Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide
Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide
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DOI：
10.1073/pnas.0504274102
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发表时间：
2005-09-06
影响因子：
11.1
通讯作者：
Minko, T
中科院分区：
文献类型：
--
作者：
Dharap, SS;Wang, Y;Minko, T
癌症化疗的中心问题是抗癌药物对健康组织的严重毒副作用。如果副作用增加，应减少剂量、延迟治疗或停止治疗。为了减少癌症化疗对健康器官的不良副作用，我们提出了一种具有针对癌细胞的特异性靶向配体的药物递送系统（DIDS）。所提出的DDS最大限度地减少了正常细胞对药物的摄取，并增强了药物在癌细胞中的流入和保留。该递送系统包括三种主要组分：（i）肿瘤诱导剂（抗癌药物），（ii）靶向部分渗透增强剂，和（iii）载体。我们描述了这样一个系统的变体之一，它利用喜树碱作为一种肿瘤诱导剂和聚（乙二醇）作为载体。促黄体生成激素释放激素（LHRH）被用作LHRH受体的靶向部分（配体），LHRH受体在几种类型的癌细胞的质膜中过表达，并且在正常内脏器官中不可检测地表达。结果表明，使用LHRH肽作为抗癌DDS中的靶向部分显著增强了化疗的功效，导致肿瘤中的细胞凋亡诱导放大，并且最小化抗癌药物对健康器官的副作用。以LHRH受体为靶点的DDS在小鼠体内未显示垂体毒性，对促黄体生成素的时程、血浆浓度及其对小鼠生殖功能的生理效应均无显著影响。
The central problem in cancer chemotherapy is the severe toxic side effects of anticancer drugs on healthy tissues. Invariably the side effects impose dose reduction, treatment delay, or discontinuance of therapy. To limit the adverse side effects of cancer chemotherapy on healthy organs, we proposed a drug delivery system (DIDS) with specific targeting ligands for cancer cells. The proposed DDS minimizes the uptake of the drug by normal cells and enhances the influx and retention of the drug in cancer cells. This delivery system includes three main components: (i) an apoptosis-inducing agent (anticancer drug), (ii) a targeting moiety-penetration enhancer, and (iii) a carrier. We describe one of the variants of such a system, which utilizes camptothecin as an apoptosis-inducing agent and poly(ethylene glycol) as a carrier. Luteinizing hormone-releasing hormone (LHRH) was used as a targeting moiety (ligand) to LHRH receptors that are overexpressed in the plasma membrane of several types of cancer cells and are not expressed detectably in normal visceral organs. The results showed that the use of LHRH peptide as a targeting moiety in the anticancer DDS substantially enhanced the efficacy of chemotherapy, led to amplified apoptosis induction in the tumor, and minimized the side effects of the anticancer drug on healthy organs. The LHRH receptor targeting DDS did not show in vivo pituitary toxicity and did not significantly influence the time course or the plasma concentration of luteinizing hormone and its physiological effects on the reproductive functions of mice.