Synthesis and biological application of BKT-140 peptide modified polymer micelles for treating tumor metastasis with an enhanced cell internalization
Synthesis and biological application of BKT-140 peptide modified polymer micelles for treating tumor metastasis with an enhanced cell internalization
复制标题
BKT-140肽修饰聚合物胶束的合成及生物应用，用于增强细胞内化治疗肿瘤转移
DOI：
10.1039/c5py01807b
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发表时间：
2016-01-01
影响因子：
4.6
通讯作者：
Hu, Fuqiang
中科院分区：
文献类型：
--
作者：
Liu, Xuan;Cheng, Bolin;Hu, Fuqiang
近年来，聚合物胶束作为靶向给药系统用于治疗肿瘤已被研究。然而，被动靶向给药系统不能在分散的肿瘤转移部位聚集，这导致肿瘤转移的预后不良。趋化因子受体CXCR4通常在转移性肿瘤细胞中高度表达，在转移过程中调节肿瘤细胞运输，并且与肿瘤细胞的侵袭性反应相关，是潜在的靶向位点。在这项研究中，BKT-140肽，一个特定的CXCR4抑制剂，被缀合在基于壳聚糖的聚合物胶束（BKT-CSOSA）的表面。肽修饰后，在CXCR 4高表达细胞中，BKT-CSOSA显示出通过受体介导的细胞内化的细胞摄取的显著增加。然而，在CXCR 4低表达细胞中，摄取效率没有明显变化，但主要摄取途径从网格蛋白介导的内吞作用改变为巨胞饮作用。阿霉素负载BKT-CSOSA胶束（BKT-CSOSA/DOX）在体外对细胞迁移和侵袭具有增强的抗转移作用。进一步证实BKT-CSOSA/DOX胶束减少了肺中肿瘤转移位点的形成。CSOSA和BKT-CSOSA胶束在体内主要分布在肝、脾和肺中，但BKT-CSOSA在肺中的蓄积增强。本研究表明，BKT-140修饰显著增加了转移性肿瘤细胞中聚合物胶束的细胞内化，并增强了对肺转移位点形成的抑制作用。
In recent years, polymer micelles have been investigated as targeted drug delivery systems for treating tumors. However, passive targeted drug delivery systems failed in accumulation at dispersive tumor metastasis sites, which led to a poor prognosis of tumor metastasis. The chemokine receptor CXCR4, which is often highly expressed in metastatic tumor cells, regulates tumor cell trafficking during the metastasis process and is related to the invasive response of tumor cells, is a potential targeting site. In this study, the BKT-140 peptide, a specific CXCR4 inhibitor, was conjugated on the surface of chitosan based polymer micelles (BKT-CSOSA). After peptide modification, in CXCR4 high expressing cells BKT-CSOSA showed a considerable increase of cell uptake by receptor-mediated cell internalization. However, in CXCR4 low expressing cells there was no obvious change in uptake efficiency but the main uptake pathway was altered from clathrin-mediated endocytosis into macropinocytosis. Doxorubicin loaded BKT-CSOSA micelles (BKT-CSOSA/DOX) showed an enhanced anti-metastasis effect on cell migration and cell invasion in vitro. It was further confirmed that BKT-CSOSA/DOX micelles decreased tumor metastasis sites’ formation in the lung. Both CSOSA and BKT-CSOSA micelles were mainly located in the liver, spleen and lung in vivo, but BKT-CSOSA showed an enhanced accumulation in the lung. This study demonstrates that BKT-140 modification notably increased the cell internalization of polymer micelles in metastatic tumor cells and enhanced the inhibition effect on lung metastasis sites’ formation.