Ligand-Targeted Delivery of Therapeutic siRNA

Abstract

RNA interference (RNAi) is a post-transcriptional gene-silencing phenomenon that is triggered by double-stranded RNA (dsRNA). Since many diseases are associated with the inappropriate production of specific proteins, attempts are being made to exploit RNAi in a clinical settings. However, before RNAi can be exploited as therapeutically, several obstacles must be overcome. For example, small interfering RNA (siRNA) is unstable in the blood stream so any effects of injected siRNA are only transient. Accordingly, methods must be developed to prolong its activity. Furthermore, the efficient and safe delivery of siRNA into target tissues and cells is critical for successful therapy. Any useful delivery method should be designed to target siRNA to specific cells and to promote gene-silencing activity once the siRNA is inside the cells. Recent chemical modifications of siRNA have overcome problems associated with the instability of siRNA, and various ligands, including glycosylated molecules, peptides, proteins, antibodies and engineered antibody fragments, appear to be very useful or have considerable potential for the targeted delivery of siRNA. The use of such ligands improves the efficiency, specificity and, as a consequence, the safety of the corresponding delivery systems.

Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting

“…Alternatively, a sulfhydryl group can be introduced on the polymer by using reagents such as dithiobis(succicimidyl propionate). Heterobifunctional PEG containing an NHS moiety on one end and a sulfhydryl-reactive maleimide or vinyl sulfone group has also been used (Mahato et al 1999;Hughes and Rao 2005;Ikeda and Taira 2006).…”

siRNA transfection by dendritic core–shell nanocarriers

“…[219] In addition to nontargeting vector/DNA polyplexes, different vector systems were developed to promote delivery into specific cell populations by incorporation of cell targeting moieties into the vector system. [168,[228][229][230][231] These moieties/ligands (e.g., transferrin, [168,[232][233][234][235][236][237][238][239] epidermal growth factor (EGF), [236,240] arginine-glycine-asparagine (RGD), [241][242][243][244][245] and folate), [242,[246][247][248][249][250] recognize cell type specific receptors in order to direct cellular uptake via receptor-mediated endocytosis, as illustrated in Figure 18. Once bound to the receptors on the cell surface, the vector/DNA polyplexes are internalized by clathrin-dependent endocytosis.…”

Microenvironmental regulation of biomacromolecular therapies

“…In principle, nucleotides that contain a sequence encoding for specific proteins or hormones can be introduced into target cells and the cell machinery can be exploited to produce the desired proteins. Alternatively, nucleotides that contain a sequence complementary to a specific gene or mRNA can be used to trigger their degradation and return abnormal gene expression to a desired state in approaches such as antisense therapies and interference therapies (siRNA) 102,103 . These nucleotide therapies can potentially alter cellular activities over longer periods of time compared with protein therapies.…”