Trifunctional constructs with tunable pharmacokinetics useful in imaging and anti-tumor therapies

1. A compound comprising:

a multi-targeted agent having a plurality of sterically unimpeded targeting domains comprising, a first targeting domain comprising a blood-protein binding domain having specific affinity for binding human serum albumin in the range of about 0.25 to 50 micromolar, a second targeting domain comprising a tumor-binding domain having specific affinity for PSMA in the range of about 0.1 to 75 nanomolar;

wherein the relative affinities of the first and second targeting domains differ in specific affinity by a factor of at least 100 to about 10,000; and a therapeutic domain comprising a cytocidal or cytostatic therapeutic agent wherein the cytocidal or cytostatic therapeutic agent is a toxin, a venom, a metabolic poison, a chemotherapeutic agent, an auger electron-emitting radionuclide, a beta-emitting radionuclide, or an alpha-emitting radionuclide.

2. The compound of claim 1 , wherein the blood-protein binding domain binds human serum albumin with an affinity in the range of about 0.4 to 20 micromolar, and the tumor-binding domain binds PSMA with an affinity in the range of about 0.1 to 15 nanomolar; wherein the relative affinities of the first and second targeting domains differ in specific affinity by a factor of about 1,000 to about 10,000.

3. The compound of claim 1 , wherein the tumor-binding domain comprises a glutamate-ureido-amino acid sequence, a glutamate-urea-lysine sequence optionally with a substituted or unsubstituted aryl group or a substituted or unsubstituted arylene group at the epsilon amine of lysine, or a derivative thereof that occludes the PSMA receptor active site.

4. The compound of claim 1 , wherein the blood-protein binding domain is selected from one or more of myristic acid, a substituted or unsubstituted indole-2-carboxylic acid, a substituted or unsubstituted thioamide, a substituted or unsubstituted 4-oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butanoic acid, a substituted or unsubstituted naphthalene acylsulfonamide, a substituted or unsubstituted diphenylcyclohexanol phosphate ester, a substituted or unsubstituted 4-iodophenylalkanoic acid, a substituted or unsubstituted 3-(4-iodophenyl)propionic acid, a substituted or unsubstituted 2-(4-iodophenyl)acetic acid, or a substituted or unsubstituted 4-(4-iodophenyl)butanoic acid.

5. The compound of claim 1 , wherein the tumor-binding domain binds to the PSMA with moderate to high affinity.

6. The compound of claim 1 , wherein the cytocidal or cytostatic therapeutic agent is a toxin, a venom, a metabolic poison, or a chemotherapeutic agent.

7. The compound of claim 1 , wherein the therapeutic domain comprises a covalently conjugated chelating agent or a covalently conjugated polyaza polycarboxylic macrocycle.

8. The compound of claim 7 , wherein the therapeutic domain further comprises an auger electron-emitting radionuclide, a beta-emitting radionuclide, or an alpha-emitting radionuclide.

9. The compound of claim 8 , wherein the therapeutic domain comprises 177 Lu 3+ , 175 Lu 3+ , 45 Sc 3+ , 66 Ga 3+ , 67 Ga 3+ , 68 Ga 3+ , 69 Ga 3+ , 71 Ga 3+ , 90 Y 3+ , 89 Y 3+ , 86 Y 3+ , 89 Zr 4+ , 90 Y 3+ , 99m Tc +1 , 111 In 3+ , 113 In 3+ , 115 In 3+ , 139 La 3+ , 136 Ce 3+ , 138 Ce 3+ , 140 Ce 3+ , 142 Ce 3+ , 151 Eu 3+ , 153 Eu 3+ , 152 Dy 3+ , 149 Tb 3+ , 159 Tb 3+ , 154 Gd 3+ , 155 Gd 3+ , 156 Gd 3+ , 157 Gd 3+ , 158 Gd 3+ , 160 Gd 3+ , 188 Re +1 , 186 Re +1 , 213 Bi 3+ , 227 Th 4+ , 226 Th 4+ , 225 Ac 3+ , 233 Ra 2+ , 152 Dy 3+ , 213 Bi 3+ , 212 Bi 3+ , 211 Bi 3+ , 212 Pb 2+ , 212 Pb 4+ , 255 Fm 3+ , or uranium-230.

10. The compound of claim 8 , wherein the therapeutic domain comprises 213 Bi 3+ , 211 At + , 225 Ac 3+ , 152 Dy 3+ , 212 Bi 3+ , 211 Bi 3+ , 217 At + , 227 Th 4+ , 226 Th 4+ , 233 Ra 2+ , 212 Pb 2+ , or 212 Pb 4+ .

11. The compound of claim 8 , wherein the therapeutic domain comprises 177 Lu 3+ , 90 Y 3+ , 188 Re +1 , or 186 Re +1 .

12. The compound of claim 8 , wherein the compound is (((S)-1-carboxy-5-(3-(3-(1-((14S,45S)-45-carboxy-14-(4-(3-(2-carboxy-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)pyridin-4-yl)thioureido)butyl)-54-(4-iodophenyl)-12,15,43,51-tetraoxo-3,6,9,19,22,25,28,31,34,37,40-undecaoxa-13,16,44,50-tetraazatetrapentacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid chelating 225 Ac 3+ .

13. The compound of claim 8 , wherein the compound is (((S)-1-carboxy-5-(3-(3-(1-((14S,45S)-45-carboxy-14-(4-(3-(2-carboxy-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)pyridin-4-yl)thioureido)butyl)-54-(4-iodophenyl)-12,15,43,51-tetraoxo-3,6,9,19,22,25,28,31,34,37,40-undecaoxa-13,16,44,50-tetraazatetrapentacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid chelating 233 Ra 2+ .

14. The compound of claim 8 , wherein the compound is (((S)-1-carboxy-5-(3-(3-(1-((14S,45S)-45-carboxy-14-(4-(3-(2-carboxy-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)pyridin-4-yl)thioureido)butyl)-54-(4-iodophenyl)-12,15,43,51-tetraoxo-3,6,9,19,22,25,28,31,34,37,40-undecaoxa-13,16,44,50-tetraazatetrapentacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid chelating 213 Bi 3+ .

15. The compound of claim 8 , wherein the compound is (((S)-1-carboxy-5-(3-(3-(1-((14S,45S)-45-carboxy-14-(4-(3-(2-carboxy-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)pyridin-4-yl)thioureido)butyl)-54-(4-iodophenyl)-12,15,43,51-tetraoxo-3,6,9,19,22,25,28,31,34,37,40-undecaoxa-13,16,44,50-tetraazatetrapentacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid chelating 212 Pb 2+ or 212 Pb 4+ .