Water soluble paclitaxel derivatives

Abstract

Disclosed are water soluble compositions of paclitaxel and docetaxel formed by conjugating the paclitaxel or docetaxel to a water soluble polymer such as poly-glutamic acid, poly-aspartic acid or poly-lysine. Also disclosed are methods of using the compositions for treatment of tumors, auto-immune disorders such as rheumatoid arthritis. Other embodiments include the coating of implantable stents for prevention of restenosis.

What is claimed is:  
     
         1 . A conjugate comprising a chemotherapeutic drug and a water soluble chelator.  
     
     
         2 . The conjugate of  claim 1 , wherein said chemotherapeutic drug comprises a taxoid.  
     
     
         3 . The conjugate of  claim 2 , wherein said taxoid comprises paclitaxel.  
     
     
         4 . The conjugate of  claim 2 , wherein said taxoid comprises docetaxel.  
     
     
         5 . The conjugate of  claim 1 , wherein said chemotherapeutic drug comprises etoposide.  
     
     
         6 . The conjugate of  claim 1 , wherein said chemotherapeutic drug comprises teniposide.  
     
     
         7 . The conjugate of  claim 1 , wherein said chemotherapeutic drug comprises camptothecin.  
     
     
         8 . The conjugate of  claim 1 , wherein said chemotherapeutic drug comprises epothilone.  
     
     
         9 . The conjugate of  claim 1 , wherein said chemotherapeutic drug comprises a radioactive isotope.  
     
     
         10 . A conjugate comprising a chemotherapeutic drug and a water soluble chelator, wherein said water soluble chelator is a metal ion.  
     
     
         11 . The conjugate of  claim 10 , wherein said chemotherapeutic drug comprises a taxoid.  
     
     
         12 . The conjugate of  claim 11 , wherein said taxoid comprises paclitaxel.  
     
     
         13 . The conjugate of  claim 11 , wherein said taxoid comprises docetaxel.  
     
     
         14 . The conjugate of  claim 10 , wherein said chemotherapeutic drug comprises etoposide.  
     
     
         15 . The conjugate of  claim 10 , wherein said chemotherapeutic drug comprises teniposide.  
     
     
         16 . The conjugate of  claim 10 , wherein said chemotherapeutic drug comprises camptothecin.  
     
     
         17 . The conjugate of  claim 10 , wherein said chemotherapeutic drug comprises epothilone.  
     
     
         18 . The conjugate of  claim 10 , wherein said chemotherapeutic drug comprises a radioactive isotope.  
     
     
         19 . The conjugate of  claim 10 , wherein said metal ion is selected from the group consisting of aluminum, boron, calcium, chromium, cobalt, copper, dysprosium, erbium, europium, gadolinium, gallium, germanium, holmium, indium, iridium, iron, magnesium, manganese, nickel, platinum, rhenium, rubidium, ruthenium, samarium, sodium, technetium, thallium, tin, yttrium or zinc.  
     
     
         20 . The conjugate of  claim 19 , wherein said chemotherapeutic drug comprises a taxoid.  
     
     
         21 . The conjugate of  claim 20 , wherein said taxoid comprises paclitaxel.  
     
     
         22 . The conjugate of  claim 20 , wherein said taxoid comprises docetaxel.  
     
     
         23 . The conjugate of  claim 19 , wherein said chemotherapeutic drug comprises etoposide.  
     
     
         24 . The conjugate of  claim 19 , wherein said chemotherapeutic drug comprises teniposide.  
     
     
         25 . The conjugate of  claim 19 , wherein said chemotherapeutic drug comprises camptothecin.  
     
     
         26 . The conjugate of  claim 19 , wherein said chemotherapeutic drug comprises epothilone.  
     
     
         27 . The conjugate of  claim 19 , wherein said chemotherapeutic drug comprises a radioactive isotope.  
     
     
         28 . The conjugate of  claim 10 , wherein said metal ion is radioactive.  
     
