Han Insook, Jun Mee Sook, Kim Moon Kyu, Kim Jung Chul, Sohn Youn Soo
Trichogene, Inc., Daegu 700-422, Korea.
Jpn J Cancer Res. 2002 Nov;93(11):1244-9. doi: 10.1111/j.1349-7006.2002.tb01230.x.
For effective administration of lipophilic trans(+/-)-1,2-diaminocyclohexaneplatinum(II) complexes of malonate derivatives [(dach)PtL, L=allylmalonate (AM), diallylmalonate (DAM), allylbenzylmalonate (ABM), or dibenzylmalonate (DBM)] in aqueous solution, we have applied three different liposome formulations and evaluated their physical and chemical properties, along with their in vitro cytotoxicity. The liposome formulations were composed of DMPC / DMPG [DMPC=1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPG=1,2-dimyristoyl-sn-glycero-3-(phospho-rac-1-glycerol) (sodium salt)] in different molar ratios (7/3 or 3/7) or an equimolar DOTAP/DOPE formulation (DOTAP=1,2-dioleoyl-3-trimethylammonium propane, DOPE=1,2-dioleoyl-sn-glycero-3-phosphoethanolamine). Preliposomal powders of the platinum complexes were prepared by lyophilization, and reconstituted in aqueous solution to obtain the final liposomal platinum complexes. Due to the lipophilicity of the malonatoplatinum complexes, the entrapment efficiency of drugs within the liposomes was over 90% except for the AM complex, and platinum drug stability was also satisfactory (>90%) in these liposomal systems. In vitro cytotoxicity was tested in human ovarian carcinoma cells sensitive (A2780) and resistant to cisplatin (A2780/PDD). In both cell lines, the liposomal DBM complex was much more cytotoxic than the corresponding DAM and ABM complexes, which means that the more hydrophobic benzyl substituent affords higher cytotoxicity than the allyl substituent in the malonato leaving group. Furthermore, the DBM complex in DMPC/DMPG formulations was effective against both sensitive and resistant A2780 cells (resistance indexes (RI)=1.10-1.49), showing lack of cross-resistance to cisplatin. Therefore, the liposomal DBM complex in the DMPC/DMPG formulations is a promising candidate for stable pharmaceutical liposomal platinum complexes.
为了在水溶液中有效地施用丙二酸酯衍生物的亲脂性反式（±）-1,2-二氨基环己烷铂（II）配合物[（dach）PtL，L =烯丙基丙二酸酯（AM）、二烯丙基丙二酸酯（DAM）、烯丙基苄基丙二酸酯（ABM）或二苄基丙二酸酯（DBM）]，我们应用了三种不同的脂质体制剂，并评估了它们的物理和化学性质以及体外细胞毒性。脂质体制剂由不同摩尔比（7/3或3/7）的DMPC / DMPG [DMPC = 1,2-二肉豆蔻酰-sn-甘油-3-磷酸胆碱，DMPG = 1,2-二肉豆蔻酰-sn-甘油-3-（磷酸-rac-1-甘油）（钠盐）]或等摩尔的DOTAP/DOPE制剂（DOTAP = 1,2-二油酰基-3-三甲基铵丙烷，DOPE = 1,2-二油酰基-sn-甘油-3-磷酸乙醇胺）组成。铂配合物的脂质体前体粉末通过冻干制备，并在水溶液中重构以获得最终的脂质体铂配合物。由于丙二酸铂配合物的亲脂性，除AM配合物外，脂质体内药物的包封率超过90%，并且在这些脂质体系统中铂药物稳定性也令人满意（>90%）。在对顺铂敏感（A2780）和耐药（A2780/PDD）的人卵巢癌细胞中测试了体外细胞毒性。在这两种细胞系中，脂质体DBM配合物的细胞毒性比相应的DAM和ABM配合物大得多，这意味着在丙二酸酯离去基团中，疏水性更强的苄基取代基比烯丙基取代基具有更高的细胞毒性。此外，DMPC/DMPG制剂中的DBM配合物对敏感和耐药的A2780细胞均有效（耐药指数（RI）= 1.10 - 1.49），显示出对顺铂无交叉耐药性。因此，DMPC/DMPG制剂中的脂质体DBM配合物是稳定的药用脂质体铂配合物的有前途的候选物。
