Targeted proapoptotic anticancer drug delivery system
Targeted proapoptotic anticancer drug delivery system
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DOI：
10.1021/mp070053o
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发表时间：
2007-09-01
影响因子：
4.9
通讯作者：
Minko, Tamara
中科院分区：
文献类型：
--
作者：
Chandna, Pooja;Saad, Maha;Minko, Tamara
本研究开发了一种新型的靶向促凋亡抗癌药物释放系统（DDS），并进行了体内外评价。该系统包含聚（乙二醇）聚合物（PEG）作为载体，喜树碱（CPT）作为抗癌药物/细胞死亡诱导剂，促黄体生成素释放激素（LHRH）肽的合成类似物作为靶向部分/渗透增强剂，和BCL 2同源3结构域（BH 3）肽的合成类似物作为细胞抗凋亡防御的抑制剂。多组分DDS的设计允许每种活性成分（CPT、LHRH和BH 3）的一个或两个拷贝与一个PEG载体分子偶联。使用原子力显微镜以纳米分辨率观察PEG缀合物的复杂结构。我们发现，针对癌细胞的配体靶向DDS优先在肿瘤中积累，并允许将活性成分递送到癌细胞的细胞质和细胞核中。同时凋亡诱导通过半胱天冬酶依赖性信号通路和抑制细胞抗凋亡防御的抑制BCL 2蛋白增强细胞毒性和抗肿瘤活性的整个DDS的水平，这是不能实现单独应用的单个组件。每分子PEG聚合物中含有两个拷贝的每种活性成分（CPT，LHRH和BH 3）的DDS在体外和体内具有最高的抗癌效率。
A novel targeted proapoptotic anticancer drug delivery system (DDS) was developed and evaluated both in vitro and in vivo. The system contains poly(ethylene glycol) polymer (PEG) as a carrier, camptothecin (CPT) as an anticancer drug/cell death inducer, a synthetic analogue of luteinizing hormone-releasing hormone (LHRH) peptide as a targeting moiety/penetration enhancer, and a synthetic analogue of BCL2 homology 3 domain (BH3) peptide as a suppressor of cellular antiapoptotic defense. The design of the multicomponent DDS allowed for a conjugation of one or two copies of each active ingredient (CPT, LHRH, and BH3) to one molecule of PEG carrier. The complex structure of the PEG conjugates was visualized at nanometer resolution using atomic force microscopy. We found that the ligand-targeted DDS for cancer cells preferentially accumulated in the tumor and allowed the delivery of active ingredients into the cellular cytoplasm and nuclei of cancer cells. Simultaneous apoptosis induction through the caspase-dependent signaling pathway and inhibition of cellular antiapoptotic defense by the suppression of BCL2 protein enhanced cytotoxicity and antitumor activity of the entire DDS to a level which could not be achieved by individual components applied separately. The DDS containing two copies of each active component (CPT, LHRH, and BH3) per molecule of PEG polymer had the highest anticancer efficiency in vitro and in vivo.