Publication date: Feb 07, 2019
New effective therapies are greatly needed for metastatic uveal melanoma which has a very poor prognosis with a median survival of less than one year. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases, and a MC1R specific ligand (MC1RL) with high affinity and selectivity for MC1R was previously developed. Methods: The Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity, tested in vitro for biostability, MC1R-specific cytotoxicity in uveal melanoma cells, and the La-DOTA-MC1RL analog was tested for binding affinity. Non-tumor bearing BALB/c mice were tested for maximum tolerated dose and biodistribution. Severe combined immunodeficient (SCID) mice bearing uveal melanoma tumors, or engineered MC1R positive and negative tumors were studied for biodistribution and efficacy. Radiation dosimetry was calculated using mouse biodistribution data and blood clearance kinetics from Sprague-Dawley rat data. Results: High biostability, MC1R-specific cytotoxicity and high binding affinity were observed. Limiting toxicities were not observed at even the highest administered activities. Pharmacokinetics and biodistribution studies revealed rapid blood clearance (
Tafreshi, N.K., Tichacek, C.J., Pandya, D.N., Doligalski, M.L., Budzevich, M.M., Kil, H., Bhatt, N.B., Kock, N.D., Messina, J.L., Ruiz, E.E., Delva, N.C., Weaver, A., Gibbons, W.R., Boulware, D.C., Khushalani, N.I., El-Haddad, G., Triozzi, P.L., Moros, E.G., McLaughlin, M.L., Wadas, T., and Morse, D. Melanocortin 1 Receptor Targeted Alpha-Particle Therapy for Metastatic Uveal Melanoma. 21638. 2019 J Nucl Med.
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