US2002173456A1PendingUtilityA1

Lipophilic peptides for macromolecule delivery

Assignee: BAYLOR COLLEGE MEDICINEPriority: Jan 8, 1996Filed: Mar 12, 2001Published: Nov 21, 2002

Est. expiryJan 8, 2016(expired)· nominal 20-yr term from priority

Inventors:Louis C. Smith James Soarrow Jochen Hauer Martha P. Mims

A61K 47/645

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References

Claims

Abstract

Peptide-macromolecule complexes for delivery of nucleic acid to a cell. The nucleic acid carrier includes a binding complex. The binding complex contains a binding moiety which noncovalently binds to the nucleic acid. The binding complex can also contain a binding moiety which is associated with a surface ligand, nuclear ligand or a lysis agent. These may be associated with the binding moiety by spacers. In addition, the carrier may include a nucleic acid with a combination of the above binding complexes or binding moieties.

Claims

exact text as granted — not AI-modified

We claim:

1 . A peptide-macromolecule complex for delivering a macromolecule into a cell, comprising:
a non-exchangeable lipophilic peptide comprising a delivery peptide associated with a lipid moiety, wherein said delivery peptide portion of said lipophilic peptide is complexed to said macromolecule.

2 . The complex of claim 1 , wherein said delivery peptide consists of a sequence of amino acids selected from the group consisting of:

STEELRVRLASHLRKLRKRLLRDADDLQKRLAVYQAGAREG,

KKQLKKQLKKQLKQWK,

KKSPKKSPKKSPKKSWK, and

KRRRRRRRRWR.

3 . The complex of claim 1 , wherein said delivery peptide consists of a sequence of amino acids selected from the group consisting of:

KLSKLEKKWSKLEK,

KLSKLEKKLSKLEKKWSKLEK,

KSLKKSLKKSLKKSWK, and

KSTPPKKKRKVEDPKDFPSELLSA.

4 . The complex of claim 1 , wherein said delivery peptide consists of a sequence of amino acids selected from the group consisting of:

KAKKKK-NK-(CH 2 ) 2 -SS-(CH 2 ) 2 COKKKKWK,

KIRRRGKNKVAARTCRQRRTDR,

KXKKXKKKXKKXKWK, (where X is A or S)

KIRRRGKNKAAARTCRERRRSK, and

KIRRRGKNKVAAQNCRKRKLDQ.

5 . The complex of claim 1 , wherein said delivery peptide consists of a sequence of amino acids selected from the group consisting of:

KIRRRGKNKVAAQNCRKRKLET,

KRRIRREKNKMAAAKCRNRRRELT,

GRPRAINKHEQEQISRLLEKGHPRQQLAIIFGIGVSTLYRY

FPASSIKKRMN, and

KSGPRPRGTRGKGRRIRR.

6 . The complex of claim 1 , wherein said delivery peptide consists of a sequence of amino acids selected from the group consisting of:

KDRSNLLERHTR,

KRPAATKKAGQAKKKL,

K(K)- n WK, where n is 4, 5, 6, 7, 8 and homologues to n is 40,
K(K) n XK, where n is 4, 5, 6, 7, 8, and homologues to n is 40 where X is any naturally occurring amino acid and analogues thereof, and
KSPLLKSMKGIKQQQHP-(SPNQQQHP) n GK, where n is 1-6.

7 . The complex of claim 1 , wherein said lipid moiety is a disteryl derivative selected from the group consisting of:
(1) N,N-distearyl-glycyl-; (2) ε-N,N-distearylglycyl-; and (3) N,N-distearylamidomethyl.

8 . The complex of claim 1 , wherein said lipid moiety is a dipalmytyl derivative selected from the group consisting of: N α , N ε ′-dipalmitoyl-, and N α , N ε -dipaimitoyl.

9 . The complex of claim 1 , wherein said complex is capable of binding with a cell surface receptor, lysing an endosome, and targeting the nucleus of said cell.

10 . The complex of claim 1 wherein said lipophilic peptide is associated with a surface ligand.

11 . The complex of claim 1 wherein said lipophilic peptide is associated with a nuclear ligand.

12 . The complex of claim 1 wherein said macromolecule is nucleic acid.

13 . The complex of claim 1 wherein said macromolecule is DNA.

14 . The complex of claim 1 wherein said macromolecule is RNA.

15 . The complex of claim 1 wherein said lipid moiety is linked to the N-terminus of said delivery peptide.

16 . The complex of claim 1 wherein said delivery peptide is non-covalently bound to said macromolecule.

17 . The complex of claim 1 wherein said macromolecule is complexed with more than one lipophilic peptides.

18 . The complex of claim 1 wherein said macromolecule is complexed with two, three, four, or five lipophilic peptides.

19 . The complex of claim 1 wherein said delivery peptide comprises a compound selected from the group consisting of:
(1) apoE-3 129-169 ;
(2) apoE-3 139-169 ; and
(3) apoE-3 129-169Q142 .

20 . A method of using a complex of anyone of claims 1 - 19 for delivering said macromolecule to a cell comprising the step of contacting said cell with said complex for a time sufficient to permit incorporation of said complex into said cell, wherein said macromolecule is delivered in a physiologically sufficient amount.

21 . The method of claim 20 further comprising contacting said complex with a biological detergent capable of solubilizing and/or enmeshing said macromolecule.

22 . The method of claim 21 wherein said detergent is selected from the group consisting of:
CHAPS, and O-octyl-glucoside.

23 . The method of claim 21 wherein said detergent is present at a final concentration below the critical micelle concentration of said detergent.

24 . The method of claim 21 wherein said detergent has a dilution ratio with said macromolecule so that the final concentration of said detergent is below its critical micelle concentration.

25 . A cell transformed with a complex of anyone of claims 1 - 19 .

26 . The complex of claim 1 wherein said delivery peptide is cationic.

27 . The complex of claim 1 wherein said delivery peptide is anionic.

28 . The complex of claim 1 wherein said delivery peptide is neutral.

29 . The complex of claim 1 wherein said delivery peptide is a glycolipid.

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