Treatment of cancer cells overexpressing somatostatin receptors using ocreotide derivatives chelated to radioisotopes

A cancer targeting composition for treating cancer cells overexpressing somatostatin receptors, the composition comprising a molecule of Formula (I) or a pharmaceutically acceptable salt thereof:

• M-Ch-L1-Tm, Formula (I)
• wherein
• M is a radioisotope selected from the group consisting of 212Pb, 203Pb, 64Cu, 67Cu, 212Bi, 68Ga, 213Bi, 225Ac, 243Am, 211At, 217At, 154Dy, 148Gd, 146Sm, 147Sm, 149Tb, 227Th, 229Th, 59Fe, 60Cu, 61Cu, 62Cu, 67Ga, 86Y, 111In, 153Gd, 153Sm, and 166Ho;
• Ch is a chelator having a structure of Formula (V), wherein
• wherein
• R5, R6, and R8 are each independently selected from the group consisting of H, D, F, Cl, (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—OR25, and (C1-C6)alkyl-C(═O)—N(—R25)—R26;
• R9, R10, R11, R12, R15, R16, R17, R18, R19, R20, R21, R22, R23, and R24 are each independently selected from the group consisting of H, D, F, Cl, and (C1-C6)alkyl;
• R7 is independently selected from the group consisting of H, D, F, Cl, (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—N(—R25)—R26, and Li;
• R13 and R14 are each independently selected from the group consisting of H, D, F, Cl, (C1-C6)alkyl, and L1;
• R25 and R26 are each independently selected from the group consisting of H, D, (C1-C6)alkyl, and (C1-C6)alkyl-C(═O)—OH;
• L1 is independently selected from a group consisting of (C1-C6)alkyl-C(═O)—NH—(C1-C6)alkyl-C(═O)—NH, (C1-C6)alkyl-(C6H4)—NH—C(═S)—NH, C(—CO2H)—(C1-C6)alkyl-(C6H4)—NH—C(═S)—NH, (C1-C6)alkyl-C(═O)—NH, (C1-C6)alkyl-C(═O)—(O—CH2—CH2)1-20—C(═O)—NH;
• and
• Tm has a structure of Formula (VI),
• wherein R27 is CH2—OH;
• and
• provided that only one of R7, R13, or R14 is L1.

A method of administering a cancer targeting composition for treating cancer cells overexpressing somatostatin receptors to a subject in need thereof, the method comprising:

• administering a therapeutically effective dosage of a cancer targeting composition, the cancer targeting composition comprising a molecule of Formula (I) or a pharmaceutically acceptable salt thereof:
• wherein
• M is a radioisotope selected from the group consisting of 212Pb, 203Pb, 64Cu, 67Cu, 212Bi, 68Ga, 213Bi, 225Ac, 243Am, 211At, 217At, 154Dy, 148Gd, 146Sm, 147Sm, 149Tb, 227Th, 229Th, 59Fe, 60Cu, 61Cu, 62Cu, 67Ga, 86Y, 111In, 153Gd, 153Sm, and 166Ho;
• Ch is a chelator having a structure selected from the group consisting of:
• Formula (II), Formula (III), Formula (IV), and Formula (V), wherein
• wherein
• R5, R6, and R8 are each independently selected from the group consisting of H, D, F, Cl, (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—OR25, and (C1-C6)alkyl-C(═O)—N(—R25)—R26;
• R9, R10, R11, R12, R15, R16, R17, R18, R19, R20, R21, R22, R23, and R24 are each independently selected from the group consisting of H, D, F, Cl, and (C1-C6)alkyl;
• R7 is independently selected from the group consisting of H, D, F, Cl, (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—N(—R25)—R26, and Li;
• R13 and R14 are each independently selected from the group consisting of H, D, F, Cl, (C1-C6)alkyl, and L1;
• R25 and R26 are each independently selected from the group consisting of H, D, and (C1-C6)alkyl, and (C1-C6)alkyl-C(═O)—OH;
• L1 is independently selected from a group consisting of, and (C1-C6)alkyl-C(═O)—NH—(C1-C6)alkyl-C(═O)—NH, (C1-C6)alkyl-(C6H4)—NH—C(═S)—NH, C(—CO2H)—(C1-C6)alkyl-(C6H4)—NH—C(═S)—NH, (C1-C6)alkyl-C(═O)—NH, and (C1-C6)alkyl-C(═O)—(O—CH2—CH2)1-20—C(═O)—NH;
• and
• Tm has a structure of Formula (VI),
• wherein R27 is independently selected from the group consisting of CH2—OH and C(═O)—OH;
• and
• provided that only one of R7, R13, or R14 is L1.

A method of administering a cancer targeting composition for treating cancer cells overexpressing somatostatin receptors to a subject in need thereof, the method comprising:

• administering a therapeutically effective dosage of a molecule of Formula (I), or a pharmaceutically acceptable salt thereof;
• and
• at least one anti-cancer compound in a pharmaceutically acceptable carrier,
• the molecule of Formula (I), wherein
• M-Ch-L1-Tm, Formula (I)
• M is a radioisotope selected from the group consisting of 212Pb, 203Pb, 64Cu, 67Cu, 212Bi, 68Ga, 213Bi, 225Ac, 243Am, 211At, 217At, 154Dy, 148Gd, 146Sm, 147Sm, 149Tb, 227Th, 229Th, 59Fe, 60Cu, 61Cu, 62Cu, 67Ga, 86Y, 111In, 153Gd, 153Sm, and 166Ho;
• Ch is a chelator having a structure selected from the group consisting of:
• Formula (II), Formula (III), Formula (IV), and Formula (V), wherein
• wherein
• R5, R6, and R8 are each independently selected from the group consisting of H, D, F, Cl, (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—OR25, and (C1-C6)alkyl-C(═O)—N(—R25)—R26;
• R9, R10, R11, R12, R15, R16, R17, R18, R19, R20, R21, R22, R23, and R24 are each independently selected from the group consisting of H, D, F, Cl, and (C1-C6)alkyl;
• R7 is independently selected from the group consisting of H, D, F, Cl, (C1-C6)alkyl, (C1-C6)alkyl-C(═O)—N(—R25)—R26, and Li;
• R13 and R14 are each independently selected from the group consisting of H, D, F, Cl, (C1-C6)alkyl, and L1;
• R25 and R26 are each independently selected from the group consisting of H, D, (C1-C6)alkyl, and (C1-C6)alkyl-C(═O)—OH;
• L1 is independently selected from a group consisting of, and (C1-C6)alkyl-C(═O)—NH—(C1-C6)alkyl-C(═O)—NH, (C1-C6)alkyl-(C6H4)—NH—C(═S)—NH, C(—CO2H)—(C1-C6)alkyl-(C6H4)—NH—C(═S)—NH, (C1-C6)alkyl-C(═O)—NH, (C1-C6)alkyl-C(═O)—(O—CH2—CH2)1-20—C(═O)—NH;
• and
• Tm has a structure of Formula (VI),
• wherein R27 is independently selected from the group consisting of CH2—OH and C(═O)—OH;
• and
• provided that only one of R7, R13, or R14 is L1.