Targeted drug delivery with a hyaluronan ligand

• US 6,593,308 B2
• Filed: 12/03/1999
• Issued: 07/15/2003
• Est. Priority Date: 12/03/1999
• Status: Expired due to Term

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Szoka, Francis C. Jr.
• Primary Examiner(s): Crouch, Deborah
• Assistant Examiner(s): WOITACH, JOSEPH T
• Application Number:
  US09/454,811
• Publication Number:
  US 20020131995A1
• Time in Patent Office: 1,320 Days
• Field of Search: 514/1, 514/2, 514/44, 514/54, 514/62, 424/450, 435/458
• US Class Current: 514/54
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911

Abstract

The invention is a drug delivery system of a delivery vehicle having a low molecular weight hyaluronan ligand with an affinity for CD44 receptors. Preferably, the delivery vehicle is a liposome but other suitable delivery vehicles include microspheres, micelles, emulsions, lipid discs, polymers, viral particles and viruses. The systems of the invention may further comprise a drug, which can be any anticancer agent or other therapeutic or diagnostic agent. The invention also comprises methods of delivering a drug to a cell that expresses CD44 by contacting the cell with the drug delivery system. Further methods include treating a patient with cancer and targeting drug delivery to cells that express CD44 by attaching a glycosaminoglycan ligand.

Claims

1. A drug delivery system comprising an encapsulating delivery vehicle and a plurality of hyaluronan ligands, wherein each hyaluronan ligand has a molecular weight of less than 10,000 and each hyaluronan ligand is attached to the delivery vehicle by way of a single link.

2. The drug delivery system of claim 1, wherein the hyaluronan is an oligosaceharide of one to eight disaccharide units.

3. The drug delivery system of claim 1, wherein the delivery vehicle comprises a liposome.

4. The drug delivery system of claim 3, further comprising the hyaluronan ligand attached to a linking agent, and a chelating agent attached to the liposome, wherein the linking agent and the chelating agent chelate a metal ion.

5. The drug delivery system of claim 4, wherein the linking agent comprises a histidine-containing peptide.

6. The drug delivery system of claim 5, wherein the histidine-containing peptide comprises two to six histidine amino acid residues.

7. The drug delivery system of claim 6, wherein the metal ion is selected from the group consisting of Ni²⁺, Cu²⁺, and Zn²⁺.

8. The drug delivery system of claim 7, wherein the metal ion is chelated to a molecule comprising nitrilotriacetic acid.

13. The drug delivery system of claim 1, wherein the hyaluronan has a molecular weight of less than about 5,000.

14. The drug delivery system of claim 13, wherein the hyaluronan has a molecular weight of less than about 1,000 and greater than 382.

15. The drug delivery system of claim 1, wherein the delivery vehicle is selected from the group consisting of microspheres, micelles, emulsions, lipid discs, polymers, viral particles and viruses.

16. The drug delivery system of claim 1, wherein the system is frozen.

17. The drug delivery system of claim 1, wherein the system is lyophilized to a dry powder.

18. The drug delivery system of claim 1, wherein the system is in solution.

19. The drug delivery system of claim 5, wherein the lipid comprises phosphatidylethanolamine.

20. The drug delivery system of claim 7, wherein the lipid is selected from the group consisting of palmitoyloleoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, and diphytanoylphosphatidylethanolamine.

9. The drug delivery system of ciaim 3, wherein the liposome comprises the hyaluronan attached to a lipid.

10. The drug delivery system of claim 9, wherein the lipid comprises N-methylpalmitoyloleoylphosphatidylethanolamine or phosphatidylserine.

11. The drug delivery system of claim 9, wherein the lipid comprises amino-polyethylene glycol phosphatidylethanolamine.

12. The drug delivery system of claim 9, wherein the mole ratio of the lipid to hyaluronan ligand is from about 0.02% to about 50%.