Balancing Cationic and Hydrophobic Content of PEGylated siRNA Polyplexes Enhances Endosome Escape, Stability, Blood Circulation Time, and Bioactivity in Vivo
| Autor: | Ann Hanna, Mukesh Kumar Gupta, Craig L. Duvall, James R. Kintzing, Joshua M. Shannon, Christopher E. Nelson |
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| Rok vydání: | 2013 |
| Předmět: |
Materials science
General Physics and Astronomy Endosomes Methacrylate Smart polymer Article Polyethylene Glycols chemistry.chemical_compound Cations Cell Line Tumor PEG ratio Polymer chemistry Humans Tissue Distribution General Materials Science RNA Small Interfering technology industry and agriculture General Engineering Cationic polymerization Chain transfer Raft chemistry Blood Circulation Drug delivery Biophysics Hydrophobic and Hydrophilic Interactions Ethylene glycol Half-Life |
| Zdroj: | ACS Nano. 7:8870-8880 |
| ISSN: | 1936-086X 1936-0851 |
| DOI: | 10.1021/nn403325f |
| Popis: | A family of pH-responsive diblock polymers composed of poly[(ethylene glycol)-b-[(2-(dimethylamino)ethyl methacrylate)-co-(butyl methacrylate)], PEG-(DMAEMA-co-BMA), was reversible addition-fragmentation chain transfer (RAFT) synthesized with 0-75 mol % BMA in the second polymer block. The relative mole % of DMAEMA and BMA was varied in order to identify a polymer that can be used to formulate PEGylated, siRNA-loaded polyplex nanoparticles (NPs) with an optimized balance of cationic and hydrophobic content in the NP core based on siRNA packaging, cytocompatibility, blood circulation half-life, endosomal escape, and in vivo bioactivity. The polymer with 50:50 mol % of DMAEMA:BMA (polymer "50 B") in the RAFT-polymerized block efficiently condensed siRNA into 100 nm NPs that displayed pH-dependent membrane disruptive behavior finely tuned for endosomal escape. In vitro delivery of siRNA with polymer 50 B produced up to 94% protein-level knockdown of the model gene luciferase. The PEG corona of the NPs blocked nonspecific interactions with constituents of human whole blood, and the relative hydrophobicity of polymer 50 B increased NP stability in the presence of human serum or the polyanion heparin. When injected intravenously, 50 B NPs enhanced blood circulation half-life 3-fold relative to more standard PEG-DMAEMA (0 B) NPs (p0.05), due to improved stability and a reduced rate of renal clearance. The 50 B NPs enhanced siRNA biodistribution to the liver and other organs and significantly increased gene silencing in the liver, kidneys, and spleen relative to the benchmark polymer 0 B (p0.05). These collective findings validate the functional significance of tuning the balance of cationic and hydrophobic content of polyplex NPs utilized for systemic siRNA delivery in vivo. |
| Databáze: | OpenAIRE |
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