title: Oligonucleotides conjugated to natural lipids: synthesis of phosphatidyl-anchored antisense oligonucleotides.
abstract: Antisense oligonucleotides are promising therapeutic agents against a variety of diseases. Effective delivery of these molecules is critical in view of their clinical application. Despite the richness of synthetic strategies addressed to the lipophilic modification of oligodeoxynucleotides (ODNs) for enhancing their pharmacokinetic behavior and trans-membrane delivery, the phosphatidyl group (1,2-di-O-acyl-sn-glycero-3-phosphoryl) has been never used as the lipophilic moiety of lipid-ODN conjugates. The present paper reports a general procedure for synthesizing 5'-phosphatidyl-ODNs. By this procedure, phosphatidyl conjugates of a VEGF antisense-ODN have been prepared, which differ in the fatty acid composition of their phosphatidyl moiety. These new lipid-ODN conjugates, which have been characterized on the basis of their physicochemical properties, showed an improved resistance to exonucleases and were able to lower the VEGF-mRNA expression in human SH-SY5Y neuroblastoma cells more effectively than the relevant free antisense-ODN did.
authors: Dipartimento di Scienze Chimiche, Università di Catania, V. le A. Doria 6, 95125 Catania, Italy.
authors: Rosa
authors: R
authors: Chillemi
authors: Valentina
authors: V
authors: Greco
authors: Vincenzo G
authors: VG
authors: Nicoletti
authors: Sebastiano
authors: S
authors: Sciuto
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D005092:Exonucleases / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000494:pharmacology*; D010712:Phosphatidic Acids / Q000737:chemistry* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D016376:Oligonucleotides, Antisense; D010712:Phosphatidic Acids; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D005092:Exonucleases