Yubin Miao

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(Arg11)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(Arg11)CCMSH seems to be a very promising radiopharmaceutical for targeted radionuclide therapy of melanoma.

In vivo evaluation of 188Re-labeled alpha-melanocyte stimulating hormone peptide analogs for melanoma therapy

The purpose of our study was to optimize melanoma tumor uptake of 188Re‐CCMSH and reduce its nonspecific kidney retention. Nephrotoxicity is often a serious problem associated with targeted radiotherapy, therefore, increasing the tumor/kidney uptake ratio of 188Re‐CCMSH is crucial for optimizing its therapeutic efficacy. Structural modification of the peptide and amino acid co‐infusion were investigated as strategies to improve the tumor/kidney uptake ratio of 188Re‐CCMSH. The substitution of Lys 11 with Arg 11 was examined to determine if removal of lysine from the peptide would improve kidney clearance without sacrificing tumor uptake. The pharmacokinetics of 188Re‐CCMSH and 188Re‐(Arg11)CCMSH were determined in B16/F1 murine melanoma‐bearing C57 mice. Tumor uptake values of 188Re‐CCMSH and 188Re‐(Arg11)CCMSH were 15.03 ± 5.20% ID/g and 20.44 ± 1.91% ID/g at 1 hr postinjection and 1.94 ± 0.47% ID/g and 3.50 ± 2.32% ID/g at 24 hr postinjection. Renal retention of 188Re‐(Arg11)CCMSH was 11.79 ± 1.29 ID/g and 3.67 ± 0.51 ID/g at 1 hr and 4 hr postinjection, which was a greater than 50% reduction compared to 188Re‐CCMSH. The Arg for Lys substitution in 188Re‐(Arg11)CCMSH resulted in improved tumor uptake and reduced kidney retention. Renal retention of both 188Re‐CCMSH and 188Re‐(Arg11)CCMSH were significantly reduced by co‐injection of 20 mg of L‐lysine, L‐arginine and a combination of L‐lysine:L‐arginine. Tumor/kidney uptake values for 188Re‐CCMSH and 188Re‐(Arg11)CCMSH were maximally reduced by 52.9% and 46.3%, respectively. However, even with amino acid co‐injection, the tumor/kidney ratio of 188Re‐CCMSH was lower than that of 188Re‐(Arg11)CCMSH. Improved tumor uptake and reduced kidney retention of 188Re‐(Arg11)CCMSH will facilitate targeted irradiation of melanoma tumors while minimizing the dose to the kidneys.

α–melanocyte‐stimulating hormone peptide analogs labeled with technetium‐99m and indium‐111 for malignant melanoma targeting

Previous studies have shown that the compact structure of a rhenium‐cyclized α–melanocyte‐stimulating hormone peptide analog, [Cys 3 , 4 , 10 ,D‐Phe 7 ]α‐MSH3–13, or Re‐CCMSH, significantly enhanced its in vivo tumor uptake and retention. In this study, the metal chelate 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) was coupled to the N‐terminus of Re‐CCMSH in order to develop a melanoma‐targeting peptide that could be labeled with a wider variety of imaging and therapeutic radionuclides.