Self-assembled micelles of amphiphilic poly(L-phenylalanine)-b-poly(L-serine) polypeptides for tumor-targeted delivery.
Self-assembled micelles of amphiphilic poly(L-phenylalanine)-b-poly(L-serine) polypeptides for tumor-targeted delivery.
复制标题
用于肿瘤靶向递送的两亲性聚（L-苯丙氨酸）-b-聚（L-丝氨酸）多肽的自组装胶束。
DOI：
10.2147/ijn.s73111
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发表时间：
2014
影响因子：
8
通讯作者：
Yin X
中科院分区：
文献类型：
--
作者：
Zhao Z;Wang Y;Han J;Wang K;Yang D;Yang Y;Du Q;Song Y;Yin X
本工作的目的是设计、合成和表征基于多肽的自组装胶束，作为潜在的抗肿瘤药物载体。以N-羧酸酐为原料，通过聚合反应制得了两亲性聚(L-苯丙氨酸)-b-聚L-丝氨酸(PFS)多肽。由于肿瘤对丝氨酸的大量需求，聚L-丝氨酸作为一种新型的亲水性链段被用于增强肿瘤靶向性。PFS可以自组装成平均直径为110-240 nm的胶束，并带有轻微的负电荷。PFS多肽在pH7.4的磷酸盐缓冲液中呈无规卷曲，在三氟乙醇诱导下可部分转化为α-螺旋。PFS胶束在pH 5~9的缓冲液和血清白蛋白溶液中稳定，临界胶束浓度为4.0μg m L−1。PFS胶束对香豆素-6的载药量为3.8%，具有缓释作用。将香豆素-6负载罗丹明B异硫氰酸酯标记的PFS胶束与Huh-7肿瘤细胞孵育，研究药物与载体在内吞过程中的相关性。药物的摄取与胶束是一致的，说明药物在细胞内的转运高度依赖胶束。PFS胶束弥散在整个细胞质中，而香豆素-6呈局域分布，表明胶束可在特定区域释放载药。PFS胶束的内化机制与胞苷介导的内吞作用和巨噬细胞吞噬作用有关。过量的丝氨酸抑制了PFS胶束的摄取，这表明丝氨酸受体在PFS的内化过程中起着积极的作用。更有趣的是，在生理浓度的丝氨酸下，摄取抑制对正常细胞有影响，但对肿瘤细胞没有影响。肿瘤细胞对PFS胶束的摄取是正常细胞的4倍，说明PFS胶束具有良好的体外肿瘤靶向性。综上所述，本文报道的PFS胶束是一种很有前途的肿瘤靶向治疗药物传递系统。
The aim of this work was to design, synthesize, and characterize self-assembled micelles based on polypeptides as a potential antitumor drug carrier. Amphiphilic poly(l-phenylalanine)-b-poly(l-serine) (PFS) polypeptides were obtained through the polymerization of N-carboxyanhydride. As a novel hydrophilic segment, poly(l-serine) was utilized to enhance tumor targeting due to a large demand of tumors for serine. PFS could self-assemble into micelles with an average diameter of 110–240 nm and a slightly negative charge. PFS polypeptides adopted random coil in pH 7.4 phosphate-buffered saline and could partly transform to α-helix induced by trifluoroethanol. PFS micelles with a low critical micelle concentration of 4.0 μg mL−1 were stable in pH 5–9 buffers and serum albumin solution. PFS micelles had a loading capacity of 3.8% for coumarin-6 and exhibited a sustained drug release. Coumarin-6 loaded rhodamine B isothiocyanate-labeled PFS micelles were incubated with Huh-7 tumor cells to study the correlation between drugs and carriers during endocytosis. The uptake of drugs was consistent with the micelles, illustrating that the intracellular transport of drugs highly depended on the micelles. PFS micelles diffused in whole cytoplasm while coumarin-6 assumed localized distribution, suggesting that the micelles could release the loaded drugs in particular areas. The internalization mechanism of PFS micelles was involved with clathrin-mediated endocytosis and macropinocytosis. Excess serine inhibited the uptake of PFS micelles, which demonstrated that serine receptors played a positive role in the internalization of PFS. The more interesting thing was that the uptake inhibition impacted on normal cells but not on tumor cells at the physiological concentration of serine. The difference in the uptake of PFS micelles was fourfold as high between the tumor cells and the normal cells, which indicated that PFS micelles had good tumor targeting in vitro. In conclusion, PFS micelles reported in this work were a promising drug delivery system for tumor targeting therapy.