Bombesin/oligoarginine fusion peptides for gastrin releasing peptide receptor (GRPR) targeted gene delivery

被引:16
作者
Begum, Anjuman Ara [1 ,2 ]
Wan, Yu [1 ,2 ]
Toth, Istvan [1 ,2 ,3 ]
Moyle, Peter M. [2 ]
机构
[1] Univ Queensland, Sch Chem & Mol Biosci, St Lucia, Qld 4072, Australia
[2] Univ Queensland, Sch Pharm, Woolloongabba, Qld 4102, Australia
[3] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia
基金
澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会;
关键词
Gastrin releasing peptide receptor; Bombesin peptide; Targeted delivery; Oligo-arginine; pDNA delivery; SOLID-PHASE SYNTHESIS; ARGININE; VECTORS; FMOC; OLIGONUCLEOTIDE; LIGAND;
D O I
10.1016/j.bmc.2017.12.013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The development of non-viral gene delivery systems, with the capacity to overcome most of the biological barriers facing gene delivery, is challenging. We have developed peptide-based, multicomponent, non-viral delivery systems, incorporating: a bombesin peptide ligand (BBN(6-14)), to selectively target the gastrin releasing peptide receptor (GRPR); oligoarginine peptides (hexa- (R-6) and nona-arginine (R-9)), for plasmid DNA (pDNA) condensation; and GALA, to facilitate endosome escape. The uptake and endosome escape efficiency of bombesin/oligoarginine and bombesin/oligoarginine/GALA fusion peptides for oligonucleotide delivery was evaluated in terms of their complex size, cellular uptake, endosome escape, and cellular toxicity. Complex size and cell uptake studies demonstrated that the nona-arginine/bombesin delivery system was more efficient at condensing and delivering pDNA into PC-3 prostate cancer cells compared to the hexa-arginine/bombesin delivery system. Further, competition with free bombesin peptide, and comparative uptake studies in Caco-2 cells, which express GRPR at a lower level, suggested that GRPR contributes to the targeted uptake of this system. The addition of GALA into the nona-arginine/bombesin-based system further increased the pDNA cellular uptake at all tested N/P ratios; facilitated endosomal pDNA release; and had limited effects on cell viability. In conclusion, the delivery system combining BBN(6-14) with nona-arginine and GALA had optimal characteristics for the delivery of pDNA into the GRPR overexpressing cell line PC-3. (C) 2017 Elsevier Ltd. All rights reserved.
引用
收藏
页码:516 / 526
页数:11
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