Biodistribution study of phosphonolipids:: a class of non-viral vectors efficient in mice lung-directed gene transfer

被引:23
作者
Delépine, P
Guillaume, C
Montier, T
Clément, JC
Yaouanc, JJ
Abbayes, HD
Berthou, F
Le Pape, A
Férec, C
机构
[1] INSERM EMI U0115, Genet Mol & Epidemiol Genet, F-29275 Brest, France
[2] EFS Bretagne, F-29275 Brest, France
[3] CHU Morvan, Lab biol Mol & Histocompatibilite, F-29609 Brest, France
[4] Univ Bretagne Occidentale, Lab Genet Somat & Constitutionnelle Transfert Gen, Brest, France
[5] UBo, UMR CNRS 6521, UFR Sci, Chim Organ Lab, F-29285 Brest, France
[6] Fac Med, Biochim Lab, F-29200 Brest, France
[7] Fac Med, Lab Imagerie Ciblage & Vectorisat, F-37200 Tours, France
关键词
lipoplexes; phosphonolipids; biodistribution; imaging; small animal model; CATIONIC PHOSPHONOLIPIDS; PLASMID-DNA; TRANSGENE EXPRESSION; TISSUE DISTRIBUTION; DELIVERY; COMPLEXES; THERAPY; INJECTION; BINDING;
D O I
10.1002/jgm.385
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Background A multitude of cationic lipids have been synthesized since they were first proposed for use in gene therapy. Cationic lipids are able to efficiently transfect cells both in vitro and in vivo. Whereas most research groups have focused their investigations on the toxicity of these molecules, and on the location of expression of the DNA transferred by these vectors, little has been done to determine their biodistribution and elimination pathways. Our group has developed a family of cationic lipids termed phosphonolipids. Following a large in vitro screening experiment, we have selected several molecules for in vivo testing, with some of these phosphonolipids forming lipoplexes efficient in transfecting mouse lungs. It was thus of interest to study their fate after intravenous injection. Methods The respective biodistributions of both the GLB43 phosphonolipid and plasmid DNA were investigated and compared with DNA expression sites. Using the optimal conditions determined for phosphonolipids, we followed the gene transfer agent and plasmid DNA distributions versus time by radiolabeling them with C-14 and P-32, respectively. Otherwise, we performed imaging by radiolabeling plasmid DNA with Tc-99m. Results The lipoplexes appear to be directly located in the lung after administration. Secondly, the plasmid is released mainly into the lungs and the phosphonolipid vector is rapidly degraded. The hydrophilic moiety of the phosphonolipid is eliminated in the urine, as is the free plasmid. Conclusions This study reveals that there are slight differences in the observed results depending on the technique used to label the DNA; secondly, results show that the residence time of phosphonolipids in the mouse body is related to the DNA binding time. Copyright (C) 2003 John Wiley Sons, Ltd.
引用
收藏
页码:600 / 608
页数:9
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