New treatments for metastatic uveal melanoma are needed because it has a median overall survival of 6-10 months. In our previous studies, we have developed a targeted alpha-particle therapy (TAT) against metastatic uveal melanoma by conjugating 225Ac-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) to MC1R-specific peptide ligand (MC1RL) and demonstrated significantly prolonged survival and decreased metastasis burden in in vivo studies. We also have observed 225Ac-DOTA-MC1RL was cleared through the liver from in vivo studies. In order to potentially optimize pharmacokinetic properties of the targeted peptide ligand, we have synthesized a series of targeted ligands with diverse linkers such as glutamic acid (Glu) and lysine (Lys) and measured log D7.4 of each targeted peptide ligand chelated with 139La as a non-radioactive surrogate for 225Ac. We also performed in vivo biodistribution (BD) studies of all the targeted peptide ligands with 225Ac-DOTA to determine the clearance routes. The biodistribution (BD) data from ex vivo gamma spectroscopy of a range of tissues, including kidney and liver was compared to log D7.4 data obtained from the shake-flask assay using LC-MS (liquid chromatography-mass spectrometry) with the 139La chelate. We found the route of clearance of each conjugate correlated to their relative hydrophilicities, with lower LogD7.4 values clearing primarily by the renal route and higher values by the hepatic route. This is important because essentially only the targeted tumor and clearance organs receive any significant radiation dose and linker selection can be adjusted to control predominant clearance radiation dosage.

La-DOTA-melanocortin 1 recector targeting ligand clearance route is controlled by linker polarity

2019 Spring National Meeting

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