新型多臂两亲性嵌段共聚物纳米粒子用于肝癌的靶向治疗

Liver is one of the most important and complex organs in the body. Liver cancer with a high mortality has led to serious threat to human health. As one of the main cancer treatment approaches, chemotherapy is often limited by the toxicity of anticancer drugs to normal tissues and cells. To reduce the side-effects and increase the therapeutic efficacy of anticancer drugs, targeted drug delivery system of nanoparticles is the most promising anticancer drug vectors. The asialoglycoprotein receptor (ASGPR) on mammalian hepatocytes has a special recognition of galactose, lactobionic acid, and lactose ligands provides a unique means for the development of liver targeted drug delivery systems. In this project, from the standpoint of materials design, the dipentaerythritol (DPTOL) is used as initiator, star-shaped copolymers with amino poly(lactide-ran-glycolide) -b-Polyethylene (6-PLGA-b-PEG-NH2) were synthesized by the ring-opening polymerization. The materials can fully retain the excellent inherent biological properties of PLGA and PEG because the chemistry components of materials do not change. The star-shaped block copolymers can generate more amino-terminated and have higher drug loading efficiency. Therefore, the nanoparticles which prepared by star-shaped copolymers can carry more targeted molecular lactobionic acid than line copolymers. The nanoparticles combine the advantages of PLGA-b-PEG and the high targeting efficiency of lactobionic acid. In order to construct the novel multi-functional targeted nanocarrier with our own intellectual property, the cytotoxicity, targeting efficiency and possible side-effects of nanoparticles are investigated through liver targeted drug delivery systems (LTDDS).

肝脏是人体的重要器官，肝癌等疾病导致了大量的死亡，严重威胁人类的健康。纳米靶向药物传递系统相对传统肝癌疗法具有高效、低毒、副作用小等优点。肝细胞表面存在大量去唾液酸糖蛋白受体(ASGPR)，可特异性识别半乳糖类化合物。本研究将从材料设计角度出发，以含多羟基的双季戊四醇(DPTOL)为引发剂合成一系列带氨基的新型多臂PLGA-b-PEG-NH2两亲性嵌段共聚物，由于没有改变材料的化学组分，因而可完全保留PLGA与PEG所固有的优异生物学性能。星型多臂的分子构型使纳米粒子具有更高载药量和更丰富的端氨基，可以携带比线性聚合物更多的靶向分子乳糖酸，将乳糖酸的高效肝靶向性和PLGA-b-PEG的优异性能相结合。通过肝靶向药物传递系统，研究纳米粒子在体内外细胞毒性、靶向效果和抑瘤效果，在分子和细胞水平上研究靶向机理，并对纳米粒子进行改进，以期获得具有我国自主知识产权的新型多功能靶向药物载体。

肝脏是人体的重要器官，肝癌等疾病导致了大量的死亡，严重威胁人类的健康。纳米靶向药物传递系统相对传统肝癌疗法具有高效、低毒、副作用小等优点。肝细胞表面存在大量去唾液酸糖蛋白受体(ASGPR)，可特异性识别半乳糖类化合物。本研究将从材料设计角度出发，成功合成了以胆酸、甘露醇、双季戊四醇和Boltorn H40为核的星型聚合物CA-PLGA-b-TPGS、M-PLGA-b-TGPS、6-PLGA-b-PEG-NH2和H40-PLA- b –TPGS。由于没有改变材料的化学组分，因而可完全保留可降解聚合物所固有的优异生物学性能。聚合物6-PLGA-b-PEG-NH2用于负载多烯紫杉醇制备纳米药物DTX/NPs。在EDC/NHS条件下，纳米药物DTX/NPs和靶向配体乳糖酸LA偶联，最终制备了对肝癌具有靶向效果的纳米药物DTX/NPs-LA。体外细胞实验表明靶向纳米药物对肝癌细胞HepG2具有明显的靶向效果，其细胞毒性优于没有偶联乳糖酸的纳米药物和商品化多烯紫杉醇制剂泰素帝Taxotere，裸鼠体内实验表明靶向纳米药物对肝癌具有明显的抑瘤效果。所有的实验结果表明这种生物相容性的靶向纳米药物在肿瘤的治疗方面具有良好的应用前景。此外，本课题还研究了载药纳米粒细胞内转运机制，即细胞可通过自噬通路吞噬、转运并降解聚合物纳米粒。研究发现细胞自噬抑制剂可以抑制化疗药物多烯紫杉醇引起的细胞自噬，同时也可以阻断细胞自噬通路降解纳米粒，保证载药纳米粒在细胞浆中持续的药物释放，从而提高药物治疗效果。本课题在Biomaterials、Acta Biomaterialia、Advanced Healthcare Materials、Particle & Particle Systems Characterization等国际知名期刊发表20余篇高水平论文，其中21篇被SCI收录，申请国家发明专利8项，授权专利3项，研究成果已达到国内领先、国际先进水平。