Yu Haiyang, Tang Zhaohui, Zhang Dawei, Song Wantong, Duan Taicheng, Gu Jingkai, Chen Xuesi
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China.
University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
Macromol Biosci. 2015 Jun;15(6):829-38. doi: 10.1002/mabi.201500040. Epub 2015 Mar 4.
A novel random copolypeptide of ornithine, arginine, glycine, and aspartic acid [Poly(ornithine-co-arginine-co-glycine-co-aspartic acid), Poly(O,R,G,D)] has been prepared through ring-opening polymerization of N-δ-carbobenzoxy-l-ornithine N-carboxyanhydride [Orn(Cbz)-NCA)], l-glycine N-carboxyanhydride (Gly-NCA) and β-benzyl l-aspartate N-carboxyanhydride [Asp(Bn)-NCA], following by subsequent deprotection and guanidization. The structure of Poly(O,R,G,D) was confirmed by nuclear magnetic resonance (NMR) spectroscopy and gel permeation chromatography (GPC). Low cytotoxicity of Poly(O,R,G,D) was confirmed from MTT assay. The Poly(O,R,G,D) contain some internal sequences of RXXR (X = O, R, G, or D) that could be proteolytically cleaved to expose the cryptic CendR element and bind to Neuropilin-1. This would lead to vascular and tissue permeabilization. Therefore trypsin-cleaved Poly(O,R,G,D) increase the vascular leakage of Evans blue from dermal microvessels at the injection site in vivo skin permeability assay. The intratumoral injection of the Poly(O,R,G,D) significantly enhanced the concentration of cisplatin-loaded nanoparticles in MCF-7 solid tumors. These results show that Poly(O,R,G,D) could increase the vascular leakage and tissue penetration of nanoparticles in a solid tumor and can be used as a potential polymeric tumor-penetrating agent.
通过N-δ-苄氧羰基-L-鸟氨酸N-羧基环酐[Orn(Cbz)-NCA]、L-甘氨酸N-羧基环酐（Gly-NCA）和β-苄基-L-天冬氨酸N-羧基环酐[Asp(Bn)-NCA]的开环聚合反应，随后进行脱保护和胍基化反应，制备了一种新型的鸟氨酸、精氨酸、甘氨酸和天冬氨酸的无规共聚物[聚（鸟氨酸-共-精氨酸-共-甘氨酸-共-天冬氨酸），聚（O，R，G，D）]。聚（O，R，G，D）的结构通过核磁共振（NMR）光谱和凝胶渗透色谱（GPC）得到证实。MTT试验证实了聚（O，R，G，D）的低细胞毒性。聚（O，R，G，D）含有一些RXXR（X = O、R G或D）的内部序列，这些序列可以被蛋白酶切割以暴露隐藏的CendR元件并与神经纤毛蛋白-1结合。这将导致血管和组织通透性增加。因此，在体内皮肤通透性试验中，胰蛋白酶切割的聚（O，R，G，D）增加了伊文思蓝从真皮微血管在注射部位的血管渗漏。聚（O，R，G，D）的瘤内注射显著提高了MCF-7实体瘤中载顺铂纳米颗粒的浓度。这些结果表明，聚（O，R，G，D）可以增加纳米颗粒在实体瘤中的血管渗漏和组织穿透，并可作为一种潜在的聚合物肿瘤穿透剂。
