Chelate based scaffolds in tumor targeting
This invention relates to novel complexes that can be used to target tumor cells. The complexes include a ligand that can bind metal ions including radioactive lanthanide ions. The complexes can mimic α ν β3 integrin receptor antagonists and deliver the complexed radioactive metals to the tumor cells.
1 . A composition comprising:
a metal-chelating ligand including a tetraazacyclododecane macrocycle ring core, and
at least two non-identical substituents covalently bonded to the ring core, wherein each of the at least two non-identical substituents contain a group capable of binding to a cell receptor.
2 . The composition of claim 1 wherein at least one of the non-identical substituents is covalently bound to a ring nitrogen.
3 . The composition of claim 1 wherein at least one of the non-identical substituents is covalently bound to a ring carbon.
4 . The composition of claim 1 wherein at least one of the non-identical substituents are covalently bound to the ring via an alkyl linking group, an alkyl carbonyl linking group, or an alkyl amide linking group.
5 . The composition of claim 1 wherein the tetraazacyclododecane macrocycle ring core is chelated to a metal ion.
6 . The composition of claim 5 wherein the metal ion is selected from the group of metals consisting of: La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y, and Sc.
7 . A composition comprising a metal-chelating ligand including tetraazacyclododecane macrocycle having one or more alkyl carboxylic acids or salts thereof appended to the ring nitrogen(s), and
a α ν β 3 receptor binding ligand covalently bonded to a ring nitrogen of the metal-chelating ligand via an alkyl linking group, an alkyl carbonyl linking group, or an alkyl amide linking group.
8 . The composition of claim 7 tetraazacyclododecane macrocycle includes two alkyl carboxylic acids or salts thereof each attached to one ring nitrogen.
9 . The composition of claim 7 wherein the alkyl carboxylic acid is acetic acid.
10 . The composition of claim 7 wherein the alkyl component of the alkyl carboxylic acid or salt thereof is a straight chain, a branched chain, cyclic or aromatic hydrocarbyl group having between 1-5 carbon atoms, and can be substituted with one or more of the following substituents, hydrogen, C1-C4 alkyl, C1-C4 branched alkyl or aromatic or heteroaromatic group or a combination of these groups.
11 . The composition of claim 7 wherein the alkyl amide linking group is —(CH 2 ) n CO 2 — wherein n is selected to be between 1 and 6.
12 . The composition of claim 7 wherein the alkyl component of the alkyl linking group, the alkyl carbonyl linking group and the alkyl amide linking group is —(CH 2 ) n CO 2 — wherein n is selected to be between 1 and 6.
13 . The composition of claim 7 wherein the alkyl component of alkyl linking group, the alkyl carbonyl linking group and the alkyl amide linking group is a straight chain, a branched chain, cyclic or aromatic hydrocarbyl group having between 1-6 carbon atoms, and can be substituted with one or more of the following substituents, hydrogen, C1-C4 alkyl C1-C4 branched alkyl, aromatic, or heteroaromatic group.
14 . The composition of claim 7 comprising a metal ion complexed to the tetraazacyclododecane macrocycle.
15 . The composition of claim 7 wherein the metal ion is radioactive.
16 . The composition of claim 1 wherein the metal ion is selected from the group consisting of: La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y, and Sc.
17 . A composition comprising:
a metal-chelating ligand including tetraazacyclododecane macrocycle having one or more alkyl carboxylic acids or salts thereof appended to the ring nitrogen(s), and
a guanidine substituent covalently bonded to a ring nitrogen of the metal-chelating ligand via an alkyl linking group, an alkyl carbonyl linking group, or an alkyl amide linking group.
18 . The composition of claim 17 wherein the alkyl component of the alkyl linking group, an alkyl carbonyl linking group or an alkyl amide linking group is a straight chain, a branched chain, cyclic and/or aromatic group.
19 . The composition of claim 17 comprising a metal ion complexed to the tetraazacyclododecane macrocycle.
20 . The composition of claim 17 wherein the metal ion is radioactive.
21 . The composition of claim 17 wherein the metal ion is selected from the group consisting of: La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Th, Dy, Ho, Er, Tm, Yb, Lu, Y, and Sc.
22 . A method of inhibiting tumor cell growth, said method comprising:
administering to the tumor cells an effective amount of a composition including a compound having a metal-chelating ligand including tetraazacyclododecane macrocycle having one or more alkyl carboxylic acids or salts thereof appended to the ring nitrogen(s), and a α ν β 3 receptor binding ligand covalently bonded to a ring nitrogen of the metal-chelating ligand via an alkyl group linking group, an alkyl carbonyl linking group, or an alkyl amide linking group.
23 . The method of claim 22 wherein the composition comprises a radioactive metal ion chelated to the metal-chelating ligand.
24 . The method of claim 22 wherein the tumor cell is selected from the group consisting of osteosarcomas, neuoroblastomas, glioblastomas, melanomas, and carcinomas.
25 . A method of inhibiting tumor cell growth, said method comprising administering to the cells a metal-chelating ligand including tetraazacyclododecane macrocycle having one or more alkyl carboxylic acids or salts thereof appended to the ring nitrogen(s), and
a guanidine substituent covalently bonded to a ring nitrogen of the metal-chelating ligand via an alkyl linking group, an alkyl carbonyl linking group, or an alkyl amide linking group.
26 . The method of claim 25 wherein the composition comprises a radioactive metal ion chelated to the metal-chelating ligand.
27 . The method of claim 25 wherein the tumor cell is selected from the group consisting of osteosarcomas, neuoroblastomas, glioblastomas, melanomas, and carcinomas.