460542 Polypeptide/Nucleic Acid Complexes As Delivery Vehicles

Sunday, November 13, 2016: 4:42 PM
Golden Gate 3 (Hilton San Francisco Union Square)
Lorraine F. Leon1, Cheng-Hsiang Kuo2, Myung-Jin Oh2, Eun Ji Chung1,3, Yun Fang2 and Matthew V. Tirrell1, (1)Institute for Molecular Engineering, University of Chicago, Chicago, IL, (2)Department of Medicine, University of Chicago, Chicago, IL, (3)Department of Biomedical Engineering, University of Southern California, Los Angeles, CA

Electrostatically driven polymer self-assembly mechanisms, such as polyelectrolyte complexation, are vastly underexplored compared to amphiphilic-based assemblies, and yet offer unique opportunities for both the encapsulation of charged therapeutics and controlled delivery, via the tailoring of intermolecular interactions using pH and salt. Nanoscale polyelectrolyte complexes micelles can be created using block-copolymers that incorporate a neutral, yet hydrophilic block to stabilize the polyelectrolyte complex on the nanoscale. The modular nature of these assemblies enables the addition of a targeting ligand conjugated to the hydrophilic block to increase the efficacy of delivering nucleic acids, creating polyelectrolyte complex micelles with a targeting ligand outside the corona of the micelle. Ultimately, we demonstrate the use of targeted polyelectrolyte complex micelles formed using therapeutic nucleic acids that inhibit microRNAs involved in atherogenesis, with the goal of creating a treatment for atherosclerosis. In doing so, we create trifunctional polymers that contain a targeting peptide (that target fibrin or endothelial cells), a polyethylene glycol domain to facilitate microphase separation, and a polylysine domain used to complex the microRNA inhibitors. We characterize these nanoscale assemblies and proceed to explore the ability of these micelles to inhibit microRNA-92a, which regulates the expression of endothelial transcription factors involved in the progression of atherosclerosis. Also we explore the ability to inhibit microRNA-33a in macrophages, which is involved in the expression of ATP binding cassette transporters involved in the trafficking of cellular cholesterol to the liver. Ultimately, we show the effectiveness and biodistribution of our targeted micelle assemblies using a murine model.

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See more of this Session: Biomaterials for Nucleic Acid Delivery
See more of this Group/Topical: Materials Engineering and Sciences Division