1. A multi-arm polymer prodrug having the structure:
R(-Q-POLY1-X-D)q\u2003\u2003I
wherein
R is an organic radical possessing from about 3 to about 150 carbon atoms,
Q is a linker,
POLY1 is a water-soluble and non-peptidic polymer,
X is a spacer comprising a hydrolyzable linkage, such that upon hydrolysis of said hydrolyzable linkage, D is released,
D is a small molecule, and
q is greater than or equal to 3.
2. The multi-arm polymer prodrug of claim 1, wherein R possesses from about 3 to about 50 carbon atoms.
3. The multi-arm polymer prodrug of claim 2, wherein R possesses from about 3 to about 25 carbon atoms.
4. The multi-arm polymer prodrug of claim 3, wherein R possesses a number of carbon atoms selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, and 10.
5. The multi-arm polymer prodrug of claim 1, wherein R is linear or cyclic.
6. The multi-arm polymer prodrug of claim 5, wherein R, taken together with Q, is a residue of a polyol, a polythiol, or a polyamine.
7. The multi-armed polymer prodrug of claim 6, wherein R, taken together with Q, is a residue of glycerol, trimethylolpropane, pentaerythritol, sorbitol, or glycerol oligomers.
8. The multi-armed polymer prodrug of claim 1, wherein Q is hydrolytically stable.
9. The multi-armed polymer prodrug of claim 8, wherein Q comprises a heteroatom.
10. The multi-armed polymer prodrug of claim 9, wherein Q contains from about 1 to about 10 atoms.
11. The multi-armed polymer prodrug of claim 10, wherein Q is selected from the group consisting of O, S, and \u2014NH\u2014C(O).
12. The multi-armed polymer prodrug of claim 1, wherein POLY1 is a polymer selected from the group consisting of poly(alkylene glycol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharide), poly(\u03b1-hydroxy acid), poly(acrylic acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), or copolymers or terpolymers thereof.
13. The multi-armed polymer prodrug of claim 12, wherein POLY1 is a polyethylene glycol.
14. The multi-armed polymer prodrug of claim 13, wherein POLY1 is linear.
15. The multi-armed polymer prodrug of claim 1, wherein the nominal average molecular weight of POLY1 ranges from about 200 to about 30,000 daltons.
16. The multi-armed polymer prodrug of claim 1, wherein the nominal average molecular weight of POLY1 ranges from about 500 to about 20,000 daltons.
17. The multi-armed polymer prodrug of claim 1, wherein the nominal average molecular weight of the prodrug is greater than about 20,000 daltons.
18. The multi-armed polymer prodrug of claim 1, wherein X has an atom length of from about 4 atoms to about 50 atoms.
19. The multi-armed polymer prodrug of claim 18, wherein X has an atom length of from about 5 atoms to about 25 atoms.
20. The multi-armed polymer prodrug of claim 1, wherein X has the structure Y-Z, wherein Y is a spacer fragment covalently attached to Z, a hydrolytically degradable linkage.
21. The multi-armed polymer prodrug of claim 20, wherein Y has the structure: \u2014(CRxRy)a\u2014K\u2014(CRxRy)b\u2014(CH2CH2O)c\u2014,
each Rx and Ry, in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl,
a ranges from 0 to 12
b ranges from 0 to 12
K is selected from the group consisting of \u2014C(O)\u2014, \u2014C(O)NH\u2014, \u2014NH\u2014C(O)\u2014, \u2014O\u2014, \u2014S\u2014, O\u2014C(O)\u2014, C(O)\u2014O\u2014, O\u2014C(O)\u2014O\u2014, O\u2014C(O)\u2014NH\u2014, NH\u2014C(O)\u2014O\u2014, and
c ranges from 0 to 25.
22. The multi-armed polymer prodrug of claim 21, wherein Z is selected from the group consisting of C(O)\u2014O\u2014, O\u2014C(O)\u2014O\u2014, \u2014O\u2014C(O)\u2014NH\u2014, and NH\u2014C(O)\u2014O\u2014.
23. The multi-armed polymer prodrug of claim 21, wherein Y has the structure: \u2014(CH2)a\u2014C(O)NH\u2014(CH2)0,1\u2014(CH2CH2O)0-10\u2014.
