Journal
BIOMATERIALS
Volume 32, Issue 6, Pages 1694-1705Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2010.10.044
Keywords
Gene therapy; Poly(L-lysine); Linear polyethylenimine; Folate targeting; TRAIL gene
Funding
- National Natural Science Foundation of China [50673103, 50830107, 20728403, 20974129]
- 863 Programs [2009AA03Z310]
- National Science and Technology Foundation of China [2009ZX09501-023]
- Natural Science Foundation [9351027501000003, 2009310004203647]
- S&T Programs of Guangdong Province [2009B030803003]
- Guangzhou Scientific Project [2008Z1-D171]
- Postdoctoral Foundation of China [2009310004109639]
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A major challenge in gene therapy is the development of effective gene delivery vectors with low toxicity. In the present study, linear poly(ethylenimine) (IPEI) 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-IPEI (PPI) for gene delivery. In such molecular design, PLL, IPEI 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. (C) 2010 Elsevier Ltd. All rights reserved.
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