TY - JOUR
T1 - In vitro and in vivo evaluation of melanin-binding decapeptide 4B4 radiolabeled with 177Lu, 166Ho, and 153Sm radiolanthanides for the purpose of targeted radionuclide therapy of melanoma
AU - Ballard, Beau
AU - Jiang, Zewei
AU - Soll, Clifford E.
AU - Revskaya, Ekaterina
AU - Cutler, Cathy S.
AU - Dadachova, Ekaterina
AU - Francesconi, Lynn C.
PY - 2011/10/1
Y1 - 2011/10/1
N2 - Melanoma is a malignancy with increasing incidence. Although primary tumors that are localized to the skin can be successfully treated by surgical removal, there is no satisfactory treatment for metastatic melanoma, a condition that has currently an estimated 5-year survival of just 6%. During the last decade, β-or α-emitter-radiolabeled peptides that bind to different receptors on a variety of tumors have been investigated as potential therapeutic agents in both the preclinical and clinical settings with encouraging results. A recent study demonstrated that 188-Rhenium ( 188Re)-labeled, via HYNIC ligand, fungal melanin-binding decapeptide 4B4 was effective against experimental MNT1 human melanoma and was safe to normal melanized tissues. The availability of radiolanthanides with diverse nuclear emission schemes and half-lives provides an opportunity to expand the repertoire of peptides for radionuclide therapy of melanoma. The melanin-binding decapeptide 4B4 was radiolabeled with 177Lu, 166Ho, and 153Sm via a DO3A chelate. The stability studies of Ln*-DO3A-4B4 in phosphate-buffered saline, serum, and a hydroxyapatite assay demonstrated that 177Lu-labeled peptide was more stable than 166Ho-and 153Sm-labeled peptides, most likely because of the smallest ionic radius of the former allowing for better complexation with DO3A. Binding of Ln*-DO3A-4B4 to the lysed highly melanized MNT1 melanoma cells demonstrated the specificity of peptides binding to melanin. In vivo biodistribution data for 177Lu-DO3A-4B4 given by intraperitoneal administration to lightly pigmented human metastatic A2058 melanoma-bearing mice demonstrated very high uptake in the kidneys and low tumor uptake. Intravenous administration did not improve the tumor uptake. The plausible explanation of low tumor uptake of 177Lu-DO3A-4B4 could be its decreased ability to bind to melanin during in vitro binding studies in comparison with 188Re-HYNIC-4B4, exacerbated by the very fast clearance from the blood and the kidneys "sink" effect.
AB - Melanoma is a malignancy with increasing incidence. Although primary tumors that are localized to the skin can be successfully treated by surgical removal, there is no satisfactory treatment for metastatic melanoma, a condition that has currently an estimated 5-year survival of just 6%. During the last decade, β-or α-emitter-radiolabeled peptides that bind to different receptors on a variety of tumors have been investigated as potential therapeutic agents in both the preclinical and clinical settings with encouraging results. A recent study demonstrated that 188-Rhenium ( 188Re)-labeled, via HYNIC ligand, fungal melanin-binding decapeptide 4B4 was effective against experimental MNT1 human melanoma and was safe to normal melanized tissues. The availability of radiolanthanides with diverse nuclear emission schemes and half-lives provides an opportunity to expand the repertoire of peptides for radionuclide therapy of melanoma. The melanin-binding decapeptide 4B4 was radiolabeled with 177Lu, 166Ho, and 153Sm via a DO3A chelate. The stability studies of Ln*-DO3A-4B4 in phosphate-buffered saline, serum, and a hydroxyapatite assay demonstrated that 177Lu-labeled peptide was more stable than 166Ho-and 153Sm-labeled peptides, most likely because of the smallest ionic radius of the former allowing for better complexation with DO3A. Binding of Ln*-DO3A-4B4 to the lysed highly melanized MNT1 melanoma cells demonstrated the specificity of peptides binding to melanin. In vivo biodistribution data for 177Lu-DO3A-4B4 given by intraperitoneal administration to lightly pigmented human metastatic A2058 melanoma-bearing mice demonstrated very high uptake in the kidneys and low tumor uptake. Intravenous administration did not improve the tumor uptake. The plausible explanation of low tumor uptake of 177Lu-DO3A-4B4 could be its decreased ability to bind to melanin during in vitro binding studies in comparison with 188Re-HYNIC-4B4, exacerbated by the very fast clearance from the blood and the kidneys "sink" effect.
KW - cancer
KW - melanoma
KW - radioimmunotherapy
KW - radiopharmaceuticals
KW - targeted therapy
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U2 - 10.1089/cbr.2011.0954
DO - 10.1089/cbr.2011.0954
M3 - Article
C2 - 21970319
AN - SCOPUS:80054696854
SN - 1084-9785
VL - 26
SP - 547
EP - 556
JO - Cancer Biotherapy and Radiopharmaceuticals
JF - Cancer Biotherapy and Radiopharmaceuticals
IS - 5
ER -