RONDEL
We are creating and developing new targeted, siRNA-containing therapeutics using our proprietary three part RNAi/Oligonucleotide Nanoparticle Delivery (RONDEL) technology, the foundation of which is our cyclodextrin-containing polymer. One of the key challenges to using RNAi therapy has been the inability to systemically deliver siRNA in humans. "Naked" siRNA is degraded and destroyed by nucleases in the bloodstream and is not taken up by cells. It also causes harmful immune reactions. With our RONDEL system, siRNA is protected by our cyclodextrin-containing polymers and thus can reach its destination and perform its intended job, for example, to stop the runaway growth of tumor cells.
Advanced Materials Engineering Meets Molecular Therapeutics
The RONDEL system takes advantage of molecular forces that generate self-assembly of an siRNA containing nanoparticle therapeutic. DNA and RNA are linear, negatively charged molecules. Component one of RONDEL is a linear polymer in which positively charged groups alternate with sugar molecules (cyclodextrin). Upon mixing with siRNA, the positively charged polymer associates with the negatively charged backbone of siRNAs. Several polymer/siRNA complexes self-assemble into a nanoparticle of less than 100nm in diameter that fully protects the siRNA from degradation in serum. This size is key to the delivery of the siRNA payload to tumor cells.
Each cyclodextrin molecule in the chain contains a hydrophobic core. Components two and three of the system contain adamantane covalently bound to polyethylene glycol (PEG). Adamantane is highly water insoluble. In aqueous solution, the adamantane end of the complex associates with the hydrophobic cores in the cyclodextrin polymer while the hydrophilic PEG extends from the hydrophobic core. The result is a siRNA containing nanoparticle coated with PEG, which acts to stabilize the nanoparticle and prevent aggregation under physiological conditions. A variety of targeting molecules that selectively attach to specified cell surface receptors can be covalently attached to the adamantane-PEG modifier, enabling the siRNA-containing particles to be coated with targeting molecules that address the nanoparticle to the tissue of interest.
The siRNA delivery system has been designed for intravenous injection. Upon delivery to the target cell, the targeting molecules bind to membrane receptors on the cell surface and the RNA-containing nanoparticle is taken into the cell by endocytosis. There, chemistry built into the polymer unpacks the siRNA from the delivery vehicle. The siRNA enters the cytoplasm where it can interact with the RNAi machinery of the cell.