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Dual Radionuclide Theranostic Pretargeting.

Outi Keinänen1, James M Brennan1, Rosemery Membreno1,2

  • 1Department of Chemistry , Hunter College, City University of New York , New York , New York 10021 , United States.

Molecular Pharmaceutics
|September 5, 2019
PubMed
Summary

This study introduces a novel in vivo pretargeting strategy for nuclear theranostics using bioorthogonal chemistry. This method enables simultaneous pretargeted PET imaging and radiotherapy with matched radioligands, improving tumor targeting and reducing off-target effects.

Keywords:
A33 antigenPETbioorthogonal chemistryclick chemistrycolorectal cancerhuA33inverse electron demand Diels−Alder reactionmultistep targetingpositron emission tomographypretargeted radioimmunotherapypretargetingtetrazinetheranosticstrans-cyclooctene

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Area of Science:

  • Nuclear medicine
  • Radiochemistry
  • Oncology

Background:

  • Nuclear theranostics combines diagnostic imaging and targeted radiotherapy using matched radiopharmaceuticals.
  • In vivo pretargeting strategies aim to improve the efficacy and safety of radiotherapeutics by separating the targeting and effector functions.

Purpose of the Study:

  • To extend the concept of nuclear theranostics to in vivo pretargeting using a bioorthogonal inverse electron demand Diels-Alder reaction.
  • To demonstrate a platform for pretargeted PET imaging and radiotherapy using a single immunoconjugate and sequential administration of radioligands.

Main Methods:

  • Utilized the bioorthogonal inverse electron demand Diels-Alder reaction between tetrazine (Tz) and trans-cyclooctene (TCO).
  • Developed a TCO-modified immunoconjugate (huA33-TCO) targeting the A33 antigen.
  • Administered [64Cu]Cu-SarAr-Tz for PET imaging and [177Lu]Lu-DOTA-PEG7-Tz for radiotherapy sequentially in a mouse model of colorectal carcinoma.

Main Results:

  • Achieved high activity concentrations of both radioligands in tumor tissue.
  • Demonstrated promising tumor-to-healthy organ activity concentration ratios.
  • Successfully applied the pretargeting strategy for both diagnostic imaging and radiotherapy.

Conclusions:

  • The developed in vivo pretargeting platform shows significant potential for nuclear theranostics.
  • This approach could enable precise delivery of fractionated doses in pretargeted radioimmunotherapy.
  • The use of isotopologue-based radioligand pairs, such as [64Cu]Cu-SarAr-Tz and [67Cu]Cu-SarAr-Tz, offers exciting possibilities for future theranostic applications.