Molecular targeting of drug delivery systems to ovarian cancer by BH3 and LHRH peptides
Molecular targeting of drug delivery systems to ovarian cancer by BH3 and LHRH peptides
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DOI：
10.1016/s0168-3659(03)00209-8
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发表时间：
2003-08-28
影响因子：
10.8
通讯作者：
Minko, T
中科院分区：
文献类型：
--
作者：
Dharap, SS;Qiu, B;Minko, T
开发并评估了新型靶向促凋亡抗癌药物递送系统。聚乙二醇（PEG）缀合物用作载体。喜树碱（CPT）被用作抗癌剂——细胞凋亡诱导剂。研究了两种类型的分子靶点：（1）卵巢癌特异性的细胞外膜受体和（2）细胞凋亡的细胞内控制机制。类似于黄体生成素释放激素 (LHRH) 和 BCL-2 同源 3 (BH3) 肽的合成肽分别用作细胞抗凋亡防御的靶向部分和抑制剂。合成了三种不同的缀合物（CPT-PEG、CPT-PEG-BH3 和 CPT-PEG-LHRH），并在 A2780 人卵巢癌细胞中进行了检查。研究了细胞毒性、编码BCL-2、BCL-XL、SMAC、APAF-1蛋白和caspases 3和9的基因的表达、caspases 3和9的活性以及细胞凋亡诱导。总而言之，结果表明，与游离喜树碱相比，PEG-喜树碱缀合物具有更高的细胞毒性和细胞凋亡诱导活性。此外，靶向CPT-PEG-BH3和CPT-PEG-LHRH缀合物的效果比非靶向PEG-CPT缀合物更明显。结果证实了这种新的两层分子靶向策略增强癌症化疗疗效的可行性。 (C) 2003 Elsevier B.V. 保留所有权利。
Novel targeted proapoptotic anticancer drug delivery systems were developed and evaluated. Poly(ethyleneglycol) (PEG) conjugates were used as carriers. Camptothecin (CPT) was used as an anticancer agent-apoptosis inductor. Two types of molecular targets were investigated: (1) an extracellular membrane receptor specific to ovarian cancer and (2) intracellular controlling mechanisms of apoptosis. Synthetic peptides similar to luteinizing hormone-releasing hormone (LHRH) and BCL-2 homology 3 (BH3) peptide were used as a targeting moiety and a suppressor of cellular antiapoptotic defense, respectively. Three different conjugates (CPT-PEG, CPT-PEG-BH3 and CPT-PEG-LHRH) were synthesized and examined in A2780 human ovarian cancer cells. Cytotoxicity, expression of genes encoding BCL-2, BCL-XL, SMAC, APAF-1 proteins and caspases 3 and 9, the activity of caspases 3 and 9 and apoptosis induction were studied. Taken together the results indicate much higher cytotoxicity and apoptosis-inducing activity of PEG-CPT conjugates when compared to free CPT. Moreover, the effects of targeted CPT-PEG-BH3 and CPT-PEG-LHRH conjugates were more pronounced than the non-targeted PEG-CPT conjugate. The results confirmed the feasibility of this new two-tier molecular targeting strategy for enhancing the efficacy of cancer chemotherapy. (C) 2003 Elsevier B.V. All rights reserved.