10.1007/s11095-005-5265-9. Epub 2005 Aug 3.
Angiogenesis is a key event in tumor growth and metastasis, chronic inflammatory disease, and cardiovascular disease. It is controlled by positive and negative regulators, which include vascular endothelial growth factor (VEGF) as the most active of these. VEGF/VEGF receptors are important targets not only for therapy but also for imaging. Based on the structural study of VEGF, we developed a novel cyclopeptide (cyclo-VEGI) that exhibits powerful antitumor properties. We herein report the design of novel molecules derived from cyclo-VEGI as potential targeting agents in cancer and other angiogenesis-related diseases.
We performed selective chemical modification of the most active VEGF-derived cyclopeptide (cyclo-VEGI). Original hydrophilic linkers were synthesized and coupled to cyclo-VEGI. These reactions provide nanocarriers for delivery. The inhibitory effect of the different compounds on VEGF binding was evaluated in competition assays with 125I-VEGF. A fluorescent cyclo-VEGI peptide was synthezised to assess direct binding and internalization of cyclo-VEGI.
Chemical modifications of cyclo-VEGI do not diminish the biological activity of cyclo-VEGI as measured in competition assays; in fact, it is even increased. Moreover there is a strong cellular accumulation of the fluorescent-labeled cyclo-VEGI. Conjugates synthesized in this study may be useful leads to design delivery systems for targeting approaches in cancer and other angiogenesis-related diseases.
The modified cyclo-VEGIs may have a wide range of applications and represent a useful tool to develop delivery/carrier systems for therapeutic targeting or imaging.
血管生成是肿瘤生长、转移、慢性炎症性疾病和心血管疾病中的关键事件。它受正性和负性调节因子控制，其中血管内皮生长因子（VEGF）是最活跃的调节因子。VEGF/VEGF受体不仅是治疗的重要靶点，也是成像的重要靶点。基于对VEGF的结构研究，我们开发了一种具有强大抗肿瘤特性的新型环肽（环VEGI）。我们在此报告从环VEGI衍生的新型分子作为癌症和其他血管生成相关疾病潜在靶向剂的设计。
我们对活性最强的VEGF衍生环肽（环VEGI）进行了选择性化学修饰。合成了原始的亲水性连接体并将其与环VEGI偶联。这些反应提供了用于递送的纳米载体。在与125I-VEGF的竞争试验中评估了不同化合物对VEGF结合的抑制作用。合成了一种荧光环VEGI肽以评估环VEGI的直接结合和内化。
环VEGI的化学修饰在竞争试验中并未降低其生物活性；事实上，其生物活性甚至有所提高。此外，荧光标记的环VEGI在细胞中有很强的积累。本研究中合成的缀合物可能是设计用于癌症和其他血管生成相关疾病靶向方法的递送系统的有用先导物。
修饰后的环VEGI可能有广泛的应用，并代表了一种开发用于治疗靶向或成像的递送/载体系统的有用工具。
