초록

Methods of making conjugates comprising an anti-cancer agent and hyaluronic acid, together with mixtures of reaction products comprising such conjugates and methods of using such conjugates in therapeutic and research applications are disclosed.

대표청구항 ▼

We claim: 1. A method of making an anti-cancer agent-hyaluronic acid conjugate comprising coupling an anti-cancer agent with a hyaluronic acid at a pH between about 7.5 to 9.0. 2. The method of claim 1 wherein the anti-cancer agent comprises at least one N-hydroxysuccinimide ester of a taxane.

We claim: 1. A method of making an anti-cancer agent-hyaluronic acid conjugate comprising coupling an anti-cancer agent with a hyaluronic acid at a pH between about 7.5 to 9.0. 2. The method of claim 1 wherein the anti-cancer agent comprises at least one N-hydroxysuccinimide ester of a taxane. 3. The method of claim 1 wherein the anti-cancer agent comprises at least one taxane. 4. The method of claim 1 wherein the anti-cancer agent comprises at least one taxane selected from the group consisting of paclitaxel, docetaxel, and a derivative thereof. 5. The method of claim 1 wherein the hyaluronic acid comprises adipic dihydrazido functionalized hyaluronic acid. 6. The method of claim 1 wherein the pH is maintained at a pH between about 7.5 to 9.0 through the use of a buffer system. 7. An anti-cancer agent-hyaluronic acid conjugate comprising an anti-cancer agent and a hyaluronic acid comprising more than one disaccharide unit, wherein the anti-cancer agent is conjugated to less than 10 percent of the disaccharide units of the hyaluronic acid. 8. The conjugate of claim 7 wherein the conjugate was made by combining an N-hydroxysuccinimide ester of a taxane and a hyaluronic acid at a pH between about 7.5 to 9.0 9. The conjugate of claim 7 wherein the anti-cancer agent comprises a N-hydroxysuccinimide ester of a taxane. 10. The conjugate of claim 7 wherein the anti-cancer agent comprises at least one taxane selected from the group consisting of paclitaxel, docetaxel, and a derivative thereof. 11. The conjugate of claim 7 wherein the hyaluronic acid comprises adipic dihydrazido functionalized hyaluronic acid. 12. An anti-tumor hyaluronic acid-based prodrug formulation comprising a single intraperitoneal administration of a sub-maximum tolerated dose of an anti-cancer agent-hyaluronic acid conjugate comprising an anti-cancer agent and a hyaluronic acid comprising more than one disaccharide unit, wherein the anti-cancer agent is conjugated to less than 10 percent of the disaccharide units of the hyaluronic acid. 13. A method of determining CD44 receptor selectivity of a prodrug comprising administering to a subject an anti-cancer agent-hyaluronic prodrug in combination with free hyaluronic acid. 14. A method of reducing or eliminating tumor growth rate in a subject in need thereof comprising administering a therapeutically effective amount of an anti-cancer agent-hyaluronic acid conjugate to the subject, wherein the conjugate comprises an anti-cancer agent and a hyaluronic acid comprising more than one disaccharide unit, and wherein the anti-cancer agent is conjugated to less than 10 percent of the disaccharide units of the hyaluronic acid. 15. A mixture comprising at least 10 percent of an anti-cancer agent-hyaluronic acid conjugate wherein said mixture was made by combining an N-hydroxysuccinimide ester of a taxane and a hyaluronic acid at a pH between about 7.5 to 9.0. 16. The mixture of claim 15 wherein the N-hydroxysuccinimide ester of a taxane comprises a paclitaxel-N-hydroxysuccinimide ester. 17. The mixture of claim 15 wherein the hyaluronic acid comprises adipic dihydrazido functionalized hyaluronic acid. 18. The method of claim 15 wherein the pH is maintained at a pH between about 7.5 to 9.0 through the use of a buffer system.