Neutral-cationic lipid for nucleic acid and drug delivery

• US 6,974,589 B1
• Filed: 10/10/2000
• Issued: 12/13/2005
• Est. Priority Date: 10/08/1999
• Status: Expired due to Term

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Zalipsky, Samuel, Zhang, Wei-Ming, Huang, Shi Kun, Quinn, Yolanda P., Jin, Bei
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US09/685,940
• Time in Patent Office: 1,890 Days
• Field of Search: 424/450, 424/1.21, 424/9.321, 424/9.51, 424/417, 424/94.3, 436/829, 935/54, 428/402.2
• US Class Current: 424/450
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/543 Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 233/54 having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

A lipid represented by the formula:
wherein each of R¹ and R² is an alkyl or alkenyl chain having between about 8 to about 24 carbon atoms; n=0–20; L is selected from the group consisting of (i) —X—(C═O)—Y—, (ii) —X—(C═O)—, and (iii) —X—CH₂—, wherein X and Y are independently selected from oxygen, NH, and a direct bond; and Z is a weakly basic moiety that has a pK of less than about 7.4 and greater than about 4.0 is described.

Claims

1. A liposome composition comprising:

a lipid having the formula

 

wherein each of R¹ and R² is an alkyl or alkenyl chain having between about 8 to about 24 carbon atoms;

n=0–

20;

L is selected from the group consisting of (i) —

X—

(C═

O)—

Y —

, (ii) —

X—

(C═

O)—

, wherein X and Y are independently selected from oxygen, NH, and a direct bond, and (iii) —

O—

CH₂—

; and

Z is a weakly basic moiety that has a pK of less than about 7.4 and greater than about 4.0.

2. The composition of claim 1, wherein X is NH and Y is oxygen.

3. The composition of claim 1, wherein L is a carbamate linkage, an ester linkage or a carbonate linkage.

4. The composition of claim 1, wherein L is NH—

(C═

O)—

O—

.

5. The composition of claim 1, wherein Z is an imidazole.

6. The composition of claim 1, comprising between about 1 to about 80 mole percent of the lipid.

7. The composition of claim 1, wherein Z is a moiety having a pK value between about 5.0 to about 6.5.

8. The composition of claim 1, wherein each of R¹ and R² is an unbranched alkyl or alkenyl chain having between about 8 to about 24 carbon atoms.

9. The composition of claim 8, wherein each of R¹ and R² is C₁₇H₃₅.

10. The composition of claim 1, wherein n is between 1–

10.

11. The composition of claim 1, further comprising a therapeutic compound entrapped in the liposomes.

12. The composition of claim 11, wherein the therapeutic agent is a nucleic acid.

13. The composition of claim 12, wherein the nucleic acid is selected from the group consisting of DNA, RNA, and their complements.

14. The composition of claim 1, further comprising a ligand for targeting the liposomes to a target site.

15. The composition of claim 14, wherein the ligand has binding affinity for endothelial tumor cells and is internalized by the cells.

16. The composition of claim 15, wherein the ligand is selected from the group consisting of E-selectin, Her-2 and FGF.

17. The composition of claim 1, wherein said liposomes further comprise between about 5 to about 20 mmole percent of a vesicle-forming lipid derivatized with a hydrophilic polymer chain.

18. The composition of claim 17, wherein the hydrophilic polymer chain is polyethyleneglycol (PEG).

19. A method for delivering a therapeutic agent to a subject, comprising:

preparing liposomes comprising a lipid having the formula

 

wherein each of R¹ and R² is an alkyl or alkenyl chain having between about 8 to about 24 carbon atoms;

n=0–

20;

L is selected from the group consisting of (i) —

X—

(C═

O)—

Y —

, (ii) —

X—

(C═

O)—

, wherein X and Y are independently selected from oxygen, NH, and a direct bond, and (iii) —

O—

CH₂—

;

Z is a weakly basic moiety that has a pK of less than about 7.4 and greater than about 4.0; and

administering the liposomes to the subject.

20. The method of claim 19, wherein the preparing comprises entrapping a nucleic acid in the liposomes.

21. The method of claim 20, wherein the nucleic acid is DNA, RNA, or their complements.

22. The method of claim 19, wherein the preparing further comprises entrapping a protein or a protein fragment in the liposomes.