A multi-domain protein for β1 integrin-targeted DNA delivery

被引:21
|
作者
Fortunati, E
Ehlert, E
van Loo, ND
Wyman, C
Eble, JA
Grosveld, F
Scholte, BJ
机构
[1] Erasmus Univ, Dept Cell Biol & Genet, NL-3000 DR Rotterdam, Netherlands
[2] Univ Munster, Inst Physiol Chem, D-4400 Munster, Germany
关键词
gene therapy; beta(1) integrin; invasin; Yersinia pseudotuberculosis; cationic liposome; polyethylenimine;
D O I
10.1038/sj.gt.3301258
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 effective receptor-targeted nonviral vectors for use in vivo is complicated by a number of technical problems. One of these is the low efficiency of the conjugation procedures used to couple protein ligands to the DNA condensing carrier molecules. We have made and characterized a multi-domain protein (SPKR)(4)inv, that is designed to target plasmid DNA to beta(1) integrins in remodeling tissue. If contains a nonspecific DNA-binding domain (SPKR)(4), a rigid or-helical linker, and the C-terminal beta(1) integrin binding domain (aa 793-987) of the Yersinia pseudotuberculosis invasin protein. (SPKR)(4)inv could be purified at high yields using a bacterial;expression system. We show that (SPKR),inv binds with high affinity to both plasmid DNA and beta(1) integrins. in a cell attachment assay, the apparent affinity of (SPKR)(4)inv for beta(1) integrins is three orders of magnitude higher than that of the synthetic peptide integrin ligand RGDS. (SPKR)(4)inv-plasmid complexes are not active in an in vitro transfection assay. However, transfection efficiencies of plasmid complexes with a cationic lipid micelle (DOTAP/Tween-20) or a cationic polymer (polyethylenimine), are significantly increased in combination with (SPKR),inv. (SPKR),inv-mediated transfection can be inhibited by a soluble form of beta(1) integrin, which is evidence for ifs receptor specificity. In conclusion, (SPKR),inv allows PI integrin-specific targeting of plasmid-carrier complexes, while avoiding inefficient and cumbersome coupling chemistry. The modular design of the expression vector allows production of similar multi-domain proteins with a different affinity. The further development of such complexes for use in vivo is discussed.
引用
收藏
页码:1505 / 1515
页数:11
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