Prostate-specific membrane antigen targeted deep-tumor penetration of polymer nanodrugs and methods of use thereof
AssigneesThe Regents of the University of California, ProLynx LLC
InventorsRobert Flavell, Henry VanBrocklin, Niranjan Meher, Gary W. Ashley, Daniel V. Santi
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Abstract
PSMA targeted metal chelate nanodrugs, methods of making these nanodrugs and methods of using them for radiodiagnosis and radiotherapy are provided.
Claims47
An imaging agent of Formula (I):
- wherein:
- PEG is branched polyethylene glycol;
- L1 and L2 are independently selected linkers;
- P is a prostate-specific membrane antigen (PSMA) targeted ligand;
- C is a chelator;
- x is an integer from 1 to 8;
- y is an integer from 1 to 8,
- such that x+y is less than or equal to 8,
- wherein each C is independently selected from a chelating agent and a chelating agent binding a radioisotope suitable for positron emission tomography (PET) and/or single-photon emission computed tomography (SPECT).
The imaging agent of any previous claim, wherein PEG is a polyethylene glycol of about 2 kD to about 100 kD.
The imaging agent of any previous claim, wherein PEG is a polyethylene glycol of about 40 kD.
The imaging agent of any previous claim, wherein L1 and L2 are independently selected from one or more of a bond, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted acyl.
The imaging agent of any previous claim, wherein L1 and L2 are independently selected from
The imaging agent of any previous claim, wherein the chelator is selected from a desferrioxamine, a tetraaza macrocycle, or a multidentate plur-hydroxypyridinone.
The imaging agent of any previous claim, wherein the chelator is desferrioxamine-B (DFB) or 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA).
The imaging agent of any previous claim, wherein the radioisotope suitable for positron emission tomography (PET) and/or single-photon emission computed tomography (SPECT) is an ion selected from 89Zr, 99mTc, 111In, 177Lu, 225Ac, 44Sc, 68Ga, 64Cu, 62Zn, 86Y, 134Ce, 149Tb, 152Tb, 155Tb, and 203Pb.
The imaging agent of claim any previous claim, wherein the radioisotope is an ion of 89Zr, 225Ac, or 177Lu.
The imaging agent of any previous claim, wherein the prostate-specific membrane antigen (PSMA) targeted is a compound of Formula (II):
- wherein:
- AA and AA′ are independently selected amino acids connected through their NH2 moieties by a urea linkage.
The imaging agent of any previous claim, wherein the prostate-specific membrane antigen (PSMA) targeted ligand is (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)pentanedioic acid (ACUPA).
The imaging agent of any previous claim, wherein the imaging agent of Formula (T) is a compound selected from Formulae 101, 102, 103, 104, and a pharmaceutically acceptable salt thereof:
- wherein:
- PEG represents a branched polyethylene glycol;
- x is an integer of 1 to 8;
- y is an integer from 1 to 8,
- such that x+y is less than or equal to 8,
- wherein one desferrioxamine-B (DFB) moiety binds a radioisotope.
The imaging agent of any previous claim, wherein the imaging agent of Formula (101) is a compound of any one of formula 1001-1028, or a pharmaceutically acceptable salt thereof, wherein one desferrioxamine-B (DFB) moiety binds a 89Zr ion:
- (101)
- Compound No.
- x
- y
- 1001
- 1
- 1
- 1002
- 1
- 2
- 1003
- 1
- 3
- 1004
- 1
- 4
- 1005
- 1
- 5
- 1006
- 1
- 6
- 1007
- 1
- 7
- 1008
- 2
- 1
- 1009
- 2
- 2
- 1010
- 2
- 3
- 1011
- 2
- 4
- 1012
- 2
- 5
- 1013
- 2
- 6
- 1014
- 3
- 1
- 1015
- 3
- 2
- 1016
- 3
- 3
- 1017
- 3
- 4
- 1018
- 3
- 5
- 1019
- 4
- 1
- 1020
- 4
- 2
- 1021
- 4
- 3
- 1022
- 4
- 4
- 1023
- 5
- 1
- 1024
- 5
- 2
- 1025
- 5
- 3
- 1026
- 6
- 1
- 1027
- 6
- 2
- 1028
- 7
- 1
The imaging agent of any previous claim, wherein the imaging agent of formula (102) is a compound of any one of formula 1029-1056, or a pharmaceutically acceptable salt thereof, wherein one desferrioxamine-B (DFB) moiety binds a 89Zr ion:
- (102)
- Compound No.
