Salt-Induced Stability and Serum-Resistance of Polyglutamate Polyelectrolyte Brushes/Nuclear Factor-魏B p65 siRNA Polyplex Enhance the Apoptosis and Efficacy of Doxorubicin

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• 作者：Yuefang Zhao ; Yuting Qin ; Yang Liang ; Haijuan Zou ; Xiao Peng ; Huan Huang ; Ming Lu ; Min Feng
• 刊名：Biomacromolecules
• 出版年：2013
• 出版时间：June 10, 2013
• 年：2013
• 卷：14
• 期：6
• 页码：1777-1786
• 全文大小：635K
• 年卷期：v.14,no.6(June 10, 2013)
• ISSN：1526-4602

文摘

Short interfering RNAs (siRNAs) as chemotherapeutic RNAi agents hold great promise for a significant improvement in cancer therapy. Despite the promise, effective transport of siRNA with minimal side effects remains a challenge. The common problem associated with the low delivery efficiencies of current polycation-based gene delivery systems is their low stability in the presence of salt and serum. In the present study we developed the polyglutamate derivatives (PGS) polyelectrolyte brushes for NF-魏B p65 siRNA delivery. The PGS polyelectrolyte brushes/siRNA polyplex was colloidally stable (150 nm diameter) in physiological saline (150 mM NaCl), likely due to the osmotic brushes of PGS. The size-controlled siRNA/PGS polyplex also showed the serum resistance resulting in their efficient cellular uptake was not negatively influenced by the presence of serum. The endothermic profile of ITC, their low values of Gibbs free energy and binding constants K_b under salt conditions provided the direct evidence that PGS polyelectrolyte brushes had a much lower binding affinity for serum proteins, compared with PEI 25KDa. PGS polyelectrolyte brushes delivering NF-魏B p65 siRNA achieved efficient down-regulation of NF-魏B p65 protein in HeLa cells. The NF-魏B p65 down-regulation mediated by PGS polyelectrolyte brushes was more significant than PEI 25KDa and comparable to Lipofectamine 2000. Furthermore, the combination treatment with PGS polyelectrolyte brushes/NF-魏B p65 siRNA polyplex and doxorubicin demonstrated synergistic apoptotic and cytotoxic effects on HeLa cancer cells. The high stability in physiological saline and salt-induced serum resistance of PGS polyelectrolyte brushes/siRNA polyplex has potential applications together with standard chemotherapies such as doxorubicin to be a viable method to improve the clinical outcomes in cancer therapies.