Therapeutic liposome composition and method

• US 6,958,241 B2
• Filed: 07/08/2003
• Issued: 10/25/2005
• Est. Priority Date: 10/11/1996
• Status: Expired due to Fees

• Current Assignee: Francis J. Martin, Samuel Zalipsky, Shi Kun Huang
• Original Assignee: Francis J. Martin, Samuel Zalipsky, Shi Kun Huang
• Inventors: Martin, Francis J., Zalipsky, Samuel, Huang, Shi Kun
• Primary Examiner(s): Ketter, James
• Assistant Examiner(s): KATCHEVES, KONSTANTINA T
• Application Number:
  US10/616,094
• Publication Number:
  US 20040009217A1
• Time in Patent Office: 840 Days
• Field of Search: 435/458, 435/375, 424/450
• US Class Current: 435/458
• 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 9/1273 Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances polymers grafted or coated on phosphatidyl liposomes A61K9/1271, on non-phosphatidyl liposomes A61K9/1272
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

A method of liposome-based therapy for a mammalian subject is disclosed. The method uses liposomes with outer surfaces that contain an affinity moiety effective to bind specifically to a biological surface at which the therapy is aimed, and a hydrophilic polymer coating effective to shield the affinity moiety from interaction with the target surface. The hydrophilic polymer coating is made up of polymer chains covalently linked to surface lipid components in the liposomes through releasable linkages. After a desired liposome biodistribution is achieved, a releasing agent is administered to cause cleaving of a substantial portion of the releasable linkages in the liposomes, to expose the affinity agent to the target surface.

Claims

1. A method of administering an affinity moiety to a mammalian subject, comprising

administering to the subject, liposomes with outer surfaces that contain (i) an affinity moiety effective to bind specifically to a target surface at which the therapy is aimed, and (ii) a hydrophilic polymer coating effective to shield the affinity moiety from interaction with the target surface, said hydrophilic polymer coating being made up of polymer chains which are covalently linked to surface lipid oomponents in the liposomes through releasable linkages, and

allowing the administered liposomes to achieve a desired biodistribution,

whereby said allowing is effective to cause release of a substantial portion of said linkages in the administered liposomes, thereby to expose the affinity moiety to the target surface.

2. The method of claim 1, wherein said releasable linkages are chemical linkages selected from the group consisting of disulfide, ester and peptide linkages.

3. The method of claim 2, wherein said releasable linkages are disulfide linkages.

4. The method of claim 1, wherein said hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropyl-methacrylamide, polymethacrylamide, polydimethyl-acrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, and polyaspartamide.

5. The method of claim 1, wherein the hydrophilic polymer chains are polyethylene glycol chains having molecular weights in the range 500 to 10,000 daltons.

6. The method of claim 1, for administering a therapeutic agent to target cells, wherein the affinity moiety is a ligand effective to bind specifically with a cell-surface receptor on the target cells, and the liposomes further include the therapeutic agent in entrapped form.

7. The method of claim 6, for treatment of a solid tumor, wherein the affinity moiety is effective to bind specifically to a tumor-specific antigen, the liposomes have an average size between 30-400 nm.

8. The method of claim 6, for treatment at a site of inflammation, wherein the affinity moiety is effective to bind specifically to infected cells, the liposomes have an average size between 30-400 nm.

9. The method of claim 1, wherein the affinity moiety is a polypeptide or polysaccharide effector capable of inhibiting binding of a first binding member, which is a pathogen or cell in the bloodstream, to a second binding member, which is a target cell or cell matrix.

10. The method of claim 9, wherein the affinity moiety is selected from the group consisting of:

(a) a CD4 glycoprotein;

(b) a polysaccharide which binds to endothelial leukocyte adhesion molecule (ELAM);

(c) polymyxin B or polymyxin B decapeptide; and

(d) a peptide.

11. The method of claim 1, wherein the liposomes further include such affinity moieties attached to distal ends of a portion of the hydrophilic polymer chains forming the hydrophilic polymer coating.

12. A liposome composition for use in treating a subject with an affinity moiety capable of inhibiting binding of a first binding member, which is a pathogen or cell in the bloodstream, to a second binding member, which is a target cell or cell matrix, comprising

liposomes having outer surfaces that contain (i) a hydrophilic polymer coating composed of polyethylene glycol chains that are covalently linked to surface lipid components in the liposomes through releasable linkages, and (ii) said affinity moiety bound to the outer surfaces of said liposomes, such that the affinity moiety is shielded by said hydrophilic polymer coating from interaction with such binding members and is exposed for interaction with such binding members when at least a portion of the hydrophilic polymer coating is released.

13. The composition of claim 12, wherein said releasable linkages are chemical linkages selected from the group consisting of disulfide, ester and peptide.

14. The composition of claim 13, wherein said releasable linkages are disulfide linkages.

15. The composition of claim 12, wherein affinity moiety is selected from the group consisting of:

(a) a CD4 glycoprotein;

(b) a polysaccharide which binds to endothelial leukocyte adhesion molecule (ELAM);

(c) polymyxin B or polymyxin B decapeptide; and

(d) a peptide.