     
         29 . The conjugate of  claim 28 , wherein said chemotherapeutic drug comprises a taxoid.  
     
     
         30 . The conjugate of  claim 29 , wherein said taxoid comprises paclitaxel.  
     
     
         31 . The conjugate of  claim 29 , wherein said antitimor drug comprises docetaxel.  
     
     
         32 . The conjugate of  claim 28 , wherein said chemotherapeutic drug comprises etoposide.  
     
     
         33 . The conjugate of  claim 28 , wherein said chemotherapeutic drug comprises teniposide.  
     
     
         34 . The conjugate of  claim 28 , wherein said chemotherapeutic drug comprises camptothecin.  
     
     
         35 . The conjugate of  claim 28 , wherein said chemotherapeutic drug comprises epothilone.  
     
     
         36 . The conjugate of  claim 28 , wherein said chemotherapeutic drug comprises a radioactive isotope.  
     
     
         37 . The conjugate of  claim 28 , wherein said metal ion is selected from the group consisting of  67 Ga,  68 Ga,  166 Ho,  111 In,  99m  Tc,  90 Y,  114m Sn and  193m Pt  
     
     
         38 . The conjugate of  claim 37 , wherein said chemotherapeutic drug comprises a taxoid.  
     
     
         39 . The conjugate of  claim 38 , wherein said taxoid comprises paclitaxel.  
     
     
         40 . The conjugate of  claim 38 , wherein said taxoid comprises docetaxel.  
     
     
         41 . The conjugate of  claim 37 , wherein said chemotherapeutic drug comprises etoposide.  
     
     
         42 . The conjugate of  claim 37 , wherein said chemotherapeutic drug comprises teniposide.  
     
     
         43 . The conjugate of  claim 37 , wherein said chemotherapeutic drug comprises camptothecin.  
     
     
         44 . The conjugate of  claim 37 , wherein said chemotherapeutic drug comprises epothilone.  
     
     
         45 . The conjugate of  claim 37 , wherein said chemotherapeutic drug comprises a radioactive isotope.  
     
     
         46 . A conjugate comprising a chemotherapeutic drug and a water soluble chelator, wherein said water soluble chelator is selected from the group consisting of diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-N,N′, N,″N′″ tetraacetate (DOTA), tetraazacyclotetradecane-N,N″,N′‘N″’-tetraacetic acid (TETA), hydroxyethylidene diphosphonate (HEDP), dimercaptosuccinic acid (DMSA), diethylenetriaminetetramethylenephosphonic acid (DTTP) and 1-(ρ-aminobenzyl)-DTPA, 1,6-diamino hexane-N,N,N′,N′-tetraacetic acid, DPDP, and ethylenebis (oxyethylenenitrilo)-tetraacetic acid.  
     
     
         47 . The conjugate of  claim 46 , wherein said chemotherapeutic drug comprises a taxoid.  
     
     
         48 . The conjugate of  claim 47 , wherein said taxoid comprises paclitaxel.  
     
     
         49 . The conjugate of  claim 47 , wherein said taxoid comprises docetaxel.  
     
     
         50 . The conjugate of  claim 46 , wherein said chemotherapeutic drug comprises etoposide.  
     
     
         51 . The conjugate of  claim 46 , wherein said chemotherapeutic drug comprises teniposide.  
     
     
         52 . The conjugate of  claim 46 , wherein said chemotherapeutic drug comprises camptothecin.  
     
     
         53 . The conjugate of  claim 46 , wherein said chemotherapeutic drug comprises epothilone.  
     
     
         54 . The conjugate of  claim 46 , wherein said chemotherapeutic drug comprises a radioactive isotope.  
     
     
         55 . The conjugate of  claim 46 , wherein said water soluble chelator comprises DTPA.  
     
     
         56 . The conjugate of  claim 55 , wherein said chemotherapeutic drug comprises a taxoid.  
     
