Lundberg B B
Department of Biochemistry and Pharmacy, Abo Akademi University, Finland.
Anticancer Drug Des. 1998 Jul;13(5):453-61.
The DNA topoisomerase I inhibitor camptothecin (CPT) and its analogues are promising anticancer agents with the ability to halt the growth of a range of human tumours. However, the insolubility and instability of the drug in its active lactone from make it very difficult to devise a suitable formulation for clinical testing. This study describes oleic acid esters of the CPT analogues 10-OH-CPT and SN-38, CPT- and SN-38-oleate, which can be intercalated into liposome bilayers and submicron lipid emulsions. The maximum incorporation of drugs was found to be approximately 10 mol% against phospholipid. The novel CPT formulations proved to be very stable against lactone ring opening and were protected from albumin binding. Their in vitro cytotoxic activity against T-47D, Caco 2 and Raji cells was shown to be equal to or higher than that of the parent drugs. Thus the experiments suggest that drug-lipid carrier complexes may be suitable formulations for i.v. and i.m. administration of lipophilic CPT analogues and markedly improve the stability of the active lactone form of the drugs in circulation.
DNA拓扑异构酶I抑制剂喜树碱（CPT）及其类似物是很有前景的抗癌药物，能够抑制多种人类肿瘤的生长。然而，该药物的活性内酯形式不溶于水且不稳定，这使得设计适合临床测试的制剂非常困难。本研究描述了CPT类似物10-羟基喜树碱（10-OH-CPT）和伊立替康（SN-38）的油酸酯，即喜树碱油酸酯和SN-38油酸酯，它们可插入脂质体双层和亚微米脂质乳剂中。发现药物的最大掺入量相对于磷脂约为10摩尔%。新型CPT制剂被证明对内酯环开环非常稳定，并且能防止与白蛋白结合。它们对T-47D、Caco 2和Raji细胞的体外细胞毒性活性显示与母体药物相当或更高。因此，实验表明药物-脂质载体复合物可能是用于静脉注射和肌肉注射亲脂性CPT类似物的合适制剂，并能显著提高药物活性内酯形式在循环中的稳定性。
