Multifunctional pH-sensitive micelles for tumor-specific uptake and cellular delivery
Multifunctional pH-sensitive micelles for tumor-specific uptake and cellular delivery
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用于肿瘤特异性摄取和细胞递送的多功能 pH 敏感胶束
DOI：
10.1039/c4py01403k
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发表时间：
2015-01-01
影响因子：
4.6
通讯作者：
Wu, Hong
中科院分区：
文献类型：
--
作者：
Yang, Tiehong;Li, Fei;Wu, Hong
细胞渗透肽（CPP）的独特能力导致人类细胞中新型药物递送方法的发展是出于治疗目的。缺乏特定的选择性是广泛使用CPP的主要障碍。开发了一种基于用于引入和保护TAT的酸敏感胶束的新型递送方法。阿霉素-TAT结合物（DOX-TAT）在黄质激素释放激素改性的聚（乙二醇） - 聚（L-吉斯汀） - 多氧素（LHRH-PEG-PEG-PHIS-DOX）胶束中加载。将DOX化学结合到聚合物主链中，不仅可以提高胶束的稳定性，还可以提高胶束的药物负荷效率。这些胶束可以解离反应的肿瘤细胞外pH（E），并释放DOX-TAT，直接通过细胞膜进入多药耐药性癌细胞的细胞质。未分离的胶束也可以通过受体介导的内吞作用积极地内化到细胞中，从而导致高细胞毒性。 LHRH-PEG-PHIS-DOX/ DOX-TAT在体外和体内表现出最高的抗肿瘤作用，与对照组相比，对体重没有明显影响。这个熟练设计的系统结合了靶向递送和TAT介导的有效进入的双重功能，即使在耐药性肿瘤细胞中也可能增加抗肿瘤活性。
The distinct ability of cell-penetrating peptides (CPPs) has led to the development of novel drug delivery methods in human cells for therapeutic purposes. The lack of specific selectivity is a main obstacle to the widespread use of CPPs. A novel delivery method based on acid-sensitive micelles used for the introduction and protection of TAT was developed. Doxorubicin-TAT conjugate (Dox-TAT) was loaded in the luteinizing hormone-releasing hormone modified poly (ethylene glycol)-poly (L-histidine)-doxorubicin (LHRH-PEG-PHIS-Dox) micelle. Dox was chemically conjugated to the polymer backbone not only to improve the stability of micelles, but also to increase the drug loading efficiency of the micelle. These micelles could dissociate the responding tumor extracellular pHe and release Dox-TAT to pass directly through the cell membrane to the cytosol of the multidrug resistant cancer cells. The undissociated micelles could also be actively internalized into the cells by receptor-mediated endocytosis, resulting in high cytotoxicity. LHRH-PEG-PHIS-Dox/Dox-TAT showed the highest antitumor effects among the four treatment groups in vitro and vivo and showed no remarkable effect on the body weight compared to the control. This skillfully designed system combined the double functions of targeted delivery and TAT-mediated efficient entry, which could increase the antitumor activity, even in drug resistant tumor cells.