Dual-functionalized liposomal delivery system for solid tumors based on RGD and a pH-responsive antimicrobial peptide.
Dual-functionalized liposomal delivery system for solid tumors based on RGD and a pH-responsive antimicrobial peptide.
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基于 RGD 和 pH 响应抗菌肽的双功能实体瘤脂质体递送系统
DOI：
10.1038/srep19800
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发表时间：
2016-02-04
影响因子：
4.6
通讯作者：
He Q
中科院分区：
文献类型：
--
作者：
Zhang Q;Lu L;Zhang L;Shi K;Cun X;Yang Y;Liu Y;Gao H;He Q
[D]-H6 L9作为一种pH响应性抗菌肽（AMP），已经被我们证明是肿瘤微环境响应性递送的极好选择，因为它可以使脂质体响应于酸化的肿瘤微环境。然而，[D]-H6 L9修饰的脂质体不能主动靶向肿瘤区域。因此，整合素αvβ3靶向肽RGD与[D]-H6 L9共修饰到脂质体[（R + D）-Lip]上以提高肿瘤递送效率。在pH 6.3下，（R + D）-Lip可被C26细胞和C26肿瘤球体（整合素αvβ3阳性）摄取，与其他组相比，摄取效率显著提高，这是由RGD和[D]-H6 L9共同贡献的，而RGD对MCF-7细胞（整合素αvβ3阴性）的细胞摄取性能没有增加。结果表明：（R + D）-Lip的细胞摄取量随RGD浓度的增加而减少，而[D]-H6 L9的细胞摄取量随[D]-H6 L9浓度的增加而增加，说明RGD和[D]-H6 L9均参与了（R + D）-Lip的细胞内化。另一方面，（R + D）-Lip可逃脱溶酶体的包封。与单独修饰RGD和[D]-H6 L9的脂质体相比，PTX负载的（R + D）-Lip对C26细胞的细胞毒性进一步增强，对C26肿瘤模型具有显著的抑瘤作用。
[D]-H6L9, as a pH-responsive anti-microbial peptide (AMP), has been evidenced by us to be an excellent choice in tumor microenvironment-responsive delivery as it could render liposomes responsive to the acidified tumor microenvironment. However, [D]-H6L9-modified liposomes could not actively target to tumor area. Therefore, integrin αvβ3-targeted peptide RGD was co-modified with [D]-H6L9onto liposomes [(R + D)-Lip] for improved tumor delivery efficiency. Under pH 6.3, (R + D)-Lip could be taken up by C26 cells and C26 tumor spheroids (integrin αvβ3-positive) with significantly improved efficiency compared with other groups, which was contributed by both RGD and [D]-H6L9, while RGD did not increase the cellular uptake performance on MCF-7 cells (integrin αvβ3-negative). Results showed that RGD could decrease cellular uptake of (R + D)-Lip while [D]-H6L9could increase it, implying the role of both RGD and [D]-H6L9in cellular internalization of (R + D)-Lip. On the other hand, (R + D)-Lip could escape the entrapment of lysosomes. PTX-loaded (R + D)-Lip could further increase the cellular toxicity against C26 cells compared with liposomes modified only with RGD and [D]-H6L9respectively and achieve remarkable tumor inhibition effect on C26 tumor models.