Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide.
Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide.
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二硒键稳定环肽介导的肿瘤靶向脂质体药物递送
DOI：
10.2147/ijn.s40498
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发表时间：
2013
影响因子：
8
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Li C;Wang Y;Zhang X;Deng L;Zhang Y;Chen Z
肽配体作为靶向部分在肿瘤靶向药物递送中发挥着重要作用。肽介导的药物递送系统的体内命运和随后的抗肿瘤作用可能很大程度上取决于肽配体的稳定性。本研究通过噬菌体展示筛选出一种肿瘤靶向环肽Lyp-1（一种在某些肿瘤中特异性结合肿瘤和肿瘤淋巴管内皮细胞的肽），通过用二硒键取代原来的分子内二硫键进行结构修饰。表面等离振子共振测定表明，所产生的类似物Syp-1（Lyp-1的硒代衍生物）保持了与靶蛋白p32的特异性结合能力（Kd = 18.54 nM），这与Lyp-1（Kd = 10.59 nM）相似。与Lyp-1相比，Syp-1对血清的稳定性显着提高。将肽附着到封装荧光团的脂质体表面后，观察到 Syp-1 介导的肿瘤对脂质体荧光团的更有效摄取。此外，Syp-1修饰的脂质体阿霉素在所有治疗组中表现出最有效的肿瘤生长抑制能力，体外对MDA-MB-435细胞的半数抑制浓度低至588 nM，体内肿瘤抑制率高达73.5%。这些发现清楚地表明Syp-1是一种稳定有效的肿瘤靶向配体，并表明硫硒替代策略可能有助于在生理条件下稳定噬菌体展示的含有二硫键的环肽，并有力地支持肽介导的药物靶向的有效性。
Peptide ligands have played an important role in tumor-targeted drug delivery as targeting moieties. The in vivo fate of peptide-mediated drug delivery systems and the following antitumor effects may greatly depend on the stability of the peptide ligand. In the current study, a tumor-targeting cyclic peptide screened by phage display, Lyp-1 (a peptide that specifically binds to tumor and endothelial cells of tumor lymphatics in certain tumors), was structurally modified by replacement of the original intramolecular disulfide bond with a diseleno bond. The produced analog Syp-1 (seleno derivative of Lyp-1) maintained specific binding ability to the target protein p32 (Kd = 18.54 nM), which is similar to that of Lyp-1 (Kd = 10.59 nM), indicated by surface plasmon resonance assay. Compared with Lyp-1, Syp-1 showed significantly improved stability against serum. After the peptide attached onto the surface of fluorophore-encapsulating liposomes, the more efficient tumor uptake of liposomal fluorophore mediated by Syp-1 was observed. Furthermore, Syp-1 modified liposomal doxorubicin presented the most potent tumor growth inhibitory ability among all the therapeutic groups, with a low half maximal inhibitory concentration of 588 nM against MDA-MB-435 cells in vitro and a high tumor inhibition rate of 73.5% in vivo. These findings clearly indicated that Syp-1 was a stable and effective tumor targeting ligand and suggest that the sulfur-to-selenium replacement strategy may help stabilize the phage-displayed cyclic peptide containing disulfide-bond under physiological conditions and strongly support the validity of peptide-mediated drug targeting.