title: Synthesis of a novel phosphatidylcholine conjugated to docosahexaenoic acid and methotrexate that inhibits cell proliferation.
abstract: Here we report the synthesis and characterization of a lipophilic phosphatidylcholine containing the omega-3 fatty acid docosahexaenoic acid (DHA) and the cytotoxic drug methotrexate (MTX). This novel phospholipid combines the fatty acid's and the drug's anticancer activities in a molecule amenable to a liposome bilayer for safe, simultaneous delivery of the two agents. Two phosphatidylcholines were synthesized, from 1-stearoyl or 1-docosahexaenoyl, 2-hydroxy-sn-glycero-3-phosphocholine, to contain MTX in the sn-2 position and either stearic acid or DHA in the sn-1 position. The products contain fatty acid, MTX and phosphorus (1:1:1), and the MTX was released by phospholipase A(2), consistent with the proposed phospholipid structure. The predominant product linked MTX to the glycerol moiety through MTX's gamma-carboxyl group. Liposomes composed of 1-stearoyl, 2-oleoyl phosphatidylcholine plus 1-stearoyl, 2-oleoyl phosphatidylethanolamine and various concentrations of the novel phospholipids caused dose-dependent inhibition of murine leukemia cell proliferation in culture. The DHA- and MTX-containing phosphatidylcholine was more effective than that containing stearic acid, and DHA appeared to synergize with MTX when they were added as free agents or covalently linked in the phospholipid. These data show the feasibility of synthesizing, and the inhibitory activity of phosphatidylcholine with DHA in the sn-1 position and MTX in the sn-2 position, and suggest the compound's potential use in cancer chemotherapy.
authors: Department of Biology, Indiana University-Purdue University, Indianapolis, IN 46202-5143, USA.
authors: Mustapha
authors: M
authors: Zerouga
authors: William
authors: W
authors: Stillwell
authors: Laura J
authors: LJ
authors: Jenski
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002849:Chromatography, Gas; D004281:Docosahexaenoic Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D005227:Fatty Acids / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy*; D008081:Liposomes; D008727:Methotrexate / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D010713:Phosphatidylcholines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D010741:Phospholipases A / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects*
chemical_list: D000964:Antimetabolites, Antineoplastic; D005227:Fatty Acids; D008081:Liposomes; D010713:Phosphatidylcholines; D004281:Docosahexaenoic Acids; D010741:Phospholipases A; D008727:Methotrexate