Melanoma therapy via peptide-targeted α-radiation

Purpose: The therapeutic efficacy of a unique melanoma-targeting peptide conjugated with an in vivo generated α-particle-emitting radionuclide was evaluated in the B16/F1 mouse melanoma animal model. α-Radiation is densely ionizing, resulting in high concentrations of destructive radicals and irreparable DNA double-strand breaks. This high linear energy transfer overcomes radiation-resistant tumor cells and oxygen effects resulting in potentially high therapeutic indices in tumors such as melanoma. Experimental Design: The melanoma targeting peptide, 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA)-Re(Arg¹¹)CCMSH, was radiolabeled with ²¹²Pb, the parent of ²¹²Bi, which decays via α and β decay. Biodistribution and therapy studies were done in the B16/F1 melanoma-bearing C57 mouse flank tumor model. Results: ²¹²Pb[DOTA]-Re(Arg ¹¹)CCMSH exhibited rapid tumor uptake and extended retention coupled with rapid whole body disappearance. Radiation dose delivered to the tumor was estimated to be 61 cGy/μCi ²¹²Pb administered. Treatment of melanoma-bearing mice with 50, 100, and 200 μCi of ²¹²Pb[DOTA]- Re(Arg¹¹)CCMSH extended their mean survival to 22, 28, and 49.8 days, respectively, compared with the 14.6-day mean survival of the placebo control group. Forty-five percent of the mice receiving 200 μCi doses survived the study disease-free. Conclusions: Treatment of B16/F1 murine melanoma-bearing mice with ²¹²Pb[DOTA]-Re(Arg¹¹)CCMSH significantly decreased tumor growth rates resulting in extended mean survival times, and in many cases, complete remission of disease. ²¹²Pb-DOTA-Re(Arg ¹¹)CCMSH seems to be a very promising radiopharmaceutical for targeted radionuclide therapy of melanoma.