Nanotechnology-based approaches for targeted delivery of siRNA or chemotherapeutics

In the thesis, Nanotechnology-based approaches for targeted delivery of siRNA or chemotherapeutics, we designed three lipid nanocarriers suitable for endothelial cell-targeted delivery of siRNA in inflammation. These lipid-based nanocarriers containing RelA siRNA can significantly downregulate inflammation-induced target gene expression in endothelial cells in vitro and in vivo. Two chapters focus on exploring a rational design of cationic lipid composition in the formulation of liposomes and LNP, for enhanced efficiency of siRNA delivery into endothelial cells. One chapter describes further development of endothelial-specific LNP for targeted functional delivery of siRNA to disease-associated vascular segments in vivo. We have introduced different strategies for effective endothelial siRNA delivery, by modulating cationic lipid composition and by applying a specific targeting ligand. Increasing endothelium affinity/tropism, enhancing cellular internalization, and improving intracellular processing are key in the optimization of targeted nanocarriers for efficient siRNA delivery into “hard-to-treat” vascular endothelial cells. Additionally, we applied state-of-the-art validation methods for endothelial-targeted siRNA delivery, such as an endothelial cell-fluorescently-labeled zebrafish model for tracking and investigating nanoparticles, and the laser microdissection (LMD) technique for studying microvascular segment LNP enrichment to unmask microvascular bed-specific gene silencing profiles. In the last part of this thesis, we described the development of a nanotechnology-based therapeutic regimen for effective anti-glioblastoma combination therapy, by combining first-line chemotherapeutic temozolomide with the natural chemosensitizer curcumin.