Pharmacokinetic variability of in vivo generated 213Bi and vector labeled 225Ac in murine cancer models

Since the approval of Xofigo® (223Ra-dichloride) against metastatic castrated resistant prostate cancer by the FDA, there has been a growing interest in α-particle emitting radiopharmaceutical therapy (αRPT). Actinium-225 is one of the α-particle emitters of interest in αRPT with a physical half-life of 10 days and a total net emission of four α-particles in its decay chain (221Fr: T1/2=4.9 min; 217At: T1/2=32.3 ms; 213Bi: T1/2=45.6 min; and 213Po: T1/2=4.2 μs). Using a chelator (e.g. DOTA) makes it possible to label 225Ac with different vectors (e.g. antibodies or small molecules), which can be used to target different types of cancers. The chemical bond between the chelator and the 225Ac atom is relatively weak (~10 eV) and is broken when the α-particle is emitted from the 225Ac atom due to the high recoil energy (~100 keV). Consequently the 225Ac decay daughters are not bound to the vector and are free to relocate in the in vivo system. Depending on the vector’s pharmacokinetics there will be different normal tissue uptake of vector labeled 225Ac. This suggests that depending on vector type the unbound decay daughters are present in different tissues at different concentrations able to redistribute within the in vivo system.

JOSEFSSON Anders;  NEDROW Jessie;  RAY Sangeeta;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  POMPER Martin;  SGOUROS G.;  HOBBS Robert F.; 

2019-07-24

ELSEVIER BV

JRC116462

1939-8654 (online),   

https://publications.jrc.ec.europa.eu/repository/handle/JRC116462,   

10.1016/j.jmir.2019.03.088 (online),