Cationic and polycationic amphiphiles, reactives containing the

Details Cationic and polycationic amphiphiles, reactives containing the Cationic and polycationic amphiphiles, reactives containing the

1997-12-05

2000-05-09

Campell, Bruce R.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

435455, 435458, 536 231, A61K 4800

Patent

active

060604557

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The invention concerns new cationic and polycationic amphiphiles which are capable of forming aggregates with macromolecules, in particular with DNA or RNA, and it concerns their delivery into prokaryotic or eukaryotic cells.
Amphiphiles (e.g. surfactants, detergents) have for some time played a general role in daily life. In contrast only recently has greater attention been paid to cationic amphiphiles through the pioneer work of Felgner since they can be used to deliver DNA and RNA into cells and transfect them in this manner (P. L. Felgner et al., Proc. Natl. Acad. Sci., USA 84, 7413-7417 (1987); P. Hawley-Nelson. WO 94/05624 et al., J. P. Behr, EP 0394111).
The individual reagents used for this are very varied. This is mostly due to the fact that they have been found empirically. Thus it has not been possible to specifically provide a compound for the application in question. Moreover the fact that compounds exist which only have an effect in a mixture with other reagents reveals the whole complexity of transfection. A review of most of the reagents that have been found up to now is given by Behr (Bioconjugate Chem., 5, 382-389 (1994) and the references cited therein). However, in general the majority of the reagents can form liposomes.
The mechanism of transfection by cationic amphiphiles is still little understood. It appears plausible that the liposomes by means of their positive charge form a more positively charged complex with the DNA and this attaches itself to the negatively polarized cell membrane (P. L. Felgner, Nature 337, 387-388 (1989)). However, it is not certain how the penetration of the cell membrane and transport to the cell nucleus takes place.
Nevertheless, apart from the transfection efficiency it is possible to define a series of other requirements for new reagents: permeabilizing the cell membrane with DMSO, a detergent such as digitonin or by scraping. effective concentration and should be preferably biologically degradable consideration to toxicity, compatibility with serum is also of major significance. This has often been the reason for a drastic decrease in the transfection efficiency.
Hence the object of the invention was to provide appropriate reagents which equally fulfill these requirements.


SUMMARY OF THE INVENTION

This object is achieved by certain cationic, lipidic amphiphiles that can be used to deliver anionic compounds such as e.g. DNA into cells and in this process surprisingly exhibit improved properties with respect to the aforementioned requirements.
In particular compounds of the general formula I serve as amphiphiles ##STR1## in which R.sub.1 represents a saturated or unsaturated C(O)--C.sub.1-23 or saturated or unsaturated C.sub.1-24 group stated for R.sub.1 and can be the same as or different from R.sub.1 Y.sup.- residue in which hydrogen, an alkyl group with 1 to 4 C atoms, a (CH.sub.2).sub.n --OH or a (CH.sub.2).sub.n --NH.sub.2 group where n=2-6, denotes hydrogen, an alkyl group with 1 to 4 C atoms, a (CH.sub.2).sub.n --OH, a (CH.sub.2).sub.n -halogenide or a ((CH.sub.2).sub.m NH).sub.o --(CH.sub.2).sub.n --NH.sub.2 group in which m is an integer from 2 to 6 and can be equal to or different from n or o wherein n can be a number from 2 to 6 and o an integer from 0 to 4, an amidically bound amino acid, an amidically bound peptide or polypeptide, a C(O)--CHR.sub.6 N(R.sub.7).sub.2, a C(O)CHR.sub.6 N.sup.+ (R.sub.7).sub.3, a C(O)--CHR.sub.6 N.sup.+ (R.sub.7).sub.2 R.sub.8 or a C(O)--CHR.sub.6 NR.sub.7 R.sub.8 group in which --N.sup.+ (R.sub.7).sub.2 R.sub.8 or a (CH.sub.2).sub.m --N.sup.+ (R.sub.7).sub.3 residue (CH.sub.2).sub.n --N.sup.+ (R.sub.7).sub.3 group in which n is a number from 2 to 4 and R.sub.7 can have the meaning stated above and is a number from 1 to 6 and q is a number from 0 to 2, polypeptide, a C(O)--CHR.sub.6 N(R.sub.7).sub.2, a C(O)--CHR.sub.6 N.sup.+ (R.sub.7).sub.3, a C(O)--CHR.sub.6 N.sup.+ (R.sub.7).sub.2 R.sub.8 or a C(O)--CHR.sub.6 NR.sub.7 R.sub.8 group and R.sub.6 to R.sub.8 and m have the aforement

REFERENCES:
patent: 5264618 (1993-11-01), Felgner et al.
patent: 5747471 (1998-05-01), Siegel et al.
patent: 5827703 (1998-10-01), Debs et al.

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