期刊
BIOMACROMOLECULES
卷 19, 期 10, 页码 4052-4058出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.biomac.8b01066
关键词
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资金
- Natural Science and Engineering Research Council of Canada
- Alberta Innovates Health Solutions (AIHS) [201201164]
Strong signaling cascades derived from upregulation and overexpression of growth factors such as the EGF-family (epidermal growth factors) have been crucially related to cancer pathogenesis. Gene silencing techniques to modulate the expression of oncogenes and tumor suppresor genes are a strategy that shows great promise for cancer management but still faces some limitations in the design of biocompatible and effective vectors. In this study, we synthesized, by reversible addition-fragmentation chain transfer (RAFT) polymerization, several acid degradable galactose-based hyperbranched cationic polymers with varying molecular weights (10 to 20 kDa) and compositions with 2-lactobioamidoethyl methacrylamide [LAEMA] and 2-aminoethyl methacrylamide hydrochloride [AEMA] at different ratios (2.0, 1.0, and 0.5). These polymers were then evaluated for their ability to enhance Epidermal Growth Factor Receptor (EGFR) knockdown in cervical carcinoma. All the polymer constructs have enhanced capabilities to condensate siRNA (small interfering RNA), showing low toxicity at higher LAEMA:AEMA ratios (1.0 and 2.0). Western blot assays were conducted to quantify the EGFR expression of each treatment group demonstrating superior gene knockdown efficiency for the polymers having a LAEMA:AEMA ratio of 2.0 than the lower ratio counterparts; while maintaining low toxicity levels. Gene silencing of EGFR of up to 60% was achieved with acid degradable polymers having 10 kDa molecular weight and a LAEMA:AEMA ratio of 2.0. The superior stability of the polyplexes under physiological conditions and the low cytotoxicity observed in the 48 h post-transfection demonstrated the high potential of these acid degradable galactose-based hyperbranched cationic polymers for EGFR silencing treatment applications at the clinical level.
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