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    Oligonucleotides Conjugated to Natural Lipids: Synthesis of Phosphatidyl-Anchored Antisense Oligonucleotides

    Year: 2013

    Journal: Bioconjugate Chem., 2013, 24 (4), pp 648–657, 20130628

    Authors: Rosa Chillemi †, Valentina Greco *‡, Vincenzo G. Nicoletti †, and Sebastiano Sciuto †

    Last authors: Sebastiano Sciuto

    Organizations: † Dipartimento di Scienze Chimiche, Università di Catania, V. le A. Doria 6, 95125 Catania, Italy ‡ Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, V. le A. Doria 6, 95125 Catania, Italy

    Country: Italy

    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.