期刊
BIOMATERIALS
卷 33, 期 33, 页码 8557-8568出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2012.07.054
关键词
Cationic nanoparticles; siRNA delivery; Histamine; Endosomal escape; Transfection; Immunotoxicity
资金
- National Heart Lung and Blood Institute of the National Institutes of Health [HHSN268201000046C]
- National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [R01-DK082546]
- Welch Foundation through W. T. Doherty-Welch Chair in Chemistry [A-0001]
Cationic shell crosslinked knedel-like nanoparticles (cSCKs) have emerged as a highly efficient transfection agent for nucleic acids delivery. In this study, a new class of cSCKs with tunable buffering capacities has been developed by altering the amounts of histamines and primary amines incorporated into their crosslinked shell regions. The effect of histamine content of these nanoparticles with a hydrodynamic diameter of ca. 20 nm, on the siRNA-binding affinity, cytotoxicity, immunogenicity, and transfection efficiency was investigated. The modification of cSCKs with histamine was found to reduce the siRNA-binding affinity and cellular binding. On the other hand, it significantly reduced the toxicity and immunogenicity of the nanoparticles with subsequent increase in the transfection efficiency. In addition, escape from endosomes was facilitated by having two species of low and high pK(a)s (i.e. histamine and primary amine groups, respectively), as demonstrated by the potentiometric titration experiments and the effect of bafilomycin A1, an inhibitor of the endosomal acidification, on the transfection efficiency of cSCKs. Histamine modification of 15 mol% was a threshold, above which cSCKs with higher histamine content completely lost the ability to bind siRNA and to transfect cells. This study highlights the potential of histamine incorporation to augment the gene silencing activity of cationic nanoparticles, reduce their toxicity, and increase their biocompatibility, which is of particular importance in the design of nucleic acids delivery vectors. (C) 2012 Elsevier Ltd. All rights reserved.
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