Modulation of angiogenesis with siRNA inhibitors for novel therapeutics

Abstract

Cancer and many other serious diseases are characterized by the uncontrolled growth of new blood vessels. Recently, RNA interference (RNAi) has reinvigorated the therapeutic prospects for inhibiting gene expression and promises many advantages over binding inhibitors, including high specificity, which is essential for targeted therapeutics. This article describes the latest developments using small-interfering RNA (siRNA) inhibitors to downregulate various angiogenic and tumor-associated factors, both in cell-culture assays and in animal disease models. The majority of research efforts are currently focused on understanding gene function, as well as proof-of-concept for siRNA-mediated anti-angiogenesis. The prospects for siRNA therapeutics, both advantages and looming hurdles, are evaluated.

Figure 1

Delivering VEGF-specific siRNA into tumor cells resulted in the downregulation of VEGF gene expression. In the cytoplasm of the transfected tumor cell, the VEGF-specific siRNAs released from the delivery carrier are incorporated into a multi-protein RNA-inducing silencing complex (RISC). The siRNA duplex is unwound within the RISC in a process that requires ATP. Once unwound, the single-stranded antisense strand guides RISC to its homologous target: VEGF mRNA that has a complementary sequence. This results in the endonucleolytic cleavage of the target VEGF mRNA and a consequent knockdown of VEGF protein levels in the transfected tumor cells.

Figure I

Dual-targeted anti-angiogenesis siRNA systemic delivery using ligand-directed nanoparticles. A layered, self-assembled siRNA nanoparticle system is used to deliver siRNAs specific to genes involved in the VEGF pathway to achieve a dual-targeted antiangiogenesis therapeutic effect. The first targeted effect is achieved by using the RGD peptide as the surface ligand of the nanoparticle to target integrin expression on tumor neovasculature and thus avoid effects on the targeted gene in normal tissues. The second target effect is achieved by using siRNA specifically against genes involved in VEGF pathway, such as VEGF, VEGFR1, and VEGFR2, to inhibit the angiogenesis activity in the targeted tumor tissue and thus generate anti-tumor efficacy.