Lipid

• US 20100297023A1
• Filed: 12/21/2007
• Published: 11/25/2010
• Est. Priority Date: 12/22/2006
• Status: Abandoned Application

• Current Assignee: Imuthes Limited University of The Witwatersrand
• Original Assignee: Imuthes Limited University of The Witwatersrand
• Inventors: Jorgensen, Michael, Thanou, Maya, Kamaly, Nazila, Arbuthnot, Patrick, Keller, Michael, Aissaoui, Abderrahim, Miller, Andrew David
• Application Number:
  US12/520,261
• Publication Number:
  US 20100297023A1
• Time in Patent Office: Days
• US Class Current: 424/9.3
• CPC Class Codes: A01K 2267/0337 Animal models for infectious diseases
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/543 Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• CPC Class Codes: A61K 47/6907 the form being a microemulsion, nanoemulsion or micelle
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 48/0025 wherein the non-active part clearly interacts with the delivered nucleic acid
• 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: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/88 using microencapsulation, e.g. using amphiphile liposome vesicle
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific
• CPC Class Codes: C12N 2730/10111 Orthohepadnavirus, e.g. hepatitis B virus
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

The present invention provides a lipid of the formula (I) R₃R₄N—[Y]_q—(C_pH_2p)—X-Linker-NR₁R₂ (I) wherein R₃ and R₄ are independently selected from H and hydrocarbyl groups; q is an integer selected from 1 to 10; Y represents a group (C_nH_2n)NR₅, wherein (i) when q is 1, n is 2, or (ii) when q is greater than 1, each Y may be the same or different and each n is an integer independently selected from 1 to 10, with the proviso that for at least one unit Y, n is 2, and (iii) each R₅ is independently selected from H and hydrocarbyl groups; p is an integer selected from 1 to 10; X is an optional group selected from —NR₇—, —C(═O)—NR₈—, —NR₉—C(═O)—, —C(═O)—, —O—, and NR₁₀—C(=0)0-, wherein each R₇, R₈, R₉ and R₁₀ is independently selected from H and hydrocarbyl groups, Linker is an optional group selected from amino acid residues, peptide residues and groups of the formula —(OCH₂CH₂)_1-10, —NR₆-(CvH_2v)—C(═O)—, wherein R₆ is H or a hydrocarbyl group and v is an integer selected from 1 to 11, and —C(=0)-(CH₂)_0-10—CH₂—C(=0)-; R₁ is selected from acyclic groups having from 4 to 30 carbon atoms; and R₂ is selected from H and acyclic groups having from 4 to 30 carbon atoms. Said lipids can be used in a delivery vehicle (e.g. micelle or liposome) for the delivery of one or more (therapeutic or diagnostic) agents.

Claims

1. A lipid of the formula (I)

R₃R₄N—

[Y]_q—

(C_pH_2p)—

X-Linker-NR₁R₂ 

 

(I)

wherein

R₃ and R₄ are independently selected from H and hydrocarbyl groups;

q is an integer selected from 1 to 10;

Y represents a group (C_nH_2n)NR₅, wherein (i) when q is 1, n is 2, or (ii) when q is greater than 1, each Y may be the same or different and each n is an integer independently selected from 1 to 10, with the proviso that for at least one unit Y, n is 2, and (iii) each R₅ is independently selected from H and hydrocarbyl groups;

p is an integer selected from 1 to 10;

X is an optional group selected from —

NR₇—

, —

C(═

O)NR₈—

, —

NR₉C(═

O)—

, —

C(═

O)—

, —

O—

, and —

NR₁₀C(═

O)O—

, wherein each R₇, R₈, R₉ and Ri₀ is independently selected from H and hydrocarbyl groups,

Linker is an optional group selected from amino acid residues, peptide residues and groups of the formulae —

(OCH₂CH₂)_1-10, —

NR₆(C_vH_2v)—

C(═

O), wherein R₆ is H or a hydrocarbyl group and v is an integer selected from 1 to 11, and —

C(═

O)(CH₂)_0-10—

CH₂—

C(═

O)—

;

R₁ is selected from acyclic groups having from 4 to 30 carbon atoms; and

R₂ is selected from H and acyclic groups having from 4 to 30 carbon atoms.

2. A lipid according to claim 1 wherein when q is greater than 1, each n is an integer independently selected from 2 to 4.

