期刊
BIOMATERIALS
卷 33, 期 5, 页码 1640-1650出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2011.11.008
关键词
Cationic carriers; siRNA; Combinatorial RNAi; Arginine-engrafted polymer; Cancer therapeutics
资金
- Korea National Research Foundation [2009-0079989, 2008-2-E00772]
- Ministry of Knowledge Economy under the KORUS Tech [KT-2008-NT-APFS0-0001]
- WCU [R332009000100360]
- National Research Foundation of Korea [2009-0079989] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Small interfering RNA (siRNA) represent an interesting class of developmental nucleic acid-based therapeutics. Cationic carriers for deoxyribonucleic acids (DNA) are potential vehicles for siRNA delivery. However, in contrast to supercoiled plasmid DNA, the physical properties of siRNA molecules induces the formation of larger, loosely packed complexes with most polycationic carriers, and consequently, poor target silencing. Here, we investigate a gene delivery agent, arginine-grafted bioreducible poly (disulfide amine) polymer (ABP) for siRNA delivery as it contains arginine residues with siRNA binding properties. ABP combines the attributes of polycations and poly disulfide-amines namely- excellent cell-penetrability and rapid release after disulphide bond reduction in the intracellular compartment. ABP bound siRNA, assembled into stable 150 nm sized nanoparticles and efficiently released complexed siRNA upon cellular entry. We investigated the utility of ABP in a combinatorial RNAi strategy for solid cancer therapy. Systemic administration of ABP-siRNA resulted in a preferential and enhanced accumulation of carrier-siRNA complexes in the tumor tissue. Two administrations of the formulation with a siRNA cocktail targeting Bcl-2, VEGF and Myc at 03 mg total siRNA/kg body weight could effectively regress advanced stage tumors. Our results establish the promise of ABP as a common systemic delivery platform for both siRNA and DNA therapeutics. (C) 2011 Elsevier Ltd. All rights reserved.
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