Cui Yani, Sui Junhui, He Mengmeng, Xu Zhiyi, Sun Yong, Liang Jie, Fan Yujiang, Zhang Xingdong
National Engineering Research Center for Biomaterials, Sichuan University , 29 Wangjiang Road, Chengdu 610064, China.
ACS Appl Mater Interfaces. 2016 Jan 27;8(3):2193-203. doi: 10.1021/acsami.5b10867. Epub 2016 Jan 12.
In this study, five kinds of reduction-degradable polyamide amine-g-polyethylene glycol/polyarginine (PAA-g-PEG/PArg) micelles with different proportions of hydrophilic and hydrophobic segments were synthesized as novel drug delivery vehicles. Polyarginine not only acted as a hydrophilic segment but also possessed a cell-penetrating function to carry out a rapid transduction into target cells. Polyamide amine-g-polyethylene glycol (PAA-g-PEG) was prepared for comparison. The characterization and antitumor effect of the DOX-incorporated PAA-g-PEG/PArg cationic polymeric micelles were investigated in vitro and in vivo. The cytotoxicity experiments demonstrated that the PAA-g-PEG/PArg micelles have good biocompatibility. Compared with DOX-incorporated PAA-g-PEG micelles, the DOX-incorporated PAA-g-PEG/PArg micelles were more efficiently internalized into human hepatocellular carcinoma (HepG2) cells and more rapidly released DOX into the cytoplasm to inhibit cell proliferation. In the 4T1-bearing nude mouse tumor models, the DOX-incorporated PAA-g-PEG/PArg micelles could efficiently accumulate in the tumor site and had a longer accumulation time and more significant aggregation concentration than those of PAA-g-PEG micelles. Meanwhile, it excellently inhibited the solid tumor growth and extended the survival period of the tumor-bearing Balb/c mice. These results could be attributed to their appropriate nanosize and the cell-penetrating peculiarity of polyarginine as a surface layer. The PAA-g-PEG/PArg polymeric micelles as a safe and high efficiency drug delivery system were expected to be a promising delivery carrier that targeted hydrophobic chemotherapy drugs to tumors and significantly enhanced antitumor effects.
在本研究中，合成了具有不同亲水和疏水链段比例的五种还原可降解聚酰胺胺 - g - 聚乙二醇/聚精氨酸（PAA - g - PEG/PArg）胶束作为新型药物递送载体。聚精氨酸不仅作为亲水链段，还具有细胞穿透功能，可快速转导进入靶细胞。制备了聚酰胺胺 - g - 聚乙二醇（PAA - g - PEG）用于比较。对负载阿霉素的PAA - g - PEG/PArg阳离子聚合物胶束进行了体外和体内表征及抗肿瘤作用研究。细胞毒性实验表明，PAA - g - PEG/PArg胶束具有良好的生物相容性。与负载阿霉素的PAA - g - PEG胶束相比，负载阿霉素的PAA - g - PEG/PArg胶束更有效地内化进入人肝癌（HepG2）细胞，并更快地将阿霉素释放到细胞质中以抑制细胞增殖。在携带4T1的裸鼠肿瘤模型中，负载阿霉素的PAA - g - PEG/PArg胶束可有效积聚在肿瘤部位，与PAA - g - PEG胶束相比，具有更长的积聚时间和更高的聚集浓度。同时，它能出色地抑制实体瘤生长并延长荷瘤Balb/c小鼠的生存期。这些结果可归因于其合适的纳米尺寸以及聚精氨酸作为表面层的细胞穿透特性。PAA - g - PEG/PArg聚合物胶束作为一种安全高效的药物递送系统，有望成为一种有前途的递送载体，将疏水性化疗药物靶向肿瘤并显著增强抗肿瘤效果。
