PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China.
Biomaterials. 2011 Feb;32(6):1694-705. doi: 10.1016/j.biomaterials.2010.10.044. Epub 2010 Nov 18.
A major challenge in gene therapy is the development of effective gene delivery vectors with low toxicity. In the present study, linear poly(ethylenimine) (lPEI) with low molecular weight was grafted onto the block copolymer (PPL) of poly(l-lysine) (PLL) and poly(ethylene glycol)(PEG), yielding a ternary copolymer PEG-b-PLL-g-lPEI (PPI) for gene delivery. In such molecular design, PLL, lPEI and PEG blocks were expected to render the vector biodegradability, proton buffering capacity, low cationic toxicity and potentially long circulation in vivo, respectively. Given proper control of molecular composition, the copolymers demonstrated lower cytotoxicity, proton buffering capacity, ability to condense pDNA and mediate effective gene transfection in various cell lines. With folate as an exemplary targeting ligand, the FA-PPI/pDNA complex showed much higher transgene activity than its nontargeting counterpart for both reporter and therapeutic genes in folate receptor(FR)-positive cells. FA-PPI mediated effective transfection of the TNF-related apoptosis-inducing ligand gene (TRAIL) in human hepatoma Bel 7402 cells, leading to cell apoptosis and great suppression of cell viability. Our results indicate that the copolymers might be a promising vector combining low cytotoxicity, biodegradability, and high gene transfection efficiency.
基因治疗的一个主要挑战是开发具有低毒性的有效基因传递载体。在本研究中，将低分子量线性聚（亚乙基亚胺）（lPEI）接枝到聚（L-赖氨酸）（PLL）和聚（乙二醇）（PEG）的嵌段共聚物（PPL）上，得到用于基因传递的三元共聚物 PEG-b-PLL-g-lPEI（PPI）。在这种分子设计中，PLL、lPEI 和 PEG 链段有望分别赋予载体生物降解性、质子缓冲能力、低阳离子毒性和潜在的体内长循环能力。通过适当控制分子组成，共聚物表现出更低的细胞毒性、质子缓冲能力、压缩 pDNA 的能力和在各种细胞系中有效转染基因的能力。以叶酸作为典型的靶向配体，FA-PPI/pDNA 复合物在叶酸受体（FR）阳性细胞中对报告基因和治疗基因的转染效率均明显高于其非靶向对应物。FA-PPI 介导 TNF 相关凋亡诱导配体基因（TRAIL）在人肝癌 Bel 7402 细胞中的有效转染，导致细胞凋亡和细胞活力的显著抑制。我们的结果表明，该共聚物可能是一种具有低细胞毒性、生物降解性和高基因转染效率的有前途的载体。
