Program Information
Dosimetry of a Novel Targeted Alpha Particle Therapy for Metastatic Uveal Melanoma
Christopher J. Tichacek1,3*, Narges K. Tafreshi2 , Michael L. Doligalski2 , Mikalai M. Budzevich4 , Epi Ruiz4 , Nella C. Delva2 , Thaddeus J. Wadas6 , Mark L. McLaughlin5 , David L. Morse1,2 , Eduardo G. Moros1,2,3 , University of South Florida, (1) Department of Physics, Medical Physics, Tampa, FL; H. Lee Moffitt Cancer Center & Research Institute, (2) Department of Cancer Imaging and Metabolism, (3) Radiation Oncology, and (4) Small Animal Imaging Core, Tampa, FL; West Virginia University, Health Sciences Center, (5) Department of Pharmaceutical Sciences, Morgantown, WV; and (6) Wake Forest School of Medicine, Departments of Radiology and Cancer Biology, Winston-Salem, NC.
Presentations
SU-J-CAMPUS-TT-5 (Sunday, July 30, 2017) 4:00 PM - 5:00 PM Room: Therapy ePoster Theater
Purpose: The melanocortin-1 receptor (MC1R) is expressed in 94% of uveal melanomas and is described as an ideal target for this untreatable disease. MC1RL is a high affinity MC1R specific peptidomimetic ligand that can serve as a scaffold for therapeutic conjugates such as alpha particle emitting isotopes. The purpose of this in-vivo study was to assess the absorbed dose to high expressing MC1R tumors and the risk to other organs as a result of using the DOTA chelator conjugated to MC1RL to deliver ²²⁵Ac: [²²⁵Ac]Ac-DOTA-Ahx-MC1RL.
Methods: 18 SCID mice bearing bilateral A375 human melanoma tumors, one with low endogenous MC1R expression and the other with high engineered MC1R expression, were intravenously injected with 4 μCi of [²²⁵Ac]Ac-DOTA-Ahx-MC1RL. After injection, four groups of animals were euthanized at 24, 96, 144 and 288 hour time points. The low- and high- expressing tumors were harvested at each time point as well as 13 other organs of interest. The isomeric gamma spectra were measured in the tissue samples using an Atomlabᵀᴹ Gamma Counter (Biodex Medical Systems, Inc.) and converted to alpha activity using factors for gamma ray abundance per alpha decay. Dosimetry was performed for each gamma emitting daughter using measured radioactivity distribution in organs and the generalized internal dosimetry schema of MIRD pamphlet #21.
Results: Calculations showed that tumors with high MC1R expression had a 10X larger total absorbed dose per administered activity at 0.41Gy/μCi compared to the low expressing tumors at 0.04Gy/μCi. Clearance organs of interest, liver and kidneys, had 2.8 Gy/μCi and 0.68 Gy/μCi respectively. All other non-clearance organs had negligible doses. All animals gained weight over the study period and no organ damage was observed by pathology.
Conclusion: Based on above results, the [²²⁵Ac]Ac-DOTA-Ahx-MC1RL radiopharmaceutical is effective in delivering a large dose to MC1R expressing tumors while sparing other organs.
Funding Support, Disclosures, and Conflict of Interest: Funding: Melanoma Research Alliance Team Science Award, NIH/NCI SBIR Phase I, NIH/NCI P50, Moffitt Skin SPORE Career enhancement Program, Moffitt Imaging and Technology COE funds. Disclosures and Conflict of Interest: This work has been performed in part, in collaboration with Modulation Therapeutics Inc.
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