title: Liposome formulations for effective administration of lipophilic malonatoplatinum(II) complexes.
abstract: 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.
authors.affiliation: Trichogene, Inc., Daegu 700-422, Korea. ishan60@hanmail.net
authors.forename: Insook
authors.initials: I
authors.lastname: Han
authors.forename: Mee Sook
authors.initials: MS
authors.lastname: Jun
authors.forename: Moon Kyu
authors.initials: MK
authors.lastname: Kim
authors.forename: Jung Chul
authors.initials: JC
authors.lastname: Kim
authors.forename: Youn Soo
authors.initials: YS
authors.lastname: Sohn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm; D008081:Liposomes; D051379:Mice; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D009944:Organoplatinum Compounds