Copolymer of poly(ethylene glycol) and poly(L-lysine) grafting polyethylenimine through a reducible disulfide linkage for siRNA delivery
Copolymer of poly(ethylene glycol) and poly(L-lysine) grafting polyethylenimine through a reducible disulfide linkage for siRNA delivery
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聚（乙二醇）和聚（L）-赖氨酸）通过可还原二硫键接枝聚乙烯亚胺的共聚物，用于 siRNA 递送
DOI：
10.1039/c3nr05024f
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发表时间：
2014-01-01
期刊：
影响因子：
6.7
通讯作者：
Shuai, Xintao
中科院分区：
文献类型：
--
作者：
Li, Jingguo;Cheng, Du;Shuai, Xintao
SiRNA治疗的研究主要集中在合成和开发高效、易生物降解、低毒的siRNA载体。在本研究中，我们通过引入二硫键将低相对分子质量的线性聚乙烯亚胺(LPEI)接枝到聚(L-赖氨酸)-聚乙二醇(PEG)嵌段共聚物上，合成了一种三元共聚物mpeg-b-pll-g-(ss-lPEI)，用于siRNA的传递。PLL封闭和二硫键使载体具有生物降解性，而lPEI接枝带来了对溶酶体siRNA释放的质子缓冲能力和低的阳离子毒性。将单链单抗(Herceptin)连接到载体上作为Her2/neu受体的靶向配体，显著提高了共聚物/siRNA纳米复合体(即多聚体)在人卵巢癌细胞株SKOV-3中的转染活性。基因表达水平和蛋白水平的检测表明，Her2靶向siRNA(XIAP SiRNA)有效下调靶向XIAP(X连锁的凋亡抑制蛋白)基因，从而促进癌细胞的凋亡，提高体内外的治疗效果。该共聚物具有细胞毒性低、易降解、siRNA转染率高等特点，是治疗肿瘤siRNA的理想候选材料。
siRNA therapy research has primarily focused on the synthesis and development of effective siRNA delivery vectors with easy biodegradability and low toxicity. In the present study, we synthesized a ternary copolymer mPEG-b-PLL-g-(ss-lPEI), denoted as PLI, by introducing disulfide bond linkages to graft low molecular weight linear polyethylenimine (lPEI) to the block copolymer of poly(L-lysine) (PLL) and poly(ethylene glycol) (PEG) for siRNA delivery. The PLL block and disulfide linkage rendered the carrier biodegradability, while lPEI grafting brought about the proton buffering capacity for lysosomal siRNA release and low cationic toxicity. Conjugation of a single chain monoclonal antibody (Herceptin) to the carrier as a targeting ligand for the Her2/neu receptor significantly increased the transfection activity of the copolymer/siRNA nanocomplex (i.e. the polyplex) in Skov-3, a human ovarian cancer cell line. Determination of gene expression at both the mRNA and protein levels demonstrated that Her2-targeted delivery of siRNA (XIAP siRNA) effectively downregulated the targeted XIAP (X-linked inhibitor of apoptosis protein) gene, resulting in enhanced cancer cell apoptosis and improved therapeutic efficacy in vitro and in vivo. The distinct features of low cytotoxicity, easy degradability, and high siRNA transfection efficiency make the copolymer a promising candidate for siRNA therapy in tumors.