Journal article
Lipophilicity Determines Routes of Uptake and Clearance, and Toxicity of an Alpha-Particle-Emitting Peptide Receptor Radiotherapy
ACS pharmacology & translational science, Vol.4(2), pp.953-965
03/12/2021
DOI: 10.1021/acsptsci.1c00035
PMCID: PMC8033749
PMID: 33860213
Abstract
Lipophilicity is explored in the
biodistribution (BD), pharmacokinetics
(PK), radiation dosimetry (RD), and toxicity of an internally administered
targeted alpha-particle therapy (TAT) under development for the treatment
of metastatic melanoma. The TAT conjugate is comprised of the chelator
DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), conjugated
to melanocortin receptor 1 specific peptidic ligand (MC1RL) using
a linker moiety and chelation of the
225
Ac radiometal.
A set of conjugates were prepared with a range of lipophilicities
(log
D
7.4
values) by varying the chemical
properties of the linker. Reported are the observations that higher
log
D
7.4
values are associated with decreased
kidney uptake, decreased absorbed radiation dose, and decreased kidney
toxicity of the TAT, and the inverse is observed for lower log
D
7.4
values. Animals administered TATs with lower
lipophilicities exhibited acute nephropathy and death, whereas animals
administered the highest activity TATs with higher lipophilicities
lived for the duration of the 7 month study and exhibited chronic
progressive nephropathy. Changes in TAT lipophilicity were not associated
with changes in liver uptake, dose, or toxicity. Significant observations
include that lipophilicity correlates with kidney BD, the kidney-to-liver
BD ratio, and weight loss and that blood urea nitrogen (BUN) levels
correlated with kidney uptake. Furthermore, BUN was identified as
having higher sensitivity and specificity of detection of kidney pathology,
and the liver enzyme alkaline phosphatase (ALKP) had high sensitivity
and specificity for detection of liver damage associated with the
TAT. These findings suggest that tuning radiopharmaceutical lipophilicity
can effectively modulate the level of kidney uptake to reduce morbidity
and improve both safety and efficacy.
Details
- Title: Subtitle
- Lipophilicity Determines Routes of Uptake and Clearance, and Toxicity of an Alpha-Particle-Emitting Peptide Receptor Radiotherapy
- Creators
- Narges K. Tafreshi - Moffitt Cancer CenterHyunJoo Kil - West Virginia UniversityDarpan N. Pandya - University of IowaChristopher J. Tichacek - Moffitt Cancer CenterMichael L. Doligalski - Moffitt Cancer CenterMikalai M. Budzevich - Moffitt Cancer CenterNella C. Delva - Moffitt Cancer CenterMichael L. Langsen - Moffitt Cancer CenterJohn A. Vallas - Moffitt Cancer CenterDavid C. Boulware - Moffitt Cancer CenterRobert W. Engelman - University of South FloridaKenneth L. Gage - Moffitt Cancer CenterEduardo G. Moros - University of South FloridaThaddeus J Wadas - University of IowaMark L. McLaughlin - Modulation TherapeuticsDavid L. Morse - University of South Florida
- Resource Type
- Journal article
- Publication Details
- ACS pharmacology & translational science, Vol.4(2), pp.953-965
- Publisher
- American Chemical Society
- DOI
- 10.1021/acsptsci.1c00035
- PMID
- 33860213
- PMCID
- PMC8033749
- ISSN
- 2575-9108
- eISSN
- 2575-9108
- Grant note
- name: Moffitt Radiology Pilot Award; name: NIH/NCI SBIR Phase 1 Contract to Modulation Therapeutics; name: Melanoma Research Alliance Team Science Award; name: H. Lee Moffitt Cancer Center & Research Institute an NCI designated Comprehensive Cancer Center, award: P30-CA076292
- Language
- English
- Date published
- 03/12/2021
- Academic Unit
- Radiology; Radiation Oncology
- Record Identifier
- 9984312976002771
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