National Glycoengineering Research Center, Shandong University, Qingdao 266237, China; NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Shandong University, Qingdao 266237, China; Shandong Provincial Technology Innovation Center of Carbohydrate, Shandong University, Qingdao 266237, China.
National Glycoengineering Research Center, Shandong University, Qingdao 266237, China; NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Shandong University, Qingdao 266237, China; Shandong Provincial Technology Innovation Center of Carbohydrate, Shandong University, Qingdao 266237, China.
Int J Biol Macromol. 2024 Mar;262(Pt 1):129671. doi: 10.1016/j.ijbiomac.2024.129671. Epub 2024 Feb 29.
Tumor growth and metastasis heavily rely on angiogenesis, crucial for solid tumor development. Inhibiting angiogenesis associated with tumors emerges as a potent therapeutic approach. Our previous work synthesized the chondroitin sulfate-modified antiangiogenic peptide CS-ES2-AF (CS-EA), which exhibited better antiangiogenic activity, longer half-life, and more robust targeting. In this work, we further evaluated the stability in vitro, cellular uptake mechanism, cell apoptosis mechanism, antitumor activity in vivo, and safety of CS-EA. The stability of CS-EA was consistently superior to that of EA at different temperatures and in different pH ranges. Furthermore, CS-EA mainly entered EAhy926 cells through the clathrin-mediated endocytosis pathway. CS-EA inhibited endothelial cell proliferation, and induced cell apoptosis through downregulating the Bcl-2, reducing mitochondria membrane potential, upregulating cytochrome c, Caspase 3, and reactive oxygen species levels. CS-EA showed better antitumor activity in the B16 xenografted tumor model, with a tumor inhibition rate 1.92 times higher than EA. Simultaneously, it was observed that CS-EA did not cause any harmful effects on the vital organs of the mice. These findings indicate that CS-EA holds significant promise for the treatment of tumors.
肿瘤的生长和转移严重依赖于血管生成，这对于实体瘤的发展至关重要。抑制与肿瘤相关的血管生成成为一种有效的治疗方法。我们之前的工作合成了硫酸软骨素修饰的抗血管生成肽 CS-ES2-AF（CS-EA），其表现出更好的抗血管生成活性、更长的半衰期和更强的靶向性。在这项工作中，我们进一步评估了 CS-EA 的体外稳定性、细胞摄取机制、细胞凋亡机制、体内抗肿瘤活性和安全性。CS-EA 的稳定性在不同温度和不同 pH 范围内始终优于 EA。此外，CS-EA 主要通过网格蛋白介导的内吞作用途径进入 EAhy926 细胞。CS-EA 通过下调 Bcl-2、降低线粒体膜电位、上调细胞色素 c、Caspase 3 和活性氧水平来抑制内皮细胞增殖并诱导细胞凋亡。CS-EA 在 B16 异种移植肿瘤模型中表现出更好的抗肿瘤活性，其肿瘤抑制率比 EA 高 1.92 倍。同时，观察到 CS-EA 对小鼠的重要器官没有造成任何有害影响。这些发现表明 CS-EA 在肿瘤治疗方面具有很大的潜力。
