Lipophilicity Determines Routes of Uptake and Clearance, and Toxicity of an Alpha-Particle-Emitting Peptide Receptor Radiotherapy

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 D7.4 values) by varying the chemical
properties of the linker. Reported are the observations that higher
log D7.4 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 D7.4 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.