24. The multi-armed polymer prodrug of claim 20, wherein Y has the structure: \u2014(CRxRy)a\u2014K\u2014(CRxRy)b\u2014(CH2CH2NH)c\u2014,
each Rx and Ry, in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl,
a ranges from 0 to 12
b ranges from 0 to 12
K is selected from the group consisting of \u2014C(O)\u2014, \u2014C(O)NH\u2014, \u2014NH\u2014C(O)\u2014, \u2014O\u2014, \u2014S\u2014, O\u2014C(O)\u2014, C(O)\u2014O\u2014, O\u2014C(O)\u2014O\u2014, O\u2014C(O)\u2014NH\u2014, NH\u2014C(O)\u2014O\u2014, and
c ranges from 0 to 25.
25. The multi-armed polymer prodrug of claim 21, wherein Rx and Ry in each occurrence are independently H or lower alkyl.
26. The multi-armed polymer prodrug of claim 19, wherein X is either \u2014CH2\u2014C(O)\u2014NH\u2014CH2\u2014C(O)O\u2014 or \u2014CH2\u2014C(O)\u2014NH\u2014(CH2CH2O)2\u2014C(O)\u2014O\u2014.
27. The multi-armed polymer prodrug of claim 1, wherein q has a value selected from the group consisting of: from about 3 to about 50, from about 3 to 25, and from about 3 to 10.
28. The multi-armed polymer prodrug of claim 27, wherein the value of q is selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, and 10.
29. The multi-armed polymer prodrug of claim 27, wherein each of said \u201cq\u201d polymer arms (-Q-POLY1-X-D) is the same.
30. The multi-armed polymer prodrug of claim 1, wherein D is a small molecule having a molecular weight of less than about 800.
31. The multi-armed polymer prodrug of claim 1, wherein D is an anticancer agent.
32. The multi-armed polymer prodrug of claim 1, wherein D is a small molecule selected from the group consisting of camptothecins, platins, oxymorphone analogues, steroids, quinolones, and nucleosides.
33. The multi-armed polymer prodrug of claim 32, wherein D is selected from the group consisting of cis-platin, hydroxyplatin, carboplatin, oxaliplatin, naloxone, methylnaltrexone, oxymorphone, codeine, oxycodone, morphone, budesonide, triamcinolone, fluticasone, ciprofloxacin, moxifloxacin, palonosetron, gemcitabine, cladribine, and fludarabine phosphate.
34. The multi-armed polymer prodrug of claim 31, wherein D is a camptothecin compound having the structure:
wherein R1-R5 are each independently selected from the group consisting of hydrogen; halo; acyl; alkyl (e.g., C1-C6 alkyl); substituted alkyl; alkoxy (e.g., C1-C6 alkoxy); substituted alkoxy; alkenyl; alkynyl; cycloalkyl; hydroxyl; cyano; nitro; azido; amido; hydrazine; amino; substituted amino (e.g., monoalkylamino and dialkylamino); hydroxcarbonyl; alkoxycarbonyl; alkylcarbonyloxy; alkylcarbonylamino; carbamoyloxy; arylsulfonyloxy; alkylsulfonyloxy; \u2014C(R7)\u2550N\u2014(O)i\u2014R8 wherein R7 is H, alkyl, alkenyl, cycloalkyl, or aryl, i is 0 or 1, and R8 is H, alkyl, alkenyl, cycloalkyl, or heterocycle; and R9C(O)O\u2014 wherein R9 is halogen, amino, substituted amino, heterocycle, substituted heterocycle, or R10\u2014O\u2014(CH2)m\u2014 where m is an integer of 1-10 and R10 is alkyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, heterocycle, or substituted heterocycle; or
R2 together with R3 or R3 together with R4 form substituted or unsubstituted methylenedioxy, ethylenedioxy, or ethyleneoxy;
R6 is H or OR\u2032, wherein R\u2032 is alkyl, alkenyl, cycloalkyl, haloalkyl, or hydroxyalkyl; and
L is the site of attachment to X.
35. The multi-armed polymer prodrug of claim 34, wherein D is has the structure:
36. The multi-armed polymer prodrug of claim 35, having the structure:
where n ranges from 40 to 500.
37. The multi-armed polymer prodrug of claim 36, wherein the overall nominal average molecular weight of the prodrug ranges from about 20,000 to about 80,000.
38. The multi-armed polymer prodrug of claim 35, having the structure:
where n ranges from 40 to 500.
39. The multi-armed polymer prodrug of claim 38, having the structure:
40. The multi-armed polymer prodrug of claim 38, wherein the overall nominal average molecular weight of the prodrug ranges from about 20,000 to about 80,000.
41. A multi-armed polymer prodrug of claim 37, wherein said prodrug, when evaluated in a suitable animal model for solid tumor-type cancers and administered in a therapeutically effective amount, is effective to suppress tumor growth to an extent that is at least twice that observed for the unmodified anticancer agent, when evaluated over a time course of 30 days.
