chapter  8
24 Pages

Chapter Delivery and Targeting of Oligonucleotides and siRNA

Oligodeoxynucleotides (ODNs) are increasingly being recognized as potential therapeutic agents to modulate aberrant gene expression for treating various diseases, including cancers1-3 and viral infections.4,5 Concerted efforts have made signicant progress in turning these nucleic acids into therapeutics. Apart from immune-stimulation and enzymatic cleavage, the most important feature

8.1 Introduction .......................................................................................................................... 147 8.2 Single-Stranded Oligonucleotides ........................................................................................ 148

8.2.1 Antisense Oligodeoxyribonucleotides ...................................................................... 148 8.2.2 Triplex-Forming Oligonucleotides ............................................................................ 149 8.2.3 Immunomodulatory Oligonucleotides ...................................................................... 150 8.2.4 Ribozyme and DNAzymes ....................................................................................... 150 8.2.5 Nucleic Acid Aptamer .............................................................................................. 151

8.3 Double-Stranded Therapeutic Oligonucleotides ................................................................... 151 8.3.1 Decoy Oligodeoxynucleotides .................................................................................. 151 8.3.2 Small Interfering RNA ............................................................................................. 152

8.4 Barriers to Oligonucleotide-Based Therapeutics .................................................................. 152 8.4.1 Instability of ODNs and siRNAs .............................................................................. 152

8.4.1.1 Phosphorothioates and Boranophosphate Modication ............................ 152 8.4.1.2 2′ Ribose Modication ............................................................................... 153

8.4.2 Nonspecic Binding and Toxicity ............................................................................ 154 8.4.3 Physiological Barriers ............................................................................................... 155

8.4.3.1 Capillary Endothelium ............................................................................... 155 8.4.3.2 Endosomal and Lysosomal Membranes .................................................... 156 8.4.3.3 Nuclear Membrane ..................................................................................... 156

8.5 Synthetic Carriers for Nucleic Acid Delivery ....................................................................... 157 8.5.1 Complex Formation .................................................................................................. 157

8.5.1.1 Cationic Lipids ........................................................................................... 157 8.5.1.2 Cationic Polymers ...................................................................................... 158

8.5.2 Bioconjugation .......................................................................................................... 159 8.6 Pharmacokinetics and Biodistribution ................................................................................. 161 8.7 Clinical Trials ....................................................................................................................... 162 8.8 Concluding Remarks ............................................................................................................ 163 Acknowledgment ........................................................................................................................... 164 References ...................................................................................................................................... 164

of ODNs is their ability to block mRNA function by sequence-specic hybridization with target mRNA.6 Theoretically, the antisense strategy can be used to target any gene in the body, which allows these nucleic acids to achieve broader therapeutic potential than small molecules.