     
         57 . The conjugate of  claim 56 , wherein said taxoid comprises paclitaxel.  
     
     
         58 . The conjugate of  claim 56 , wherein said taxoid comprises docetaxel.  
     
     
         59 . The conjugate of  claim 55 , wherein said chemotherapeutic drug comprises etoposide.  
     
     
         60 . The conjugate of  claim 55 , wherein said chemotherapeutic drug comprises teniposide.  
     
     
         61 . The conjugate of  claim 55 , wherein said chemotherapeutic drug comprises camptothecin.  
     
     
         62 . The conjugate of  claim 55 , wherein said chemotherapeutic drug comprises epothilone.  
     
     
         63 . The conjugate of  claim 55 , wherein said chemotherapeutic drug comprises a radioactive isotope.  
     
     
         64 . The conjugate of  claim 57  wherein said conjugate is  111 In-DTPA paclitaxel  
     
     
         65 . The conjugate of  claim 57 , wherein said conjugate is Na-DTPA-paclitaxel.  
     
     
         66 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 1 .  
     
     
         67 . The method of  claim 66 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         68 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 2 .  
     
     
         69 . The method of  claim 68 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         70 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 3 .  
     
     
         71 . The method of  claim 70 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         72 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 4 .  
     
     
         73 . The method of  claim 72 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         74 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 7 .  
     
     
         75 . The method of  claim 74 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         76 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 10 .  
     
     
         77 . The method of  claim 76 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         78 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 11 .  
     
     
         79 . The method of  claim 78 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         80 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 12 .  
     
     
         81 . The method of  claim 80 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         82 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 13 .  
     
     
         83 . The method of  claim 82 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         84 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 16 .  
     
     
         85 . The method of  claim 84 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         86 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 19 .  
     
     
         87 . The method of  claim 86 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         88 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 20 .  
     
     
         89 . The method of  claim 88 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         90 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 21 .  
     
     
         91 . The method of  claim 90 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         92 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 22 .  
     
     
         93 . The method of  claim 92 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         94 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 25 .  
     
     
         95 . The method of  claim 94 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         96 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 27 .  
     
     
         97 . The method of  claim 96 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         98 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 28 .  
     
     
         99 . The method of  claim 98 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         100 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 29 .  
     
     
         101 . The method of  claim 100 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         102 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 30 .  
     
     
         103 . The method of  claim 102 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         104 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 34 .  
     
     
         105 . The method of  claim 104 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         106 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 37 .  
     
     
         107 . The method of  claim 106 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         108 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 38 .  
     
     
         109 . The method of  claim 108 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         110 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 39 .  
     
     
         111 . The method of  claim 110 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         112 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 40 .  
     
     
         113 . The method of  claim 112 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         114 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 43 .  
     
     
         115 . The method of  claim 114 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         116 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 46 .  
     
     
         117 . The method of  claim 116 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         118 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 47 .  
     
     
         119 . The method of  claim 118 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         120 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 48 .  
     
     
         121 . The method of  claim 120 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         122 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 49 .  
     
     
         123 . The method of  claim 122 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         124 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 52 .  
     
     
         125 . The method of  claim 124 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         126 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 55 .  
     
     
         127 . The method of  claim 126 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         128 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 56 .  
     
     
         129 . The method of  claim 128 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         130 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 57 .  
     
     
         131 . The method of  claim 130 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         132 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 58 .  
     
     
         133 . The method of  claim 132 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         134 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 61 .  
     
     
         135 . The method of  claim 134 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         136 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 64 .  
     
     
         137 . The method of  claim 136 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.  
     
     
         138 . A method for treating a condition responsive to a therapeutic agent comprising administering to a subject an effective amount of a conjugate of  claim 65 .  
     
     
         139 . The method of  claim 138 , wherein the condition is selected from the group consisting of prostate, breast, ovarian, colon, leukemia and lung cancers, malignant melanoma, head and neck cancers, gastric cancer and Kaposi's sarcoma.