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Biodistribution and Clearance of Small Molecule Hapten Chelates for Pretargeted Radioimmunotherapy

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Abstract

Purpose

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.

Procedures

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.

Results

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.

Conclusions

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.

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Acknowledgments

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).

Author information

Authors and Affiliations

  1. Department of Chemical Engineering, Massachusetts Institute of Technology, 400 Main Street E19-551, Cambridge, MA, 02139, USA

    Kelly Davis Orcutt & K. Dane Wittrup

  2. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    K. Dane Wittrup

  3. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    K. Dane Wittrup

  4. Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA

    Khaled A. Nasr, David G. Whitehead & John V. Frangioni

  5. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA

    John V. Frangioni

Authors
  1. Kelly Davis Orcutt
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  2. Khaled A. Nasr
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  3. David G. Whitehead
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  4. John V. Frangioni
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  5. K. Dane Wittrup
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Corresponding author

Correspondence to K. Dane Wittrup.

Additional information

Significance:

We present here a quantitative in vivo analysis of four 177Lu-labeled DOTA-based small molecules in an effort to determine what form(s) of the DOTA chelate result in the fastest clearance and lowest tissue retention for pretargeted radioimmunotherapy applications and also to determine how various chemical moieties affect in vivo behavior of small molecules.

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Orcutt, K.D., Nasr, K.A., Whitehead, D.G. et al. Biodistribution and Clearance of Small Molecule Hapten Chelates for Pretargeted Radioimmunotherapy. Mol Imaging Biol 13, 215–221 (2011). https://doi.org/10.1007/s11307-010-0353-6

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  • DOI: https://doi.org/10.1007/s11307-010-0353-6

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