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Enhanced shRNA delivery and ABCG2 silencing by charge-reversible layered nanocarriers.

Small (Weinheim an der Bergstrasse, Germany) (2014-10-22)
Zhenzhen Chen, Lifen Zhang, Yuling He, Youqing Shen, Yanfeng Li
ABSTRACT

Polycationic vectors have been used to deliver short hairpin RNAs (shRNAs) to knock-down genes for cancer therapies, but their inefficiency in lysosomal escape and shRNA release causes their low gene transcription efficiency. Herein, a three-layered polyethyleneimine (PEI)-coated gold nanocomplex interlaid with a pH-responsive charge-reversible chitosan-aconitic anhydride (CS-Aco) is constructed: a Au-PEI/CS-Aco/PEI/shRNA nanoparticle. The negatively charged CS-Aco hydrolyzes into positively charged CS in lysosomes, causing the nanocomposite to disassemble. The released Au-PEI nanoparticles efficiently rupture the lysosomes and thus release the PEI/shRNA polyplexes into cytoplasm, where they quickly disassociate because the PEI chains are short (1.2 kDa). As a consequence, the nanocomplexes display higher shRNA delivery efficiency than the 25 kDa PEI, and efficiently deliver shABCG2 to tumors and markedly silence ABCG2 expression, which sensitizes HepG2 cells to the drugs with minimal toxicity.

MATERIALS
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Product Description

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