Journal article
Biodistribution and Multicompartment Pharmacokinetic Analysis of a Targeted alpha Particle Therapy
Molecular pharmaceutics, Vol.17(11), pp.4180-4188
11/02/2020
DOI: 10.1021/acs.molpharmaceut.0c00640
PMID: 32960613
Abstract
Targeted alpha particle therapy (TAT) is ideal for treating disease while minimizing damage to surrounding non-targeted tissues due to short path length and high linear energy transfer (LET). We developed a TAT for metastatic uveal melanoma, targeting the melanocortin-1 receptor (MC1R), which is expressed in 94% of uveal melanomas. Two versions of the therapy are being investigated: Ac-225-DOTA-Ahx-MC1RL (Ac-226-Ahx) and Ac-225-DOTA-di-D-Glu-MCIRL (Ac-226-di-n-Glu). The biodistribution (BD) from each was studied and a multi-compartment pharmacokinetic (PK) model was developed to describe drug distribution rates. Two groups of 16 severe combined immunodeficient (SCID) mice bearing high MC1R expressing tumors were intravenously injected with Ac-225-Ahx or Ac-225-di-D-Glu. After injection, four groups (n = 4) were euthanized at 24, 96, 144, and 288 h time points for each cohort. Tumors and 13 other organs were harvested at each time point. Isomeric gamma spectra were measured in tissue samples using a scintillation gamma detector and converted to a activity using factors for gamma ray abundance per a decay. Time activity curves were calculated for each organ. A five-compartment PK model was built with the following compartments: blood, tumor, normal tissue, kidney, and liver. This model is characterized by a system of five ordinary differential equations using mass action kinetics, which describe uptake, intercompartmental transitions, and clearance rates. The ordinary differential equations were simultaneously solved and fit to experimental data using a genetic algorithm for optimization. The BD data show that both compounds have minimal distribution to organs at risk other than the kidney and liver. The PK parameter estimates had less than 5% error. From these data, Ac-225-Ahx showed larger and faster uptake in the liver. Both compounds had comparable uptake and clearance rates for other compartments. The BD and PK behavior for two targeted radiopharmaceuticals were investigated. The PK model fit the experimental data and provided insight into the kinetics of the compounds systematically.
Details
- Title: Subtitle
- Biodistribution and Multicompartment Pharmacokinetic Analysis of a Targeted alpha Particle Therapy
- Creators
- Christopher J. Tichacek - Moffitt Cancer CenterNarges K. Tafreshi - Moffitt Cancer CenterHyunJoo Kil - West Virginia UniversityRobert W. Engelman - University of South FloridaMichael L. Doligalski - Moffitt Cancer CenterMikalai M. Budzevich - University of South FloridaKenneth L. Gage - Moffitt Cancer CenterMark L. McLaughlin - Modulation TherapeuticsThaddeus J. Wadas - University of IowaAriosto Silva - Moffitt Cancer CenterEduardo Moros - Moffitt Cancer CenterDavid L. Morse - Moffitt Cancer Center
- Resource Type
- Journal article
- Publication Details
- Molecular pharmaceutics, Vol.17(11), pp.4180-4188
- DOI
- 10.1021/acs.molpharmaceut.0c00640
- PMID
- 32960613
- NLM abbreviation
- Mol Pharm
- ISSN
- 1543-8384
- eISSN
- 1543-8392
- Publisher
- Amer Chemical Soc
- Number of pages
- 9
- Grant note
- 402889 / Melanoma Research Alliance Team Science Award P30-CA076292 / Small Animal Imaging Laboratory shared resource at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center
- Language
- English
- Date published
- 11/02/2020
- Academic Unit
- Radiology; Radiation Oncology
- Record Identifier
- 9984313093002771
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