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KMID : 1094720150200030550
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Biotechnology and Bioprocess Engineering
2015 Volume.20 No. 3 p.550 ~ p.560
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Candesartan-graft-polyethyleneimine cationic micelles for effective co-delivery of drug and gene in anti-angiogenic lung cancer therapy
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Hao Shanhu
Yan Ying
Ren Xue
Xu Ying
Chen Lanlan
Zhang Haibo
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Abstract
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A multifunctional polymer-drug conjugate candesartan-graft-polyethyleneimine (CD-PEI, CP) containing low molecular weight polyethyleneimine (PEI) and candesartan (CD) conjugated via an amide bond was fabricated as a co-delivery micelle of drug and siRNA for potential lung cancer therapy. Here, CD as an angiotensin II type 1 receptor blocker rich in imidazole and tetrazole rings was utilized to strengthen endosomal buffering capacity of CP and suppress tumor angiogenesis. The selfassembled CP/siRNA complexes exhibited desirable and homogenous particle size, moderate positive charges, and efficient release of drug and siRNA in vitro. In addition, CD and siRNA could readily detached from nanovectors in tumor cells via an amidase-responsive mechanism and they achieved synergistic anti-angiogenesis efficacy by effectively downregulating the expression of vascular endothelial growth factor (VEGF) mRNA and protein via different pathways in vitro. In vivo investigation on nude mice bearing A549 tumor xenografts revealed that CP/siRNA complexes possessed strong antitumor activity. These findings suggested that CP could be an ideal nanovector for simultaneous transfer of drug and siRNA, and a multifunctional CP/siRNA co-delivery system with enhanced endosomal buffering capacity, amidase-responsive drug release and synergistic anti-angiogenesis efficacy might be a new promising strategy for effective lung cancer therapy.
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KEYWORD
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micelles, co-delivery, candesartan, siRNA, anti-angiogenesis, lung cancer
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