Covalent lipid-drug conjugates for drug targeting

• US 5,149,794 A
• Filed: 11/01/1990
• Issued: 09/22/1992
• Est. Priority Date: 11/01/1990
• Status: Expired due to Term

• Current Assignee: Oregon State University (Oregon University System)
• Original Assignee: State of Oregon
• Inventors: Stowell, Michael H. B., Parks, David W., Witte, John F., McClard, Ronald W., Yatvin, Milton B.
• Primary Examiner(s): Rollins, John W.
• Application Number:
  US07/607,982
• Time in Patent Office: 691 Days
• Field of Search: 424/450, 514/78, 514/946, 514/943, 514/557, 514/51, 260/389, 260/404, 260/313, 536/29
• US Class Current: 536/26.8
• CPC Class Codes: A61K 47/543 Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• CPC Class Codes: A61K 47/544 Phospholipids
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

This invention relates to a novel method of drug targeting which comprises covalently binding a drug to a lipid carrier. This composition has the unique ability to both enhance the rate at which an antineoplastic or antiviral drug crosses the plasma membrane, and to direct the drug within the cell to specific organelles. The versatility of these conjugates may be further enhanced by including a spacer group between the drug and the lipid which may act to modulate drug release at the target site.

Claims

1. A composition of matter comprising an antiviral or antineoplastic drug, a polar lipid carrier, two linker functional groups and a spacer, wherein the spacer has a first end and a second end and wherein the polar lipid is attached to the first end of the spacer through a first linker functional group and the antiviral or antineoplastic drug is attached to the second end of the spacer through a second linker functional group.

2. A composition of matter according to claim 1 wherein the spacer allows the drug to act without being released at an intracellular site and wherein the first linker functional group attached to the first end of the spacer is strong and the second linker functional group attached to the second end of the spacer is weak.

3. A composition of matter according to claim 1 wherein the spacer allows the drug to facilitate hydrolytic release of the drug at an intracellular site and wherein the first linker functional group attached to the first end of the spacer is strong and the second linker functional group attached to the second end of the spacer is weak.

4. A composition of matter according to claim 1 wherein the spacer allows the drug to facilitate enzymatic release of the drug at an intracellular site and wherein the first linker functional group attached to the first end of the spacer is strong and the second linker functional group attached to the second end of the spacer is weak.

5. A composition of matter according to claim 1 wherein the polar lipid is sphingosine, ceremide, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl ethanolamine or phosphatidic acid.

6. A composition of matter according to claim 1 wherein the spacer is a peptide of formula_n, wherein n is an integer between 2 and 25, and the peptide comprises a polymer of a particular amino acid.

7. A composition of matter comprising an antiviral or antineoplastic drug having a first functional linker group, and a polar lipid carrier having a second functional linker group, wherein the antiviral or antineoplastic drug is covalently linked to the polar lipid carrier by a chemical bond between the first and second functional linker groups.

8. A composition of matter according to claim 7 wherein the first functional linker group is a hydroxyl group, a primary or secondary amino group, a phosphate group or substituted derivatives thereof or a carboxylic acid group.

9. A composition of matter according to claim 7 wherein the second functional linker group is a hydroxyl group, a primary or secondary amino group, a phosphate group or substituted derivatives thereof or a carboxylic acid group.

10. A composition of matter according to claim 7 wherein the polar lipid is sphingosine, ceremide, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl ethanolamine or phosphatidic acid.