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-snglycero-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.

Oligonucleotides conjugated to natural lipids: synthesis of phosphatidyl-anchored antisense oligonucleotides

Greco V;NICOLETTI, Vincenzo Giuseppe;SCIUTO, Sebastiano
2013-01-01

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-snglycero-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.
File in questo prodotto:
File Dimensione Formato  
Chillemi 2013 (Oligonucleotides Conjugated to Natural Lipids).pdf

solo gestori archivio

Licenza: Non specificato
Dimensione 1.71 MB
Formato Adobe PDF
1.71 MB Adobe PDF   Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/27953
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 17
  • ???jsp.display-item.citation.isi??? 16
social impact