Enhanced active targeting via cooperative binding of ligands on liposomes to target receptors.
Enhanced active targeting via cooperative binding of ligands on liposomes to target receptors.
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DOI：
10.1371/journal.pone.0067550
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Oku N
中科院分区：
文献类型：
--
作者：
Sugiyama T;Asai T;Nedachi YM;Katanasaka Y;Shimizu K;Maeda N;Oku N
为了在药物递送系统中实现有效的主动靶向，我们先前开发了双靶向（DT）脂质体，其修饰有血管内皮生长因子受体-1（VEGFR-1）靶向的APRPG和CD 13靶向的GNGRG肽配体，用于肿瘤新生血管，并观察到用包封多柔比星的DT脂质体治疗对Colon 26 NL-17荷瘤小鼠肿瘤生长的抑制增强。在本研究中，我们检查了具有不同配体对的DT脂质体的结合特性，即APRPG和整联蛋白αvβ3靶向GRGDS肽。与修饰有APRPG或GRGDS的单靶向（ST）脂质体相比，这些DT脂质体协同地与刺激的人脐静脉内皮细胞相关联。表面等离子体共振分析结果表明，用APRPG或GRGDS肽修饰的ST脂质体分别选择性地结合固定的VEGFR-1或整合素αvβ3。DT脂质体对VEGFR-1和整合素αvβ3的亲和力高于ST脂质体，说明这2种配体在脂质体表面协同结合。在生物分布测定中，DT脂质体在Colon 26 NL-17荷瘤小鼠的肿瘤中的蓄积程度显著高于其他脂质体。此外，通过共聚焦显微镜检查的脂质体的肿瘤内分布表明，DT脂质体不仅靶向血管生成内皮细胞，而且由于GRGDS装饰的肿瘤细胞。这些发现表明，“双靶向”增强了脂质体对靶细胞的亲和力，因此可用于癌症治疗的主动靶向药物递送。
To achieve effective active targeting in a drug delivery system, we previously developed dual-targeting (DT) liposomes decorated with both vascular endothelial growth factor receptor-1 (VEGFR-1)-targeted APRPG and CD13-targeted GNGRG peptide ligands for tumor neovessels, and observed the enhanced suppression of tumor growth in Colon26 NL-17 tumor-bearing mice by the treatment with the DT liposomes encapsulating doxorubicin. In this present study, we examined the binding characteristics of DT liposomes having a different couple of ligands, namely, APRPG and integrin αvβ3-targeted GRGDS peptides. These DT liposomes synergistically associated to stimulated human umbilical vein endothelial cells compared with single-targeting (ST) liposomes decorated with APRPG or GRGDS. The results of a surface plasmon resonance assay showed that ST liposomes modified with APRPG or GRGDS peptide selectively bound to immobilized VEGFR-1 or integrin αvβ3, respectively. DT liposomes showed a higher affinity for a mixture of VEGFR-1 and integrin αvβ3 compared with ST liposomes, suggesting the cooperative binding of these 2 kinds of ligand on the liposomal surface. In a biodistribution assay, the DT liposomes accumulated to a significantly greater extent in the tumors of Colon26 NL-17 tumor-bearing mice compared with other liposomes. Moreover, the intratumoral distribution of the liposomes examined by confocal microscopy suggested that the DT liposomes targeted not only angiogenic endothelial cells but also tumor cells due to GRGDS-decoration. These findings suggest that "dual-targeting" augmented the affinity of the liposomes for the target cells and would thus be useful for active-targeting drug delivery for cancer treatment.
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