Polyethylene glycol modified ceramide lipids and liposome uses thereof

• US 5,820,873 A
• Filed: 06/07/1995
• Issued: 10/13/1998
• Est. Priority Date: 09/30/1994
• Status: Expired due to Term

• Current Assignee: University of British Columbia
• Original Assignee: University of British Columbia
• Inventors: Webb, Murray S., Madden, Thomas D., Choi, Lewis S. L.
• Primary Examiner(s): Achutamurthy, Ponnathapura
• Assistant Examiner(s): Ponnaluri, Padmashri
• Application Number:
  US08/486,214
• Time in Patent Office: 1,224 Days
• Field of Search: 424/283.1, 424/450, 424/184.1, 424/885, 424/1, 424/417, 424/812, 424/1.21, 514/885, 436/529, 436/535
• US Class Current: 424/283.1
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• 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: C08G 65/329 with organic compounds
• CPC Class Codes: Y10S 424/812 Liposome comprising an antibody, antibody fragment, antigen, or other specific or nonspecific immunoeffector

Abstract

The present invention provides a novel class of polyethylene glycol modified ceramide lipids. The lipids can be used to form liposomes optionally containing various biological agents or drugs, such as anti-cancer agents. In addition, methods of use for the liposomes are provided.

Claims

1. A lipid compound of the formula ##STR8## wherein:

R¹, R², and R³ are independently hydrogen, C₁ -C₆ alkyl, acyl, or aryl;

R⁴ is hydrogen, C₁ -C₃₀ alkyl, C₂ -C₃₀ alkenyl, C₂ -C₃₀ alkynyl, or aryl;

R⁵ is hydrogen, alkyl, acyl, aryl, or PEG;

X¹ is --O--, --S--, or --NR⁶ --, where R⁶ is hydrogen, C₁ -C₆ alkyl, acyl or aryl;

or when R⁵ is PEG and b is 1, X¹ is also --Y¹ -alk-Y² ;

Y is --NR⁷ --, where R⁷ is hydrogen, C₁ -C₆ alkyl, acyl or aryl, or Y is --O--, --S-- or --Y¹ -alk-Y² --, wherein Y¹ and Y² are independently amino, amido, carboxyl, carbamate, carbonyl, carbonate, urea, or phosphoro; and

alk is C₁ -C₆ alkylene;

PEG is a polyethylene glycol with an average molecular weight from about 550 to about 8,500 daltons optionally substituted by C₁ -C₃ alkyl, alkoxy, acyl or aryl;

wherein a is 0 or 1; and

b is 1 unless R⁵ is PEG wherein b is 0 or 1.

2. The lipid of claim 1, wherein R¹, R², R³, and R⁵ are hydrogen;

R⁴ is alkyl;

X¹ is O;

Y is succinate; and

PEG has an average molecular weight of about 2,000 to about 5,000 daltons and is substituted with methyl at the terminal hydroxyl position.

3. The lipid of claim 1, wherein R¹, R², R³, and R⁵ are hydrogen, R⁴ is alkyl;

X¹ is O;

Y is --NH--; and

PEG has an average molecular weight of about 2,000 to about 5,000 daltons and is substituted with methyl at the terminal hydroxyl position.

4. A liposome comprising the lipid of claim 1.

5. The liposome of claim 4 further comprises one or more bioactive agents.

6. A method of delivering a bioactive agent to cells comprising encapsulating the agent in a liposome of claim 4 to form a liposome-bioactive complex and contacting the cells with the complex.

7. The method of claim 6 wherein the bioactive agent is selected from the group consisting of antitumor agents, antibiotics, immunomodulators, anti-inflammatory drugs and drugs acting on the central nervous system.

8. The method of claim 6 wherein the bioactive agent is a protein or a peptide.

9. A method of treating a disease in a patient comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition containing one or more bioactive agents encapsulated in a liposome of claim 4.

10. A method for delivering a vaccine to a patient comprising encapsulating a bioactive agent for a vaccine in a liposome of claim 4 to form a liposome-coated vaccine and administering the liposome-coated vaccine to the patient.

11. A method of immunizing a patient comprising encapsulating an antigen in a liposome of claim 4 to form a liposome-encapsulated antigen and administering the liposome-encapsulated antigen to the patient.

12. A pharmaceutical formulation comprising the liposome of claim 5 and a physiologically-acceptable adjuvant thereof.

13. The formulation of claim 1, wherein the bioactive agent is vincristine.

14. A kit for labeling liposome of claim 5, comprising a container with at least two compartments wherein the first compartment comprises materials for preparing a label and the second compartment comprises the liposome of claim 5.

15. A lipid complex comprising the lipid of claim 1.

16. The liposome of claim 5 comprising a gene construct for therapeutic use.

17. The liposome of claim 5 comprising an oligonucleotide for therapeutic use.

18. The lipid of claim 1, wherein R¹, R², R³ and R⁵ are hydrogen;

R⁴ is C₇ -C₂₃ alkyl;

X¹ is O;

Y is succinate; and

PEG has an average molecular weight of about 2,000 Daltons, and is substituted with monomethoxy.

19. The lipid of claim 18, wherein R⁴ is C₁₃ -C₁₉ alkyl.

20. The lipid of claim 19, wherein R⁴ is C₁₉ alkyl.

21. The lipid of claim 19, wherein R⁴ is C₁₃ alkyl.

22. A liposome comprising the lipid of claim 18.

23. The liposome of claim 22 further comprises one or more bioactive agents.

30. A pharmaceutical formulation comprising the liposome of claim 22 and a physiologically-acceptable adjuvant therefor.

24. A liposome comprising a lipid compound of the formula ##STR9## wherein:

R¹, R², R³ and R⁵ are hydrogen;

R⁴ is C₇ -C₂₃ alkyl;

X¹ is O;

Y is succinate; and

PEG has an average molecular weight of about 2,000 Daltons, and is substituted with monomethoxy;

said liposome further comprising DOPE, DODAC and one or more bioactive agents.

25. The liposome of claim 24, wherein mole percent ratio of the lipid is about 0.01 to about 60.

26. The liposome of claim 25, wherein R⁴ is C₁₃ -C₁₉ alkyl.

27. A method of delivering a bioactive agent to cells comprising encapsulating the agent in a liposome to form a liposome-bioactive complex, said liposome comprising a lipid compound of the formula ##STR10## wherein:

R¹, R², R³ and R⁵ are hydrogen;

R⁴ is C₇ -C₂₃ alkyl;

X¹ is O;

Y is succinate; and

PEG has an average molecular weight of about 2,000 Daltons, and is substituted with monomethoxy; and

contacting the cells with the liposome-bioactive complex.

28. The method of claim 27, wherein R⁴ is C₁₃ -C₁₉ alkyl.

29. The method of claim 28, wherein the liposome additionally comprises DOPE and DODAC.