Lipid-peptide-polymer conjugates for long blood circulation and tumor specific drug delivery systems
The present invention relates to conjugates of a lipid, substrate peptide of an enzyme secreted from the cells of mammals, including humans, and a water-soluble polymer that can be used as colloidal carriers and the like of tissue-specific drug delivery systems, methods of producing these conjugates, peptide-water-soluble polymer conjugates optionally having protective groups that are useful as the intermediates of these conjugates, colloidal carriers made from these conjugates, and tissue-specific drug delivery systems that use these colloidal carriers.
1. A conjugate comprising a lipid, a peptide, and a water-soluble polymer,
wherein the lipid is conjugated to the amino terminus of the peptide by a peptide bond and the water-soluble polymer is conjugated to the carboxy terminus of the peptide by a peptide bond, wherein:
the lipid is selected from the group consisting of phospholipids, fatty acids, glycolipids, ceramides, glycerides, and cholesterols;
the peptide consists of a sequence selected from the group consisting of Gly-Pro-Gln-Gly-lle-Ala-Gly-Trp-Gly (SEQ ID NO:22), Gly-Pro-Leu-Gly-lle-Ala-Gly-Gln-Gly (SEQ ID NO:17), Gly-Pro-Gln-Gly-lle-Trp-Gly-Gln-Gly (SEQ ID NO:18), and Gly-Hyp-Ala-Ser-Chg-Gln-Ser-Leu-Gly (SEQ ID NO:19), said peptide being a substrate for a secreted mammalian enzyme; and
the water-soluble polymer is selected from the group consisting of polyethylene glycols, polyamino acids, polyhydroxyethylamino acids, and polyvinyl pyrrolidones.
2. The conjugate of claim 1 , wherein the secreted mammalian enzyme is matrix metalloprotease-2 (MMP- 2 ).
3. The conjugate of claim 1 , wherein the secreted mammalian enzyme is prostate-specific antigen.
4. The conjugate according to claim 1 , wherein the peptide is Gly-Pro-Gln-Gly-Ile-Ala-Gly-Trp-Gly (SEQ ID NO:22).
5. The conjugate according to claim 1 , wherein the peptide is Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gin-Gly (SEQ ID:17).
6. The conjugate according to claim 1 , wherein B is Gly-Pro-Gln-Gly-Ile-Trp-Gly-Gln-Gly (SEQ ID:18).
7. The conjugate according to claim 1 , wherein the peptide is Gly-Hyp-Ala-Ser-Chg-Gln-Ser-Leu-Gly (SEQ ID:19).
8. The conjugate according to claim 1 , wherein the lipid is a phospholipid.
9. The conjugate according to claim 1 , wherein the water-saluble polymer is a polyethylene glycol.
10. The conjugate of claim 1 , wherein the lipid is substituted with a carboxylic anhydride.
11. The conjugate of claim 1 , wherein the lipid has an activated carboxyl group.
12. The conjugate of claim 1 , wherein one end of the water-soluble polymer is substituted with one or more methoxy groups.
13. The conjugate of claim 1 , wherein one end of the water-soluble polymer is substituted with an amino group.