Nanocarriers for systemic siRNA delivery to tumor vasculature

Abstract

Currently there is a high need for efficacious medicines in cancer therapy. The use of conventional medicines to treat cancer is often hampered by their unfavorable safety profile which limits their dosing. By using targeted delivery systems, toxicity in non-target tissues can be reduced. An interesting therapeutic target in malignancies is the tumor neovasculature. After reaching a size of ~1-2 mm3, tumors initiate angiogenesis, the formation of new blood vessels from pre-existing ones. Inhibiting the processes which are involved in angiogenesis are therefore valuable to stop access of tumor cells to nutrients and oxygen. Moreover, normalization of the tumor vasculature by low doses of anti-angiogenic therapeutics could potentially lead to better accessibility of chemotherapeutics to tumor cells. The main shortcoming of the current anti-angiogenic therapeutics is that they can exhibit severe adverse effects due to non-specificity. A promising alternative class of anti-angiogenic therapeutics currently under investigation is siRNA. siRNA are double-stranded non-coding small RNA involved in gene silencing. These molecules can be rapidly designed to molecularly target the protein or proteins that are driving the angiogenic response. VEGF is a protein with a predominant role in promoting angiogenesis by binding to VEGFR-2 present on the endothelial cells of the tumor vasculature. This interaction results in the activation of certain signaling pathways which lead to pro-angiogenic events. Thus, silencing of VEGFR-2 expression by a specific siRNA could be an attractive approach in cancer therapy. In this thesis, we have studied a lipid-based targeted nanoparticle system (Angiplex) for delivery of siVEGFR-2 to tumor endothelial cells in vitro and in vivo.