Journal
ACS NANO
Volume 5, Issue 3, Pages 1877-1887Publisher
AMER CHEMICAL SOC
DOI: 10.1021/nn102711d
Keywords
siRNA delivery; PAMAM dendrimer; BCL2 silencing; siRNA stability
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Funding
- NIH, National Cancer Institute [CA100098, CA111766, CA138533]
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A novel triblock poly(amido amine)-poly(ethylene glycol)-poly-L-lysine (PAMAM-PEG-PLL) nanocarrier was designed, synthesized and evaluated for the delivery of siRNA. The design of the nanocarrier is unique and provides a solution to most of the common problems associated with the delivery and therapeutic applications of siRNA. Every component in the triblock nanocarrier plays a significant role and performs multiple functions: (1) tertiary amine groups in the PAMAM dendrimer work as a proton sponge and play a vital role In the endosomal escape and cytoplasmic delivery of siRNA; (2) PEG a linker connecting PLL and PAMAM dendrimers renders nuclease stability and protects siRNA in human plasma; (3) PLL provides primary amines to form polyplexes with siRNA through electrostatic Interaction and also acts as penetration enhancer; and (4) conjugation to PEG and PAMAM reduced toxicity:of PLL and the entire triblock nanocarrier PAMAM-PEG-PLL. The data obtained show that the polyplexes resulted from the conjugation of siRNA, and the proposed nanocarriers were effectively taken up by cancer cells and induced the knock down of the target BCL2 gene. In addition, triblock nanocarrier/siRNA polyplexes showed excellent stability in human plasma.
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