Delivery of siRNAs to Target Cells

Targeted suppression of HIV-1 has been achieved through siRNAs directed against HIV-1 tat and rev [43—45], reverse transcriptase [45-47], TAR and the 3 untranslated region [48], Vif [48], as weU as gag. 

Once a siRNA targeting a particular viral RNA or promoter has been designed, tested and shown to be effective in vitro, it will probably be necessary to stably express 

There are severable methodologies for expressing siRNAs. One method for stable and controlled expression of siRNAs from the context of the cell is via the use of len-tiviral vectors. Lentiviruses, unlike retroviruses such as Moloney murine leukemia virus (MoMLV), tend to preferentially integrate downstream of active promoters within the active transcriptional unit, potentially limiting their overall oncogenicity 

ICMvlvsv-G(env8iope) sv40-PoiyA Envelope Plasmid 

1 1 demyor, V. 2003. 20 years since human immunodeficiency vims discovery considerations for the next decade. Pharmacotherapy 23, 384— 387. 

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The major bottleneck in the development of siRNA therapeutics is the efficient delivery of siRNA to target cells. The difficulty is mainly due to the... 

Ligand-Targeted Delivery of siRNA to Tumor Cells... 

To develop an efficient siRNA cancer therapy, targeted delivery of siRNA to tumor cells is the primary requisite to overcome nonspecific side effects, as well as increase the therapeutic effect. Most cancer cells express unique or overexpressed receptors/antigens on their cell surface which can bind various ligands including antibodies, antibody fragments, small molecules, peptides, and aptamers. A number of tumor-specific ligands have been modified to the siRNA delivery system to enhance the specific cellular uptake in tumor cells. The most commonly used ligands are described below. 

Transferrin-containing CD polymer-based nanoparticles were studied as nucleic acid delivery system that can be modified for targeted delivery of small interfering ribonucleic acid (siRNA) to cancer cells. Molecular studies showed that the siRNA CD nanoparticles reduced levels of Ewing s transcript by 80% and inhibited growth of cultured Ewing s tumor cell line. It was also reported that this delivery system indicated a lack of toxicity [39],... 

The crucial challenge of in vivo application of RNAi therapy is developing efficient delivery system to transport the siRNA into the tissue and finally into the cytoplasm or shRNA into the nucleus of target cells [4]. Several studies have demonstrated efficient delivery of siRNA in vivo as well as its therapeutic effect in animal model. Recently in 2008, FDA approved the first clinical study using targeted cyclodextrin-containing nanoparticle for the systemic delivery of an anti-cancer siRNA, RONDEL , developed by Calando Pharmaceutical Inc. 

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