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

1. A cancer targeting composition comprising a molecule of Formula (I) or a pharmaceutically acceptable salt thereof:

M-Ch-L 1 -Tm,  Formula (I)

wherein:

M is 212 Pb or 203 Pb;

Ch is a chelator having a structure of Formula (V):

wherein:

R 5 , R 6 , and R 8 are each (C 1 -C 6 )alkyl-C(═O)—N(—R 25 )—R 26 ;

R 9 , R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 are each independently H, D, F, Cl, or (C 1 -C 6 )alkyl;

R 7 is (C 1 -C 6 )alkyl-C(═O)—N(—R 25 )—R 26 or L 1 ;

R 13 and R 14 are each independently H, D, F, Cl, (C 1 -C 6 )alkyl, or L 1 ;

R 25 and R 26 are each independently H, D, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl-C(═O)—OH;

L 1 is R(C 1 -C 6 )alkyl-C(═O)—NH—(C 1 -C 6 )alkyl-C(═O)—NH, (C 1 -C 6 )alkyl-(C 6 H 4 )—NH—C(═S)—NH, C(—CO 2 H)—(C 1 -C 6 )alkyl-(C 6 H 4 )—NH—C(═S)—NH, (C 1 -C 6 )alkyl-C(═O)—NH, or (C 1 -C 6 )alkyl-C(═O)—(O—CH 2 —CH 2 ) 1-20 —C(═O)—NH; and

Tm has a structure of Formula (VI):

wherein:

R 27 is CH 2 —OH or C(═O)—OH; and

(L 1 ) is L 1 and connects to Ch to Tm,

provided that only one of R 7 , R 13 , or R 14 is L 1 .

2. The cancer targeting composition of claim 1 , having a structure of Formula (VII) or a pharmaceutically acceptable salt thereof:

wherein:

M is 212 Pb or 203 Pb;

R 5 , R 6 , and R 8 are each independently (C 1 -C 6 )alkyl-C(═O)—N(—R 25 )—R 26 ;

R 9 , R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 are each independently H, D, F, Cl, or (C 1 -C 6 )alkyl;

R 13 and R 14 are each independently H, D, F, Cl, or (C 1 -C 6 )alkyl;

R 25 and R 26 are each independently H, D, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl-C(═O)—OH;

L 1 is (C 1 -C 6 )alkyl-C(═O)—NH—(C 1 -C 6 )alkyl-C(═O)—NH, (C 1 -C 6 )alkyl-(C 6 H 4 )—NH—C(═S)—NH, C(—CO 2 H)—(C 1 -C 6 )alkyl-(C 6 H 4 )—NH—C(═S)—NH, (C 1 -C 6 )alkyl-C(═O)—NH, or (C 1 -C 6 )alkyl-C(═O)—(O—CH 2 —CH 2 ) 1-20 —C(═O)—NH; and

R 27 is CH 2 —OH or C(═O)—OH.

3. The cancer targeting composition of claim 1 , having a structure of Formula (VIII) or a pharmaceutically acceptable salt thereof:

wherein:

M is 212 Pb or 203 Pb;

R 5 , R 6 , and R 8 are each independently (C 1 -C 6 )alkyl-C(═O)—N(—R 25 )—R 26 ;

R 9 , R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 are each independently H, D, F, Cl, or (C 1 -C 6 )alkyl;

R 7 is (C 1 -C 6 )alkyl-C(═O)—N(—R 25 )—R 26 ;

R 13 is H, D, F, Cl, or (C 1 -C 6 )alkyl;

R 25 and R 26 are each independently H, D, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl-C(═O)—OH;

L 1 is (C 1 -C 6 )alkyl-(C 6 H 4 )—NH—C(═S)—NH; and

R 27 is CH 2 —OH or C(═O)—OH.

