pH-sensitive cationic lipids, and liposomes and nanocapsules containing the same
View Patent ↗The invention suggests a pH-sensitive cationic lipid with a pK a value between 3.5 and 8, according to the general formula cation-spacer-Y-spacer-X-lipid, wherein Y and X represent linking groups. Furthermore, liposomes are described, which liposomes include said optionally cationic lipids.
1. A lipid of formula (I):
Cation-spacer2-Y-spacer1-amphiphilic component (I)
wherein
(a) the cation is a morpholine group,
(b) spacer 1 and spacer 2 are each, independently of one another, a linear C 1 to C 8 alkyl having 0 to 4 hydroxyl groups,
(c) Y is absent or —(C═O)—O—; —(C═O)—NH—; —NH—(C═O)—O—; —O—; —NH—; —CH═N—; —O—(O═C)—; —S—; —(O═C)—; —NH—(O═C)—; —O—(O═C)—NH—, —N═CH— or —S—S—,
(d) the amphiphilic component is a compound according to formula (II):
wherein
R 1 and R 2 independently are C 8 -C 30 alkyl or acyl chains having 0, 1 or 2 ethylenically unsaturated bonds, and
X is absent or —O—(C═O); —NH—(C═O)—; —S—(C═O)—; —O—; —NH—; —S—; —(O═C)—O—; —S—(O═C)—; —NH—(O═C)—; —N═CH— or —S—S—.
2. The lipid according to claim 1 , wherein R 1 and R 2 are, independently from each other, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl, or linoleoyl or a corresponding alkyl moiety thereof.
3. The lipid according to claim 1 , which has a pKa value between 4 and 6.5.
4. The lipid according to claim 1 , wherein X and Y are, independently, —(C═O)—O—, —O—, —NH—, —S—, —O—(O═C), —NH—(O═C)—, or —N═CH—.
5. A liposome which comprises a lipid according to claim 1 and an additional lipid compound.
6. The liposome according to claim 5 , which comprises between 5 and 50 mole-% of said lipid of formula I.
7. The liposome according claim 5 , wherein the additional lipid compound is phosphatidyl choline, phosphatidyl ethanolamine, ceramide, sphingolipid, tetraether lipid, cholesterol or diacylglycerol, phosphatidyl serine, phosphatidic acid or CHEMS.
8. The liposome according claim 5 , wherein the additional lipid compound is an anionic lipid.
9. The liposome according to claim 5 , wherein said liposome has an average size of between 50 and 1000 nm.
10. The liposome according to claim 5 , which comprises an active substance which is a protein, a peptide, a carbohydrate, a DNA, an RNA, an antisense nucleotide, and/or a decoy nucleotide.
11. The liposome according to claim 8 , which further comprises an active substance which is a protein, a peptide, a DNA, an RNA, an antisense nucleotide, or a decoy nucleotide.
12. The liposome according to claim 10 , wherein at least 50 μg of active substance per mg lipid is entrapped inside the liposome.
13. Nanocapsules comprising the lipids according to claim 1 and/or a liposomes containing them.
14. A composition which comprises at least one lipid according to claim 1 and a medically active substance which is a protein, a peptide, a carbohydrate, a DNA, an RNA, an antisense nucleotide, and/or a decoy nucleotide.
15. The composition according to claim 14 , wherein the active substance is a protein, a peptide, or a DNA.
16. A pharmaceutical composition comprising at least one lipid according to claim 1 and a pharmaceutically tolerable carrier.
17. A kit comprising at least one lipid according to claim 1 and information for providing a formulation comprising said lipid, optionally together with an algorithm of administering said formulation to a recipient.
18. An in vivo transfection system, characterized in that said system includes the liposomes according to claim 5 loaded with genetic material.
19. A method of loading the liposomes according to claim 5 with active substance, characterized in that a defined pH value for encapsulation and a second pH value for removal of unbound active substance is used.
20. The lipid according to claim 1 , wherein the acyl is from a fatty acid.