Design of Polymeric Supramolecular-assembly for Targeted Therapy of Liver

为了设计用于肝脏靶向治疗的两亲性糖基共聚物，合成了能够识别多种肝细胞的寡糖载体聚合物。载乳糖聚苯乙烯(PVLA)聚合物胶束及其包被纳米粒可通过去唾液酸辅蛋白受体(ASGP-R)有效地掺入肝细胞。含有半胱氨酸酶抑制剂(Z-Asp)的PVLA包被的聚乳酸纳米粒成功地靶向于肝脏中的肝细胞，并有效地被释放以挽救肝炎相关细胞的凋亡。由肝脏凝集素1和2(HL-1，2)组成的ASGP-R被转染CHO-K1细胞表明，HL-1和2的寡聚结合导致了PVLA包被的纳米粒具有更高的细胞识别能力。基于这一发现，合成了聚(L-赖氨酸)主链与阿拉伯半乳糖(β-Galactos富含多年生多烯类多糖)为载体的树枝状接枝共聚物，并研究了其对肝细胞和肝癌细胞的识别作用；合成了载玻尿酸的聚(L-赖氨酸)用于肝窦内皮细胞的特异性基因靶向。

In order to design amphiphilic glycopolymers for targeted therapy of liver, oligosaccharide-carrying polymers which can recognize various kinds of liver cells were synthesized. Polymeric micel of lactose-carrying polystyrene (PVLA) and its coated nanoparticle were found out to be efficiently incorporated into hepatocyte mediated by asialogly coprotein receptor (ASGP-R). Poly (lactic acid) nanopaticles coated with PVLA involving caspase inhibitor (Z-Asp) were successfully targeted to hepatocytes in liver and effectively released to rescue hepatitis related cell apoptosis.The transfections of ASGP-R consisting of hepatic lectin 1 and 2 (HL-1,2) into CHO-Kl cells indicated that oligomeric association of HL-1 and 2 are responsible to higher cell-recognition of PVLA-coated nanoparticle.Based on the finding, dendritic graft copolymers of poly (L-lysine) main chain and arabiogalactan (β-galactos rich multi-anntenary polysaccharide) as DNA carrier were synthesized and evaluated for the recognition by ASGP-R of hepatocytes and hepatoma cells.Hyaluronic acid carrying poly (L-lysine) were also synthesized to be applied for specific DNA-targeting to liver sinusoidal endothelial cells.The concept of supramolecular-assembly systems such as polymeric micels, nanoparticles and polymer complex are successfully proposed.