A Novel Targeted Small Interfering Ribonucleic Acid (siRNA) Nanomedicine for the Treatment of Fibrosis
thesisposted on 20.06.2014, 00:00 by Fatima A. Khaja
Since its discovery in 1998, siRNA has been considered a potent tool for modulating gene expression as it specifically targets proteins that are not easily accessible by conventional small molecules. Hence, RNAi therapeutics have demonstrated great potential in the treatment of many devastating diseases caused by faulty protein expression such as fibrosis and cancer. Here we developed a unique targeted nanomedicine to tackle current siRNA delivery issues by formulating a biocompatible, biodegradable and relatively inexpensive nanocarrier of sterically stabilized phospholipid nanoparticles (SSLNPs). This nanocarrier is capable of incorporating siRNA in its core through electrostatic interactions with a novel cationic lipid, composed of naturally occuring phospholipids and amino acids. This self-assembly protects and delivers efficient amount of siRNA to downregulate over-expressed protein in target cells through the conjugation of a targeting ligand that interact with cell surface receptors and mediates endocytosis. In this study we demonstrate the potential of our novel siRNA nanomedicine to be used for the treatment of hepatic and renal fibrosis. Our siRNA cargo is targeted against connective tissue growth factor (CTGF), of which downregulation is considered to be the master switch for the reversal of fibrosis. In addition, we use Galactosamine as a targeting ligand, which enhances the nanoparticles uptake by hepatocytes and renal tubular epithelial cells, the major producers of CTGF in fibrosis. Furthermore, our nanocarrier demonstrates special biodistribution properties to hepatic and renal tissues due to its unique particle size and passive targeting making it of great potential for the treatment of both hepatic and renal diseases.