Liu Yanxi, Li Qiuyi, Xiong Xiaofeng, Huang Yuan, Zhou Zhou
Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P. R. China.
J Mater Chem B. 2018 Dec 14;6(46):7674-7683. doi: 10.1039/c8tb02621a. Epub 2018 Nov 6.
Targeting drugs at mitochondria may provide an effective means of inducing cell death for cancer therapy. Here, we introduce a conjugate of a dual-ligand-modified N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer with α-tocopheryl succinate (α-TOS) (P-TOS-SS20-dNP2), which could simultaneously enhance cellular uptake via the cell-penetrating peptide dNP2 and implement delivery to mitochondria by means of the mitochondria-targeting peptide SS20. The results showed that co-modification with SS20 and dNP2 peptides successfully made up for the deficiencies of each peptide: copolymers singly modified with dNP2 were unable to increase their mitochondrial distribution in spite of increased cellular uptake, whereas copolymers singly modified with SS20 exhibited restricted mitochondrial targeting because of their poor uptake. The combination of these two functional peptides resulted in conspicuous cellular uptake and a 7.6-fold increase in accumulation in mitochondria in comparison with unmodified HPMA polymer-drug conjugates in vitro. Moreover, the dual-modified polymer-drug conjugate P-TOS-SS20-dNP2 exhibited the greatest increase in the generation of reactive oxygen species in HeLa cells, followed by great opening of mitochondrial permeability transition pores and a sharp reduction in the mitochondrial membrane potential. This further led to superior cell apoptosis in comparison with singly or non-peptide-modified HPMA copolymer-drug conjugates. The results demonstrated that combining a mitochondria-targeting peptide and a cell-penetrating peptide would substantially increase the distribution of HPMA copolymers in mitochondria, which implied an efficient strategy for promoting mitochondrial targeting efficiency.
将药物靶向线粒体可能为癌症治疗提供一种诱导细胞死亡的有效方法。在此，我们介绍一种双配体修饰的N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物与α-生育酚琥珀酸酯(α-TOS)的缀合物(P-TOS-SS20-dNP2)，它可以通过细胞穿透肽dNP2同时增强细胞摄取，并通过线粒体靶向肽SS20实现向线粒体的递送。结果表明，用SS20和dNP2肽进行共修饰成功弥补了每种肽的不足：单独用dNP2修饰的共聚物尽管细胞摄取增加，但无法增加其线粒体分布，而单独用SS20修饰的共聚物由于摄取不佳而表现出线粒体靶向受限。这两种功能肽的组合导致明显的细胞摄取，并且与未修饰的HPMA聚合物-药物缀合物相比，线粒体中的积累增加了7.6倍。此外，双修饰的聚合物-药物缀合物P-TOS-SS20-dNP2在HeLa细胞中活性氧生成的增加最大，其次是线粒体通透性转换孔的大量开放和线粒体膜电位的急剧降低。这进一步导致与单肽或非肽修饰的HPMA共聚物-药物缀合物相比具有更高的细胞凋亡率。结果表明，将线粒体靶向肽和细胞穿透肽结合起来将大大增加HPMA共聚物在线粒体中的分布，这意味着一种提高线粒体靶向效率的有效策略。