4. The cancer targeting composition of claim 1 , having a structure of Formula (IX) or a pharmaceutically acceptable salt thereof:

wherein:

M is 212 Pb or 203 Pb;

R 5 , R 6 , and R 8 are each independently (C 1 -C 6 )alkyl-C(═O)—N(—R 25 )—R 26 ;

R 9 , R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 are each independently H, D, F, Cl, or (C 1 -C 6 )alkyl;

R 13 and R 14 are each independently H, D, F, Cl, or (C 1 -C 6 )alkyl;

R 25 and R 26 are each independently H, D, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl-C(═O)—OH; and

R 27 is CH 2 —OH or C(═O)—OH.

5. A cancer targeting kit for treatment of cancer cells overexpressing somatostatin receptors, the cancer targeting kit comprising:

the cancer targeting composition of claim 1 ; and

at least one of a pharmaceutically acceptable buffer, an antioxidant, and a scavenger.

6. The cancer targeting kit of claim 5 , which comprises 25 μg to 50 μg of the cancer targeting composition and 0.4M ammonium acetate buffer.

7. The cancer targeting kit of claim 5 , wherein the pharmaceutically acceptable buffer is an ammonium acetate buffer.

8. The cancer targeting kit of claim 5 , wherein the antioxidant is ascorbic acid, gentisic acid, ethanol, or a combination thereof.

9. The cancer targeting kit of claim 5 , wherein the scavenger is diethylenetriaminopentaacetic; ethylene diamine tetraacetic acid; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic; or a combination thereof.

10. A pharmaceutical formulation comprising the cancer targeting composition of claim 1 and a pharmaceutically acceptable buffer.

11. A method of 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:

M-Ch-L 1 -Tm,  Formula (I)

wherein:

M is 212 Pb or 203 Pb;

Ch is a chelator having a structure of Formula (V):

wherein:

R 5 , R 6 , and R 8 are each (C 1 -C 6 )alkyl-C(═O)—N(—R 25 )—R 26 ;

R 9 , R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 are each independently H, D, F, Cl, or (C 1 -C 6 )alkyl;

R 7 is (C 1 -C 6 )alkyl-C(═O)—N(—R 25 )—R 26 or L 1 ;

R 13 and R 14 are each independently H, D, F, Cl, (C 1 -C 6 )alkyl, or L 1 ;

R 25 and R 26 are each independently H, D, or (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl-C(═O)—OH;

L 1 is (C 1 -C 6 )alkyl-C(═O)—NH—(C 1 -C 6 )alkyl-C(═O)—NH, (C 1 -C 6 )alkyl-(C 6 H 4 )—NH—C(═S)—NH, C(—CO 2 H)—(C 1 -C 6 )alkyl-(C 6 H 4 )—NH—C(═S)—NH, (C 1 -C 6 )alkyl-C(═O)—NH, or (C 1 -C 6 )alkyl-C(═O)—(O—CH 2 —CH 2 ) 1-20 —C(═O)—NH;

Tm has a structure of Formula (VI):

wherein:

R 27 is CH 2 —OH or C(═O)—OH; and

(L 1 ) is L 1 and connects to Ch to Tm, provided that only one of R 7 , R 13 , or R 14 is L 1 .

12. The method of claim 11 , wherein the cancer comprises cells overexpressing somatostatin receptors.

13. The method of claim 11 , wherein the cancer is a cardiac cancer, a lung cancer, a gastrointestinal cancer, genitourinary tract cancer, a liver cancer, a bone cancer, a nervous system cancer, gynecological cancer, a hematologic cancer, or a combination thereof.

14. The method of claim 11 , wherein the subject is a mammal.

15. The method of claim 11 , wherein the cancer targeting composition is administered in combination with at least one anti-cancer compound, wherein the at least one anti-cancer compound is aldesleukin; alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; asparaginase; BCG Live; bexarotene; bleomycin; busulfan; calusterone; capecitabine; carboplatin; carmustine; carmustine with polifeprosan 20 implant; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin, actinomycin D; darbepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin; denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; dromostanolone propionate; Elliott's B Solution; epirubicin; epoetin alfa estramustine; etoposide; exemestane; filgrastim; floxuridine; fludarabine; 5-fluorouracil; fulvestrant; gemcitabine; gemtuzumab ozogamicin; imatinib; goserelin; hydroxyurea; ibritumomab tiuxetan; idarubicin; ifosfamide; imatinib mesylate; interferon alfa-2a; interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine; mechlorethamine; megestrol; melphalan; 6-mercaptopurine; mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nofetumomab; LOddC; oprelvekin; oxaliplatin; paclitaxel; pamidronate; pegademase; pegaspargase; pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; rasburicase; rituximab; sargramostim; streptozocin; surafenib; talbuvidine; talc; tamoxifen; erlotinib; temozolomide; teniposide; testolactone; 6-thioguanine; thiotepa; topotecan; toremifene; tositumomab; trastuzumab; tretinoin; uracil mustard; valrubicin; valtorcitabine; vinblastine; vinorelbine; zoledronate; or a mixture thereof.

