Biologically active camptothecin derivatives for incorporation into liposome bilayers and lipid emulsions

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.