A pH-responsive cell-penetrating peptide-modified liposomes with active recognizing of integrin αvβ3 for the treatment of melanoma
A pH-responsive cell-penetrating peptide-modified liposomes with active recognizing of integrin αvβ3 for the treatment of melanoma
复制标题
一种可主动识别整合素α(v)β(3)的pH响应性细胞穿透肽修饰脂质体，用于治疗黑色素瘤
DOI：
10.1016/j.jconrel.2015.09.009
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发表时间：
2015-11-10
影响因子：
10.8
通讯作者：
He, Qin
中科院分区：
文献类型：
--
作者：
Shi, Kairong;Li, Jianping;He, Qin
使用ph反应性细胞穿透肽（CPPs）是一种有吸引力的体内药物递送策略，然而，它们仍然不能主动靶向所需的位点。本文设计了一种ph响应型CPP (TR)，具有主动靶向整合素α (v) β(3)的能力，整合素α (v) β是一种由主动靶向配体肽（c(RGDfK)）和ph响应型CPP （TH）组成的串联肽。通过分子模拟和对接研究评估整合素对TR的靶向效率。TR肽修饰脂质体（TR- lip）在pH 7.4和pH 6.5下的亲和力试验充分证明了TR- lip与整合素α (v) β的pH响应性结合效果(3)。在pH 6.5时，cfpe标记的TR-Lip对整合素α (v) β(3)-过表达的B16F10细胞的细胞摄取分别是cfpe标记的PEG-、RGD-和th修饰脂质体的41.67倍、30.67倍和11.90倍，这表明与TH-Lip相比，TR-Lip不仅可以主动靶向α (v) β(3)-过表达的细胞，而且与RGD- lip相比，TR-Lip的细胞摄取也显著增加。在紫杉醇（PTX）浓度为20 μ g/mL时，负载PTX的TR-Lip （PTX-TR-Lip）对B16F10细胞的杀伤活性分别比负载PTX的PEG-、RGD-、th修饰脂质体和游离PTX在pH 6.5时高1.80倍、1.45倍、1.30倍、1.15倍。体内成像显示，与其他组相比，did标记的TR-Lip在肿瘤部位的积累最大。与PBS相比，PTX-TR-Lip对B16F10荷瘤小鼠的抑瘤率为85.04%。在B16F10荷瘤小鼠中，PTX-TR-Lip的存活率明显高于其他各组。总之，体外和体内的所有结果表明，TR-Lip可能是PTX治疗整合素α (v) β(3)-过表达的荷瘤小鼠的潜在递送系统。(c) 2015 Elsevier B.V.版权所有
The use of pH-responsive cell-penetrating peptides (CPPs) is an attractive strategy for drug delivery in vivo, however, they still could not actively target to the desired sites. Here, we designed a pH-responsive CPP (TR) with the ability of active targeting to integrin alpha(v)beta(3), which was a tandem peptide consisted of active targeting ligand peptide (c(RGDfK)) and pH-responsive CPP (TH). The targeting efficiency of TR with integrin was evaluated by molecular simulation and docking studies. The affinity assays of TR peptide modified liposomes (TR-Lip) at pH 7.4 and pH 6.5 demonstrated adequately the pH-responsive binding efficacy of TR-Lip with integrin alpha(v)beta(3). The cellular uptake of CFPE-labeled TR-Lip on integrin alpha(v)beta(3)-overexpressing B16F10 cells was 41.67-, 30.67-, and 11.90-fold higher than that of CFPE-labeled PEG-, RGD-, and TH-modified liposomes at pH 6.5, respectively, suggesting that TR-Lip could not only actively target to alpha(v)beta(3)-overexpressing cells compared to TH-Lip, but also significantly increased cellular uptake compared to RGD-Lip. At the concentration of 20 mu g/mL paclitaxel (PTX), the killing activity of PTX-loaded TR-Lip (PTX-TR-Lip) against B16F10 cells was 1.80-, 1.45-, 1.30-, 1.15-time higher than that of PTX-loaded PEG-, RGD-, TH-modified liposomes and free PTX at pH 6.5, respectively. In vivo imaging displayed the maximum accumulation of DiD-labeled TR-Lip at tumor sites compared to the other groups. Tumor inhibition rate of B16F10 tumor-bearing mice treated with PTX-TR-Lip was 85.04%, relative to that of PBS. In B16F10 tumor-bearing mice, PTX-TR-Lip showed significantly higher survival rate compared with the other groups. Collectively, all the results in vitro and in vivo suggested that TR-Lip would be a potential delivery system for PTX to treat integrin alpha(v)beta(3)-overexpressing tumor-bearing mice. (c) 2015 Elsevier B.V. All rights reserved.