PMID- 15685706
OWN - NLM
STAT- MEDLINE
DCOM- 20050825
LR  - 20191210
IS  - 1099-498X (Print)
IS  - 1099-498X (Linking)
VI  - 7
IP  - 6
DP  - 2005 Jun
TI  - New multivalent cationic lipids reveal bell curve for transfection efficiency 
      versus membrane charge density: lipid-DNA complexes for gene delivery.
PG  - 739-48
AB  - BACKGROUND: Gene carriers based on lipids or polymers-rather than on engineered 
      viruses-constitute the latest technique for delivering genes into cells for gene 
      therapy. Cationic liposome-DNA (CL-DNA) complexes have emerged as leading 
      nonviral vectors in worldwide gene therapy clinical trials. To arrive at 
      therapeutic dosages, however, their efficiency requires substantial further 
      improvement. METHODS: Newly synthesized multivalent lipids (MVLs) enable control 
      of headgroup charge and size. Complexes comprised of MVLs and DNA have been 
      characterized by X-ray diffraction and ethidium bromide displacement assays. 
      Their transfection efficiency (TE) in L-cells was measured with a luciferase 
      assay. RESULTS: Plots of TE versus the membrane charge density (sigmaM, average 
      charge/unit area of membrane) for the MVLs and monovalent 
      2,3-dioleyloxypropyltrimethylammonium chloride (DOTAP) merge onto a universal, 
      bell-shaped curve. This bell curve leads to the identification of three distinct 
      regimes, related to interactions between complexes and cells: at low sigmaM, TE 
      increases with increasing sigmaM; at intermediate sigmaM, TE exhibits saturated 
      behavior; and unexpectedly, at high sigmaM, TE decreases with increasing sigmaM. 
      CONCLUSIONS: Complexes with low sigmaM remain trapped in the endosome. In the 
      high sigmaM regime, accessible for the first time with the new MVLs, complexes 
      escape by overcoming a kinetic barrier to fusion with the endosomal membrane 
      (activated fusion), yet they exhibit a reduced level of efficiency, presumably 
      due to the inability of the DNA to dissociate from the highly charged membranes 
      in the cytosol. The intermediate, optimal regime reflects a compromise between 
      the opposing demands on sigmaM for endosomal escape and dissociation in the 
      cytosol.
CI  - Copyright (c) 2005 John Wiley & Sons, Ltd.
FAU - Ahmad, Ayesha
AU  - Ahmad A
AD  - Departments of Materials, Physics, and Molecular, Cellular and Development 
      Biology, University of California, Santa Barbara, Santa Barbara, CA 93106-5121, 
      USA.
FAU - Evans, Heather M
AU  - Evans HM
FAU - Ewert, Kai
AU  - Ewert K
FAU - George, Cyril X
AU  - George CX
FAU - Samuel, Charles E
AU  - Samuel CE
FAU - Safinya, Cyrus R
AU  - Safinya CR
LA  - eng
GR  - AI-12520/AI/NIAID NIH HHS/United States
GR  - AI-20611/AI/NIAID NIH HHS/United States
GR  - NIH GM-59288/GM/NIGMS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - J Gene Med
JT  - The journal of gene medicine
JID - 9815764
RN  - 0 (1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine)
RN  - 0 (Cations)
RN  - 0 (Fatty Acids, Monounsaturated)
RN  - 0 (Lipid Bilayers)
RN  - 0 (Liposomes)
RN  - 0 (Phosphatidylethanolamines)
RN  - 0 (Quaternary Ammonium Compounds)
RN  - 9007-49-2 (DNA)
RN  - EC 1.13.12.- (Luciferases)
RN  - MR86K0XRQP (1,2-dioleoyloxy-3-(trimethylammonium)propane)
SB  - IM
MH  - Animals
MH  - Cations
MH  - DNA/*chemistry/*pharmacokinetics
MH  - Fatty Acids, Monounsaturated/chemistry
MH  - *Gene Transfer Techniques
MH  - Genes, Reporter
MH  - Genetic Therapy
MH  - L Cells
MH  - Lipid Bilayers/chemistry/pharmacokinetics
MH  - Liposomes/*chemistry/*pharmacokinetics
MH  - Luciferases/metabolism
MH  - Mice
MH  - Models, Biological
MH  - Models, Chemical
MH  - Normal Distribution
MH  - Phosphatidylethanolamines/chemistry
MH  - Quaternary Ammonium Compounds/chemistry
MH  - *Transfection
MH  - X-Ray Diffraction
EDAT- 2005/02/03 09:00
MHDA- 2005/08/27 09:00
CRDT- 2005/02/03 09:00
PHST- 2005/02/03 09:00 [pubmed]
PHST- 2005/08/27 09:00 [medline]
PHST- 2005/02/03 09:00 [entrez]
AID - 10.1002/jgm.717 [doi]
PST - ppublish
SO  - J Gene Med. 2005 Jun;7(6):739-48. doi: 10.1002/jgm.717.