Biodistribution and Clearance of Small Molecule Hapten Chelates for Pretargeted Radioimmunotherapy
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The favorable pharmacokinetics and clinical safety profile of metal-chelated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) suggests that it might be an ideal hapten for pretargeted radioimmunotherapy. In an effort to minimize hapten retention in normal tissues and determine the effect of various chemical adducts on in vivo properties, a series of DOTA-based derivatives were evaluated.
Biodistribution and whole-body clearance were evaluated for 177Lu-labeled DOTA, DOTA-biotin, a di-DOTA peptide, and DOTA-aminobenzene in normal CD1 mice. Kidney, liver, and bone marrow doses were estimated using standard Medical Internal Radiation Dose methodology.
All haptens demonstrated similar low tissue and whole-body retention, with 2–4% of the injected dose remaining in mice 4 h postinjection. The kidney is predicted to be dose limiting for all 177Lu-labeled haptens tested with an estimated kidney dose of approximately 0.1 mGy/MBq.
We present here a group of DOTA-based haptens that exhibit rapid clearance and exceptionally low whole-body retention 4 h postinjection. Aminobenzene, tyrosine–lysine, and biotin groups have minimal effects on the blood clearance and biodistribution of 177Lu-DOTA.
Key wordsPretargeted radioimmunotherapy DOTA Biodistribution Clearance Radiation dosimetry
The authors acknowledge Elaine P. Lunsford and Gaurav Gulati for technical assistance and Hak Soo Choi for helpful discussions. This work was supported by the Lewis Family Fund (JVF), National Institutes of Health grant R01-CA-101830 (KDW), and a National Science Foundation Graduate Research Fellowship (KDO).