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Effects of the anti-angiogenic carbohydrate-peptide conjugate, chitooligosaccharide-ES2 on endothelial cells and tumor-bearing mice

Wang, Zhendong, Li, Yan, Xing, Liang, Sun, Feng, Yang, Zhifang, Wang, Fengshan, Tan, Haining
Carbohydrate polymers 2019 v.208 pp. 302-313
angiogenesis, antineoplastic activity, apoptosis, caspase-3, cell cycle, chemical bonding, chitooligosaccharides, clathrin, endocytosis, endothelial cells, half life, immunohistochemistry, lipids, mice, neoplasms, pharmacokinetics, vascular endothelial growth factors
Most solid tumors require neovascularization during their growth. In our previous study, ES2 (IVRRADRAAVP) was covalently conjugated to soluble chitooligosaccharide chloride (HTCOSC) to form one novel HTCOSC-ES2 conjugate, which displayed better anti-angiogenic activity. In this work, the intracellular distribution and endocytosis of the conjugate in endothelial cells, as well effects on endothelial cell cycle and apoptosis were investigated. In addition, pharmacokinetic and antitumor studies were conducted. HTCOSC-ES2 entered the cell via clathrin and lipid valve pathway and was transported to the nucleus via lysosomal transport mechanism. Unlike ES2, HTCOSC-ES2 effectively inhibited the growth of endothelial cells and promoted apoptosis; thus, it could inhibit tumor angiogenesis, resulting in strong anti-tumor activity in vivo. The half-life of HTCOSC-ES2 was also prolonged, and its clearance was delayed. Immunohistochemistry assays showed that HTCOSC-ES2 obviously reduced the microvessel density, decreased the expression of VEGF, and increased the expression of caspase-3.