Taxane derivatives for targeted therapy of cancer

• US 6,191,290 B1
• Filed: 02/23/2000
• Issued: 02/20/2001
• Est. Priority Date: 02/24/1999
• Status: Expired due to Term

• Current Assignee: UAB Research Foundation (University of Alabama System)
• Original Assignee: UAB Research Foundation (University of Alabama System)
• Inventors: Safavy, Ahmad
• Primary Examiner(s): Trinh, Ba K.
• Application Number:
  US09/510,896
• Time in Patent Office: 363 Days
• Field of Search: 514/449, 549/510, 549/511
• US Class Current: 549/510
• CPC Class Codes: A61K 47/6425 the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention describes for the first time the design and synthesis of a soluble tumor-directed paclitaxel prodrug which may establish a new mode of utilization of the taxane class of anticancer agents in cancer therapy.

Claims

1. A pharmaceutical compound, wherein said compound comprising a taxane moiety conjugated to a receptor ligand peptide.

2. The pharmaceutical compound of claim 1, wherein said taxane moiety is a taxane derivative.

3. The pharmaceutical compound of claim 1, wherein said taxane is selected from the group consisting of paclitaxel (taxol) and taxotere (docetaxel).

4. The pharmaceutical compound of claim 1, wherein said taxane is paclitaxel or docetaxel, conjugated at a position selected from the group consisting of 2′

-, 1-, 7- and 10-.

5. The pharmaceutical compound of claim 1, wherein said receptor ligand peptide is selected from the group consisting of a bombesin/gastrin-releasing peptide (BBN/GRP) receptor-recognizing peptide (BBN[7-13]), a somatostatin receptor recognizing peptide, an epidermal growth factor receptor recognizing peptide, a monoclonal antibody or a receptor recognizing carbohydrate.

6. The pharmaceutical compound of claim 1, wherein said compound is water soluble and tumor directed.

7. The pharmaceutical compound of claim 6, wherein said compound is readily soluble in water at the concentration of up to about 250 mg/mL.

8. The pharmaceutical compound of claim 6, wherein said tumor is selected from the group consisting of breast tumor, ovarian tumor, skin tumor, lung tumor, head tumor and neck tumor.

9. A method of synthesizing the pharmaceutical compound of claim 1, comprising the steps of:

conjugating covalently said receptor ligand peptide to a solubilizing linker; and

ligating the peptide-conjugated linkers to said taxane moiety.

10. The method of claim 9, wherein said solubilizing linker is ligated to said taxane moiety at the site selected from the group consisting of 2′

-hydroxyl group, 2-hydroxyl group, 7-hydroxyl group and 10-hydroxyl group.

11. The method of claim 9, wherein the synthesized pharmaceutical compound has improved cytotoxicities in a concentration-dependent manner by a factor of 1.5-3 compared to corresponding unconjugated taxane moiety at an equimolar concentration.

12. A method of treating an individual having a cancer, comprising the step of:

administering the pharmaceutical compound of claim 1 to said individual.

13. The method of claim 12, wherein said cancer is selected from the group consisting of breast cancer, ovarian cancer, skin carcinoma, lung carcinoma, head carcinoma and neck carcinoma.

14. The method of claim 12, wherein said pharmaceutical compound is administered by the means of injection or intravenous infusion.