Lipophilicity Determines Routes of Uptake and Clearance, and Toxicity of an Alpha-Particle-Emitting Peptide Receptor Radiotherapy
Narges K Tafreshi, HyunJoo Kil, Darpan N Pandya, Christopher J Tichacek, Michael L Doligalski, Mikalai M Budzevich, Nella C Delva, Michael L Langsen, John A Vallas, David C Boulware, Robert W Engelman, Kenneth L Gage, Eduardo G Moros, Thaddeus J Wadas, Mark L McLaughlin, David L Morse, Narges K Tafreshi, HyunJoo Kil, Darpan N Pandya, Christopher J Tichacek, Michael L Doligalski, Mikalai M Budzevich, Nella C Delva, Michael L Langsen, John A Vallas, David C Boulware, Robert W Engelman, Kenneth L Gage, Eduardo G Moros, Thaddeus J Wadas, Mark L McLaughlin, David L Morse
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 225Ac 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.
Conflict of interest statement
The authors declare the following competing financial interest(s): D.L.M. and N.K.T. are co-inventors of an awarded patent. D.L.M., T.J.W., M.L.M., H.K., and N.K.T. are co-inventors on a pending patent application. Modulation Therapeutics, Inc., has licensed related intellectual property, and M.L.M. is a co-founder of that company.
© 2021 American Chemical Society.
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Source: PubMed