National Glycoengineering Research Centre, Shandong University, Jinan 250012, Shandong, PR China; Shandong Provincial Key Laboratory of Carbohydrate chemistry and Glycobiology, Shandong University, Jinan, 250012, Shandong, PR China.
National Glycoengineering Research Centre, Shandong University, Jinan 250012, Shandong, PR China; Shandong Provincial Key Laboratory of Carbohydrate chemistry and Glycobiology, Shandong University, Jinan, 250012, Shandong, PR China; Institute of Advanced Medical Sciences, Shandong University, Jinan 250012, Shandong, PR, China.
J Control Release. 2018 Oct 28;288:1-13. doi: 10.1016/j.jconrel.2018.08.038. Epub 2018 Aug 29.
Anti-flt1 peptide (GNQWFI, AF) specifically binds to Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), thereby inhibiting the interaction of VEGFR1 with a series of ligands. ES2 (IVRRADRAAVP) can effectively inhibit the proliferation and invasion of endothelial cells and play a key role in anti-angiogenesis. AF and ES2 peptides differ in their activity. To better exploit the advantages of both, we designed a new peptide called ES2-AF (IVRRADRAAVPGGGGGGNQWFI). Hyaluronic acid (HA) is widely used in the pharmaceutical industry because of its biodegradable and high load performance. The HA-specific cell surface receptor CD44 was highly expressed in the tumour site during the anti-tumour study. Therefore, we used HA as a modifier to chemically modify ES2-AF; it was expected that the modified compound would have preferable solubility, stronger targeting, longer half-life, and better anti-angiogenesis effects in vivo. In this study, the anti-proliferative, anti-migration and targeting activities of HA-ES2-AF in vitro were studied by MTT, ELISA, transwell and SPR assays. Meanwhile, the anti-neovascularization activity of HA-ES2-AF in vivo was studied by CAM assay, and the targeting of HA-ES2-AF to tumour tissue was studied by bioimaging techniques. Finally, we also studied the half-life of HA-ES2-AF in vivo. In short, the bioactivity of the new peptide ES2-AF was enhanced to a certain extent, and ES2-AF modified by HA had higher anti-neovascularization activity in vitro and in vivo, had stronger targeting to tumour tissue, and had a significantly prolonged half-life in vivo. These results laid the foundation for its further development into targeting anti-tumour drugs.
抗 Flt1 肽（GNQWFI，AF）特异性结合血管内皮生长因子受体 1（VEGFR1），从而抑制 VEGFR1 与一系列配体的相互作用。ES2（IVRRADRAAVP）能有效抑制内皮细胞的增殖和侵袭，在抗血管生成中起关键作用。AF 和 ES2 肽在活性上存在差异。为了更好地发挥两者的优势，我们设计了一种新的肽，称为 ES2-AF（IVRRADRAAVPGGGGGGNQWFI）。透明质酸（HA）因其具有可生物降解和高负载性能而被广泛应用于制药工业。在抗肿瘤研究中，肿瘤部位的肿瘤细胞表面高表达透明质酸特异性细胞表面受体 CD44。因此，我们使用 HA 作为修饰剂对 ES2-AF 进行化学修饰；预计修饰后的化合物将具有更好的溶解性、更强的靶向性、更长的半衰期和更好的体内抗血管生成作用。在这项研究中，通过 MTT、ELISA、transwell 和 SPR 测定法研究了 HA-ES2-AF 在体外的抗增殖、抗迁移和靶向活性。同时，通过 CAM 测定法研究了 HA-ES2-AF 在体内的抗血管生成活性，并通过生物成像技术研究了 HA-ES2-AF 对肿瘤组织的靶向性。最后，我们还研究了 HA-ES2-AF 在体内的半衰期。总之，新肽 ES2-AF 的生物活性在一定程度上得到了增强，HA 修饰的 ES2-AF 具有更高的体外和体内抗血管生成活性，对肿瘤组织具有更强的靶向性，体内半衰期显著延长。这些结果为其进一步开发为靶向抗肿瘤药物奠定了基础。
