Lipopolyamines as transfection agents and pharamaceutical uses t

Details Lipopolyamines as transfection agents and pharamaceutical uses t Lipopolyamines as transfection agents and pharamaceutical uses t

1997-06-04

2000-08-22

Barts, Samuel

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

560170, 560180, 560157, 560158, 560188, 564224, A61K 3170

Patent

active

061072869

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel compounds belonging to the family of lipopolyamines, to pharmaceutical compositions containing them and to their applications for the in vivo and/or in vitro transfection of nucleic acids.
Many genetic diseases are associated with an expression defect and/or abnormal expression, that is to say deficient or excessive expression, of one or more nucleic acids. The main aim of gene therapy is to correct genetic anomalies of this type by means of in vivo or in vitro cellular expression of cloned genes.
At the present time, several methods are proposed for the intracellular delivery of genetic information of this type. One of these methods, in particular, is based on the use of chemical or biochemical vectors. Synthetic vectors have two main functions, to compact the DNA to be transfected and to promote its binding to the cell as well as its passage across the plasma membrane and, where appropriate, across the two nuclear membranes.
Significant progress was made in this mode of transfection with the development of technology based on the use of a cationic lipid. It has thus been demonstrated that a positively charged cationic lipid, N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium (DOTMA) chloride, interfered, in the form of liposomes or small vesicles, spontaneously with DNA, which is negatively charged, to form lipid-DNA complexes capable of fusing with cell membranes, and thus allowed the intracellular delivery of the DNA. However, although this molecule is effective as regards transfection, it has the disadvantage of being non-biodegradable and of having a toxic nature towards cells.
Since DOTMA, other cationic lipids have been developed on this structural model: lipophilic groups associated with an amino group via a so-called "spacer" arm. Among these lipids, there may more particularly be mentioned those comprising, as lipophilic group, two fatty acids or a cholesterol derivative, and also containing, where appropriate, as free amino group, a quaternary ammonium group. DOTAP, DOBT or ChOTB may be mentioned in particular as representatives of this category of cationic lipids. Other compounds, such as DOSC and ChOSC, are characterized by the presence of a choline group in place of the quaternary ammonium group. In general, however, the transfecting activity of these compounds remains fairly low.
Another category of cationic lipids, the lipopolyamines, has also been described. In this type of compound, the cationic group is represented by the L-5-carboxyspermine radical which contains four ammonium groups, two primary and two secondary. DOGS and DPPES in particular form part thereof. These lipopolyamines are more particularly effective for the transfection of primary endocrine cells.
In fact, an ideal synthetic transfection agent should exhibit a high level of transfection for a wide spectrum of cells, should have no toxicity or, at least, a very minimized toxicity at the doses of use, and, lastly, should be biodegradable so as to rid itself of any side effects on the treated cells.
The very subject of the present invention is indeed to propose novel compounds which are capable of being used effectively in the in vitro and/or in vivo transfection of cells and, in particular, for the vectorization of nucleic acids.
The first subject of the invention is lipopolyamines, in D, L or DL form and the salts thereof, represented by the general formula I: ##STR1## in which m is an integer between 2 and 6 inclusively, and 5 with a single group R other than hydrogen present in the general formula and values of m which are variable or identical in the various groups ##STR2## and --(CH.sub.2).sub.m --R represents a hydrogen atom or a radical of general formula II ##STR3## in which X and X' represent, independently of each other, an oxygen atom, a methylene group --(CH.sub.2).sub.q -- with q equal to 0, 1, 2 or 3, or an amino group --NH-- or --NR'-- with R' representing a C.sub.1 to C.sub.4 alkyl group, carbonyl group or a C.dbd.S group, hydrogen atom or a substituted or unsubstitu

REFERENCES:
patent: 4014933 (1977-03-01), Boettger et al.
patent: 5616745 (1997-04-01), Behr
patent: 5641662 (1997-06-01), Debs et al.
Chem Abstract, 1991:217, Shvelashvili et al, rn=107-15-3 Month Unavailable 1990.
Behr, J.-P. et al., Efficient Gene Transfer into Mammalian Primary Endocrine Cells with Lipopolyamine-coated DNA, Proceedings of the National Academy of Sciences of USA , 86, 6982-6986 (1989) Month Unavailable.
Remy, J-S. et al., Gene Transfer with a Series of Lipophilic DNA-Binding Molecules, Bioconjugate Chemistry, 5, 647-654 (1994) Month Unavailable.
Behr, J-P., DNA Strongly Binds to Micelles and Vesicles Containing Lipopolyamines or Lipointercalants, Tetrahedron Letters, 27, 5861-5864 (1986) Month Unavailable.

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