42. A multi-armed polymer prodrug of claim 37, wherein said prodrug, when evaluated in a suitable animal model for solid tumor-type cancers and administered in a therapeutically effective amount, is effective to suppress tumor growth to an extent that is at least 1.5 times that observed for the unmodified anticancer agent when similarly administered over a time course of 30 days.
43. A multi-armed polymer prodrug of claim 37, wherein said prodrug, when evaluated in a suitable animal model for solid tumor-type cancers and administered in a therapeutically effective amount, is effective to suppress tumor growth to an extent that is at least 1.5 times that observed for the unmodified anticancer agent when similarly administered over a time course of 60 days.
44. A multi-armed polymer prodrug of claim 37, wherein said prodrug, when evaluated in a suitable animal model for solid tumor-type cancers and administered in a therapeutically effective amount, is effective to suppress tumor growth to an extent that is at least 2 times that observed for the unmodified anticancer agent when similarly administered over a time course of 60 days.
45. A pharmaceutical composition comprising a multi-arm polymer prodrug of claim 1.
46. A method of delivering a prodrug to a mammalian subject, said method comprising:
(i) providing a multi-arm polymer prodrug of claim 1, and
(ii) administering to a mammalian subject in need thereof, a therapeutically effective amount of said prodrug.
47. A method of treating a topoisomerase I inhibitor-related disease in a mammalian subject, said method comprising administering a therapeutically effective amount of a multi-arm polymer prodrug of claim 34 to a mammalian subject in need thereof.
48. The method of claim 47, wherein said administering step comprises administering said prodrug parenterally.
49. A method of targeting a solid tumor in a mammalian subject, said method comprising:
(i) administering a therapeutically effective amount of a multi-arm polymer prodrug of claim 31 to a subject diagnosed as having one or more cancerous solid tumors,
whereby as a result of said administering, said prodrug is effective to produce an inhibition of solid tumor growth in said subject that is increased over the inhibition of solid tumor growth resulting from administration of said anticancer agent alone.
50. The method of claim 49, wherein D is a camptothecin compound having the structure:
wherein R1-R5 are each independently selected from the group consisting of hydrogen; halo; acyl; alkyl (e.g., C1-C6 alkyl); substituted alkyl; alkoxy (e.g., C1-C6 alkoxy); substituted alkoxy; alkenyl; alkynyl; cycloalkyl; hydroxyl; cyano; nitro; azido; amido; hydrazine; amino; substituted amino (e.g., monoalkylamino and dialkylamino); hydroxcarbonyl; alkoxycarbonyl; alkylcarbonyloxy; alkylcarbonylamino; carbamoyloxy; arylsulfonyloxy; alkylsulfonyloxy; \u2014C(R7)\u2550N\u2014(O)i\u2014R8 wherein R7 is H, alkyl, alkenyl, cycloalkyl, or aryl, i is 0 or 1, and R8 is H, alkyl, alkenyl, cycloalkyl, or heterocycle; and R9C(O)O\u2014 wherein R9 is halogen, amino, substituted amino, heterocycle, substituted heterocycle, or R10\u2014O\u2014(CH2)m\u2014 where m is an integer of 1-10 and R10 is alkyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, heterocycle, or substituted heterocycle; or
R2 together with R3 or R3 together with R4 form substituted or unsubstituted methylenedioxy, ethylenedioxy, or ethyleneoxy;
R6 is H or OR\u2032, wherein R\u2032 is alkyl, alkenyl, cycloalkyl, haloalkyl, or hydroxyalkyl; and
L is the site of attachment to X,
and said multi-arm polymer prodrug has a nominal average molecular weight that is greater than about 15,000.
51. The method of claim 50, wherein D is irinotecan.
52. A method for preparing a multi-arm polymer prodrug of the invention, said method comprising:
(i) providing a small molecule, D, comprising a functional group, F, suitable for forming a hydrolyzable linkage, Z
(ii) reacting the small molecule with a bifunctional spacer, Y\u2032, comprising each a first and a second functional group, F1 and F2, wherein F2 is suitable for reaction with F and F1 is optionally in protected form (F1-Y\u2032-F2), under conditions effective to form a partially modified active agent comprising a hydrolyzable linkage, Z, resulting from reaction of F and F2 (D-Z-Y\u2032-F1),
(iii) optionally, if in protected form, deprotecting F1 contained in the partially modified active agent from (ii), and
(iii) reacting the partially modified active agent, D-Z-Y\u2032-F1, with a multi-armed water-soluble polymer comprising the structure:
R(-Q-POLY1-F3)q
where
R is an organic radical possessing from about 3 to about 150 carbon atoms,
Q is a linker,
POLY1 is a water-soluble and non-peptidic polymer,
q is greater than or equal to 3, and
F3 is a functional group that is reactive with F1,
under reaction conditions effective to promote reaction between F3 and F1 to convert Y\u2032 to Y to thereby form a polymer prodrug having the structure
R(-Q-POLY1-Y-Z-D)q,
where Y is a spacer fragment, and Z is a hydrolyzable linkage, which, upon hydrolysis, releases D.
