Poly-amino acidic oligonucleotide-carrier

Details Poly-amino acidic oligonucleotide-carrier Poly-amino acidic oligonucleotide-carrier

1996-06-06

1999-06-15

Huff, Sheela

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

525 5411, 525 542, C08G 6348

Patent

active

059123001

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a poly-amino acidic oligonucleotide-carrier. More particularly, the present invention relates to a novel poly-amino acidic carrier for oligonucleotide, which carrier is useful when transporting a plasmid DNA vector which possesses a drug oligonucleotide to be incorporated into chromosome thereby expressing RNA of the oligonucleotide in cells, or a drug which contains, as an effective ingredient, oligonucleotide having a specific function against mRNA of viral gene.


BACKGROUND ART

Fundamental studies on medical use of oligonucleotide (for example, antisense oligomer) have recently been actively carried out, and are now entering a stage of concretely searching for potentiality thereof. Actually, there are available many reports of in vitro studies on oligonucleotide: stability against solvent, selection of a target gene sequence to antisense oligomer, membrane permeability in cell lines, life span, nuclease resistance, intercellular distribution and the like.
Along with the progress of these fundamental studies, it has come to be considered very important to select an appropriate carrier substance when using oligonucleotide as a medical drug, and development of such a carrier substance and solution of problems for this purpose are now becoming inevitable tasks. More specifically, for example, important problems for this carrier include exclusion of positive charge of carrier complex which is unfavorable in biological dynamics of administration pathways such as intravenous injection, establishment of an efficient targeting system including cell membrane permeability, and improvement of life span and stability of oligonucleotide drugs and improvement of uptake efficient into cells.
Since oligonucleotide itself is very unstable and susceptible to decomposition under the effect of external conditions, research efforts are actively made to develop a drug delivery carrier for stably and efficiently carrying oligonucleotide to a target organ.
Overview of the process of the past research and development demonstrates that many of the conventional carrier are based on liposome which is a structure having a lipid bilayer configuration similar to a biological membrane. For example, an oligonucleotide drug included in liposome is reported, in which the oligonucleotide is stable in liposome, and at the same time, chemical or cellular specificity of the oligonucleotide is increased by chemical modification from liposome (Alain R. Thierry and Anatoly Dritschils, Nucleic Acid Res., 20, 5691-5698(1992)).
However, fine particle of liposome have a demerit of having a short half-life in blood. To overcome this disadvantage, improvements have recently been made in chemical stability such as oxidation stability, biological stability and colloidal chemical stability, and a new-generation liposome having a long half-life and an immunoliposome (a liposome having an antibody imbedded onto the surface thereof) are being developed, while practical problems have not however as yet been solved.
On the other hand, research efforts have suddenly increased which propose a technique of, by the utilization of anionicity of oligonucleotide, bonding oligonucleotide to a cationic natural protein or a cationic synthetic poly-amino acid, and delivering the resultant ionic complex to or into target cells (Nature, 271, 130-135 (1978), J. Biol. Chem., 262, 4429-4432 (1987), J. Biol. Chem., 263, 14621-14624 (1988), Proc. Natl. Acad. Sci. USA, 87, 3410-3414 (1990)). This technique is based on the fact that oligonucleotide is bonded in terms of charge to a cationic side chain of amino acid such as .epsilon.-amino group of lysine (Lys) residue, for example, and forms a relatively stable complex (Lemaitre, M., et al., Proc. Natl. Acad. Sci. U.S.A., 84, 648-651(1987)). There is however a problem in that formation of these complexes leads to generation of precipitation. In all these studies, therefore, a limit is that complexes are cationic heterogeneous ones.
For example, poly-L-Lys (PLL) is a well-known

REFERENCES:
patent: 5132230 (1992-07-01), Rosenthal et al.
Ca 122:38716, 1994.

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