Journal article
Melanocortin 1 Receptor-Targeted α-Particle Therapy for Metastatic Uveal Melanoma
The Journal of nuclear medicine (1978), Vol.60(8), pp.1124-1133
08/2019
DOI: 10.2967/jnumed.118.217240
PMCID: PMC6681690
PMID: 30733316
Abstract
New effective therapies are greatly needed for metastatic uveal melanoma, which has a very poor prognosis with a median survival of less than 1 y. 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.
The
Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity and was tested in vitro for biostability and for MC1R-specific cytotoxicity in uveal melanoma cells, and the lanthanum-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 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.
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 (<15 min), renal and hepatobillary excretion, MC1R-specific tumor uptake, and minimal retention in other normal tissues. Radiation dosimetry calculations determined pharmacokinetics parameters and absorbed α-emission dosages from
Ac and its daughters. Efficacy studies demonstrated significantly prolonged survival and decreased metastasis burden after a single administration of
Ac-DOTA-MC1RL in treated mice relative to controls.
These results suggest significant potential for the clinical translation of
Ac-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma.
Details
- Title: Subtitle
- Melanocortin 1 Receptor-Targeted α-Particle Therapy for Metastatic Uveal Melanoma
- Creators
- Narges K Tafreshi - Moffitt Cancer CenterChristopher J Tichacek - University of South FloridaDarpan N Pandya - Wake Forest UniversityMichael L Doligalski - Moffitt Cancer CenterMikalai M Budzevich - Moffitt Cancer CenterHyunJoo Kil - Modulation TherapeuticsNikunj B Bhatt - Wake Forest UniversityNancy D Kock - Wake Forest UniversityJane L Messina - University of South FloridaEpifanio E Ruiz - Moffitt Cancer CenterNella C Delva - Moffitt Cancer CenterAdam Weaver - University of South FloridaWilliam R Gibbons - University of South FloridaDavid C Boulware - Moffitt Cancer CenterNikhil I Khushalani - Moffitt Cancer CenterGhassan El-Haddad - Moffitt Cancer CenterPierre L Triozzi - Wake Forest UniversityEduardo G Moros - Moffitt Cancer CenterMark L McLaughlin - Modulation TherapeuticsThaddeus J Wadas - Wake Forest UniversityDavid L Morse - Moffitt Cancer Center
- Resource Type
- Journal article
- Publication Details
- The Journal of nuclear medicine (1978), Vol.60(8), pp.1124-1133
- DOI
- 10.2967/jnumed.118.217240
- PMID
- 30733316
- PMCID
- PMC6681690
- ISSN
- 0161-5505
- eISSN
- 1535-5667
- Grant note
- U54 GM104942 / NIGMS NIH HHS P30 CA076292 / NCI NIH HHS
- Language
- English
- Date published
- 08/2019
- Academic Unit
- Radiology; Radiation Oncology
- Record Identifier
- 9984312961702771
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