3. A lipid according to claim 1 wherein q is 2.

4. A lipid according to claim 1 wherein p is 2 or 3.

5. A lipid according to claim 1 wherein each R₃, R₄ and R₅ is independently selected from H and C_1-3 alkyl groups.

6. A lipid according to claim 1 wherein each R₃, R₄ and R₅ is independently selected from H and methyl.

7. A lipid according to claim 1 wherein each R₃, R₄ and R₅ are the same.

8. A lipid according to claim 1 selected from lipids of the formulae

H₂N—

(CH₂)₂—

HN—

(CH₂)₂—

X-Linker-NR₁R₂

H₂N—

(CH₂)₃—

HN—

(CH₂)₂—

X-Linker-NR₁R₂

H₂N—

(CH₂)₄—

HN—

(CH₂)₂—

X-Linker-NR₁R₂

H₂N—

(CH₂)₂—

HN—

(CH₂)₃—

X-Linker-NR₁R₂

H₂N—

(CH₂)₂—

HN—

(CH₂)₃—

HN—

(CH₂)₂—

X-Linker-NR₁R₂

H₂N—

(CH₂)₂—

HN—

(CH₂)₃—

HN—

(CH₂)₃—

X-Linker-NR₁R₂

H₂N—

(CH₂)₂—

HN—

(CH₂)₄—

HN—

(CH₂)₂—

X-Linker-NR₁R₂

H₂N—

(CH₂)₃—

HN—

(CH₂)₂—

HN—

(CH₂)₂—

X-Linker-NR₁R₂

H₂N—

(CH₂)₃—

HN—

(CH₂)₄—

HN—

(CH₂)₂—

X-Linker-NR₁R₂

H₂N—

(CH₂)₂—

HN—

(CH₂)₃—

HN—

(CH₂)₄—

HN—

(CH₂)₃—

X-Linker-NR₁R₂

Me₂N—

(CH₂)₂—

NMe—

(CH₂)₂—

X-Linker-NR₁R₂

Me₂N—

(CH₂)₃—

NMe—

(CH₂)₂—

X-Linker-NR₁R₂

Me₂N—

(CH₂)₄—

NMe—

(CH₂)₂—

X-Linker-NR₁R₂

Me₂N—

(CH₂)₂—

NMe—

(CH₂)₃—

X-Linker-NR₁R₂

Me₂N—

(CH₂)₂—

NMe—

(CH₂)₃—

NMe—

(CH₂)₂—

X-Linker-NR₁R₂

Me₂N—

(CH₂)₂—

NMe—

(CH₂)₃—

NMe—

(CH₂)₃—

X-Linker-NR₁R₂

Me₂N—

(CH₂)₂—

NMe—

(CH₂)₄—

NMe—

(CH₂)₂—

X-Linker-NR₁R₂

Me₂N—

(CH₂)₃—

NMe—

(CH₂)₂—

NMe—

(CH₂)₂—

X-Linker-NR₁R₂

Me₂N—

(CH₂)₃—

NMe—

(CH₂)₄—

NMe—

(CH₂)₂—

X-Linker-NR₁R₂

Me₂N—

(CH₂)₂—

NMe—

(CH₂)₃—

NMe—

(CH₂)₄—

NMe—

(CH₂)₃—

X-Linker-NR₁R₂

9. A lipid according to claim 1 wherein R₁ and R₂ are each independently selected from alkyl, alkenyl and alkynyl groups having from 4 to 30 carbon atoms.

10. A lipid according to claim 1 wherein R₁ and R₂ are each independently selected from alkyl groups having 18 carbon atoms.

11. A lipid according to claim 1 wherein X is present.

12. A lipid according to claim 11 wherein X is —

C(═

O)—

.

13. A lipid according to claim 1 wherein Linker is an amino acid residue, peptide residue or group of the formula —

NR₆—

(C_vH_2v)—

C(═

O)—

.

14. A lipid according to claim 13 wherein Linker is an amino acid residue.

15. A lipid according to claim 1 of the formula

H₂N—

(CH₂)₂—

HN—

(CH₂)₃—

HN—

(CH₂)₂—

C(═

O)NH—

CH₂—

C(═

O)—

N[(CH₂)₁₇CH₃]₂ or.

Me₂N—

(CH₂)₂—

NMe—

(CH₂)₃—

NMe—

(CH₂)₂—

C(═

O)NH—

CH₂—

C(═

O)—

N[(CH₂)₁₇CH₃]₂.

17. A micelle formed from or comprising a lipid according to claim 1.

18. A liposome formed from or comprising a lipid according to claim 1.

19. A delivery vehicle comprising (i) a lipid according to claim 1 and (ii) one or more agents.

20. A delivery vehicle according to claim 19 comprising an ABCD nanoparticle, wherein A is one or more agents, B comprises the lipid, C is an optional component comprising polymers having stealth/biocompatibility properties and D is an optional component comprising a targeting moiety.

21. A delivery vehicle according to claim 19, wherein the one or more agents comprises a therapeutic or diagnostic agent.

22. A delivery vehicle according to claim 21, wherein the therapeutic agent comprises siRNA.

23. A method of treating a subject having a disorder, a condition or a disease or diagnosing the subject as suffering from the disorder, the condition or the disease which comprises using the lipid according to claim 1.

24. The method of claim 23 wherein the method comprises delivering the lipid to the subject or using the lipid for imaging.

25. The method of claim 23, wherein the disorder is a genetic disorder or the disease, disorder or condition is associated with liver disease and/or liver damage, and cancer.

28. A method for delivering one or more agents to one or more cells comprising administering a composition comprising a) a lipid according to claim 1 and b) one or more agents.

33. A composition comprising a lipid according to claim 1, further comprising additional lipids, sterols, fatty acids, dicetyl phosphate, cholesterol hemisuccinate, preservatives PEGylated derivatives of phosphatidylethanolamine, conjugates of sugars and hydrophobic components, diagnostic markers, contrasting media, imaging aids and/or amphiphilic compounds.

34. The composition according to claim 33, wherein the additional lipid is a neutral lipid, sterol lipid, fluorescent lipid, magnetic resonance imaging lipid, nuclear magnetic resonance imaging lipid, electron microscopy and image processing lipid, electron spin resonance lipid or radioimaging lipid.

16. (canceled)

26-27. -27. (canceled)

29-32. -32. (canceled)

35-36. -36. (canceled)