53. The method of claim 52, wherein in step (iii), a stoichiometric excess in an amount greater than \u201cq\u201d moles of the partially modified active agent, D-Z-Y\u2032-F1, is reacted with the multi-armed water-soluble, R(-Q-POLY1-F3)q.
54. The method of claim 52, wherein said small molecule D comprises additional functional groups reactive with F2, and said method further comprises protecting said additional functional groups with suitable protecting groups prior to reaction with said bifunctional spacer.
55. The method of claim 54, further comprising (iv) removing said protecting groups from the small molecules of said prodrug, R(-Q-POLY1-Y-Z-D)q.
56. A method for preparing a multi-arm polymer prodrug of the invention, said method comprising:
(i) providing a reactive multi-arm polymer having the structure, R(-Q-POLY1-F3)q, where
R is an organic radical possessing from about 3 to about 150 carbon atoms,
Q is a linker,
POLY1 is a water-soluble and non-peptidic polymer,
q is greater than or equal to 3, and
F3 is a reactive functional group
(ii) reacting the multi-arm polymer with a bifunctional spacer, Y\u2032, comprising each a first and a second functional group, F1 and F2, wherein F1 is suitable for reaction with F3, and F1 is optionally in protected form (F1-Y\u2032-F2), under conditions effective to form an intermediate multi-arm polymer resulting from reaction of F3 and F1, R(-Q-POLY1-Y-F2)q, and
(iii) optionally, if in protected form, deprotecting F2 in the intermediate multi-arm polymer, R(-Q-POLY1-Y-F2)q, and
(iv) reacting the intermediate multi-arm polymer, R(-Q-POLY1-Y-F2)q with a small molecule, D, comprising a functional group, F, suitable for forming a hydrolyzable linkage, Z, upon reaction of F with F2, under conditions effective to thereby form a prodrug having the structure:
R(-Q-POLY1-Y-Z-D)q,
where Z is a hydrolyzable linkage, which, upon hydrolysis, releases D.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A phase sequence switching device for a three-phase power supply, which is provided in a power feed path from a three-phase power supply to a load, the device comprising:
a power-supply side relay including two Form C contact relays connected to two phases of the three-phase power supply respectively;
a load side relay including two Form C contact relays connected between the power-supply side relay and the load; and
a switching circuit connected between the power-supply side relay and the load side relay and wired to be capable of switching by a relay action between a state where the three-phase power supply is connected to a positive phase so that power is supplied to the load side and a state where the three-phase power supply is connected to a reverse phase so that power is supplied to the load side.
2. The device according to claim 1, wherein the switching circuit supplies the three-phase power to the load in a positive phase connection when one of the power-supply side relay and the load side relay carries out a relay action, and the switching circuit supplies the three-phase power to the load in a reverse phase connection when the other relay carries out a relay action.
3. The device according to claim 2, further comprising a controller configured to detect phase voltages of the three-phase power supply and to cause the power-supply side relay or the load side relay to carry out the relay action so that the detected phase voltages correspond to a current carrying direction required of the load.
4. The device according to claim 2, wherein the power-supply side relay and the load side relay have respective Form C contact relays corresponding to the remaining phase of the three-phase power supply, and the switching circuit is wired between the Form C contact relays provided in the remaining phase so that the remaining phase of the three-phase power supply is connected to the load when one of the power-supply side and load side relays is operated and so that the remaining phase of the three-phase power supply is disconnected from the load when both relays are in an off-state or both relays are operated.
5. The device according to claim 3, wherein the power-supply side relay and the load side relay have respective Form C contact relays corresponding to the remaining phase of the three-phase power supply, and the switching circuit is wired between the Form C contact relays provided in the remaining phase so that the remaining phase of the three-phase power supply is connected to the load when one of the power-supply side and load side relays is operated and so that the remaining phase of the three-phase power supply is disconnected from the load when both relays are in an off-state or both relays are operated.