16. The method of claim 15 , wherein the anti-cancer compound is administered in a therapeutically effective dosage.

17. A method of 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,

M-Ch-L 1 -Tm,  Formula (I)

wherein:

M is 212 Pb or 203 Pb;

Ch is a chelator having a structure of Formula (V):

wherein

R 5 , R 6 , and R 8 are each (C 1 -C 6 )alkyl-C(═O)—N(—R 25 )—R 26 ;

R 9 , R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 are each independently H, D, F, Cl, or (C 1 -C 6 )alkyl;

R 7 is (C 1 -C 6 )alkyl-C(═O)—N(—R 25 )—R 26 or L 1 ;

R 13 and R 14 are each independently H, D, F, Cl, (C 1 -C 6 )alkyl, or L 1 ;

R 25 and R 26 are each independently H, D, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl-C(═O)—OH;

L 1 is (C 1 -Q)alkyl-C(═O)—NH—(C 1 -C 6 )alkyl-C(═O)—NH, (C 1 -C 6 )alkyl-(C 6 H 4 )—NH—C(═S)—NH, C(—CO 2 H)—(C 1 -C 6 )alkyl-(C 6 H 4 )—NH—C(═S)—NH, (C 1 -C 6 )alkyl-C(═O)—NH, or (C 1 -C 6 )alkyl-C(═O)—(O—CH 2 —CH 2 ) 1-20 —C(═O)—NH; and

Tm has a structure of Formula (VI):

wherein:

R 27 is CH 2 —OH or C(═O)—OH; and

(L 1 ) is L 1 and connects to Ch to Tm,

provided that only one of R 7 , R 13 , or R 14 is L 1 .

18. The method of claim 17 , wherein the at least one anti-cancer compound is aldesleukin; alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; asparaginase; BCG Live; bexarotene; bleomycin; busulfan; calusterone; capecitabine; carboplatin; carmustine; carmustine with polifeprosan 20 implant; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin, actinomycin D; darbepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin; denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; dromostanolone propionate; Elliott's B Solution; epirubicin; epoetin alfa estramustine; etoposide; exemestane; filgrastim; floxuridine; fludarabine; 5-fluorouracil; fulvestrant; gemcitabine; gemtuzumab ozogamicin; imatinib; goserelin; hydroxyurea; ibritumomab tiuxetan; idarubicin; ifosfamide; imatinib mesylate; interferon alfa-2a; interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine; mechlorethamine; megestrol; melphalan; 6-mercaptopurine; mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; nofetumomab; LOddC; oprelvekin; oxaliplatin; paclitaxel; pamidronate; pegademase; pegaspargase; pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; rasburicase; rituximab; sargramostim; streptozocin; surafenib; talbuvidine; talc; tamoxifen; erlotinib; temozolomide; teniposide; testolactone; 6-thioguanine; thiotepa; topotecan; toremifene; tositumomab; trastuzumab; tretinoin; uracil mustard; valrubicin; valtorcitabine; vinblastine; vinorelbine; zoledronate; or a combination or a mixture thereof.

19. The method of claim 18 , wherein the at least one anti-cancer compound is administered in a therapeutically effective dosage.

20. The cancer targeting composition of claim 2 , having the structure represented by the following Formula:

21. The cancer targeting composition of claim 3 , having the structure represented by the following Formula:

22. The method of claim 14 , wherein the mammal is a dog, a cat, or a horse.