- x
- y
- 1029
- 1
- 1
- 1030
- 1
- 2
- 1031
- 1
- 3
- 1032
- 1
- 4
- 1033
- 1
- 5
- 1034
- 1
- 6
- 1035
- 1
- 7
- 1036
- 2
- 1
- 1037
- 2
- 2
- 1038
- 2
- 3
- 1039
- 2
- 4
- 1040
- 2
- 5
- 1041
- 2
- 6
- 1042
- 3
- 1
- 1043
- 3
- 2
- 1044
- 3
- 3
- 1045
- 3
- 4
- 1046
- 3
- 5
- 1047
- 4
- 1
- 1048
- 4
- 2
- 1049
- 4
- 3
- 1050
- 4
- 4
- 1051
- 5
- 1
- 1052
- 5
- 2
- 1053
- 5
- 3
- 1054
- 6
- 1
- 1055
- 6
- 2
- 1056
- 7
- 1
The imaging agent of any previous claim, wherein the imaging agent of formula (103) is a compound ofany one of formula 1057-1084, or a pharmaceutically acceptable salt thereof, wherein one desferrioxamine-B (DFB) moiety binds a 89Zr ion:
- (103)
- Compound No.
- x
- y
- 1057
- 1
- 1
- 1058
- 1
- 2
- 1059
- 1
- 3
- 1060
- 1
- 4
- 1061
- 1
- 5
- 1062
- 1
- 6
- 1063
- 1
- 7
- 1064
- 2
- 1
- 1065
- 2
- 2
- 1066
- 2
- 3
- 1067
- 2
- 4
- 1068
- 2
- 5
- 1069
- 2
- 6
- 1070
- 3
- 1
- 1071
- 3
- 2
- 1072
- 3
- 3
- 1073
- 3
- 4
- 1074
- 3
- 5
- 1075
- 4
- 1
- 1076
- 4
- 2
- 1077
- 4
- 3
- 1078
- 4
- 4
- 1079
- 5
- 1
- 1080
- 5
- 2
- 1081
- 5
- 3
- 1082
- 6
- 1
- 1083
- 6
- 2
- 1084
- 7
- 1
The imaging agent of any previous claim, wherein the imaging agent of formula (104) is a compound of any one of formula 1085-1112, or a pharmaceutically acceptable salt thereof, wherein one desferrioxamine-B (DFB) moiety binds a 89Zr ion:
- (104)
- Compound No.
- x
- y
- 1085
- 1
- 1
- 1086
- 1
- 2
- 1087
- 1
- 3
- 1088
- 1
- 4
- 1089
- 1
- 5
- 1090
- 1
- 6
- 1091
- 1
- 7
- 1092
- 2
- 1
- 1093
- 2
- 2
- 1094
- 2
- 3
- 1095
- 2
- 4
- 1096
- 2
- 5
- 1097
- 2
- 6
- 1098
- 3
- 1
- 1099
- 3
- 2
- 1100
- 3
- 3
- 1101
- 3
- 4
- 1102
- 3
- 5
- 1103
- 4
- 1
- 1104
- 4
- 2
- 1105
- 4
- 3
- 1106
- 4
- 4
- 1107
- 5
- 1
- 1108
- 5
- 2
- 1109
- 5
- 3
- 1110
- 6
- 1
- 1111
- 6
- 2
- 1112
- 7
- 1
The imaging agent of any previous claim, wherein the imaging agent is selected from:
- wherein one desferrioxamine-B (DFB) moiety binds a 89Zr ion.
The imaging agent of any previous claim, wherein prostate-specific membrane antigen (PSMA)-expressing cells exhibit cell binding and internalization of the imaging agent relative to cells that do not express PSMA.
The imaging agent of any previous claim, wherein the imaging agent exhibits enhanced permeability and retention (EPR) in prostate-specific membrane antigen (PSMA)-expressing tumors relative to tumors that do not express PSMA.
The imaging agent of any previous claim, wherein the imaging agent exhibits targeted accumulation in prostate-specific membrane antigen (PSMA)-expressing tumors relative to tumors that do not express PSMA.
The imaging agent of any previous claim, wherein the imaging agent exhibits deep-tumor penetration in prostate-specific membrane antigen (PSMA)-expressing tumors relative to tumors that do not express PSMA.
The imaging agent of any previous claim, wherein the imaging agent exhibits a dissociation constant (Kd) from about 30 nM to about 800 nM.
The imaging agent of any previous claim, wherein the imaging agent exhibits a dissociation constant (Kd) from about 52 nM to about 66 nM.
The imaging agent of any previous claim, wherein the imaging agent exhibits IC50 values from about 359 nM to about 706 nM.
The imaging agent of any previous claim, wherein the imaging agent exhibits IC50 values from about 459 nM to about 575 nM.
The imaging agent of any previous claim, wherein the imaging agent exhibits IC50 values from about 687 nM to about 1380 nM.
Dependencies are inferred from the claim text.