Protease-triggered siRNA delivery vehicles
| Autor: | David B. Rozema, So C. Wong, Vladimir S. Trubetskoy, Almeida Lauren J, Jonathan D. Benson, Julia Hegge, Darren H. Wakefield, Holly Hamilton, Jeffrey C. Carlson, Jon A. Wolff, Eric A. Kitas, David L. Lewis, Qili Chu, Jason Klein, Anthony Nicholas, Collin M. Hagen, Andrei V. Blokhin |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Small interfering RNA Proteases Erythrocytes Lysis Polymers medicine.medical_treatment Pharmaceutical Science Endocytosis Hemolysis siRNA polymer conjugate medicine Animals RNA Small Interfering Mice Inbred ICR Protease Chemistry Subcutaneous Gene Transfer Techniques Factor VII Ligand (biochemistry) Rats Cell biology Macaca fascicularis Membrane Biochemistry Female Asialoglycoprotein receptor Targeted delivery Peptide Hydrolases |
| Zdroj: | Journal of Controlled Release. 209:57-66 |
| ISSN: | 0168-3659 |
| DOI: | 10.1016/j.jconrel.2015.04.012 |
| Popis: | The safe and efficacious delivery of membrane impermeable therapeutics requires cytoplasmic access without the toxicity of nonspecific cytoplasmic membrane lysis. We have developed a mechanism for control of cytoplasmic release which utilizes endogenous proteases as a trigger and results in functional delivery of small interfering RNA (siRNA). The delivery approach is based on reversible inhibition of membrane disruptive polymers with protease-sensitive substrates. Proteolytic hydrolysis upon endocytosis restores the membrane destabilizing activity of the polymers thereby allowing cytoplasmic access of the co-delivered siRNA. Protease-sensitive polymer masking reagents derived from polyethylene glycol (PEG), which inhibit membrane interactions, and N-acetylgalactosamine, which targets asialoglycoprotein receptors on hepatocytes, were synthesized and used to formulate masked polymer-siRNA delivery vehicles. The size, charge and stability of the vehicles enable functional delivery of siRNA after subcutaneous administration and, with modification of the targeting ligand, have the potential for extrahepatic targeting. |
| Databáze: | OpenAIRE |
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