Comparative evaluation of novel177lu-labeled pna probes for affibody-mediated pna-based pretargeting

Hanna Tano, Maryam Oroujeni, Anzhelika Vorobyeva, Kristina Westerlund, Yongsheng Liu, Tianqi Xu, Daniel Vasconcelos, Anna Orlova, Amelie Eriksson Karlström, Vladimir Tolmachev

Research output: Contribution to journalArticlepeer-review

Abstract

Affibody-mediated PNA-based pretargeting is a promising approach to radionuclide therapy of HER2-expressing tumors. In this study, we test the hypothesis that shortening the PNA pretargeting probes would increase the tumor-to-kidney dose ratio. The primary probe ZHER2:342-SR-HP15 and the complementary secondary probes HP16, HP17, and HP18, containing 9, 12, and 15 nucleobases, respectively, and carrying a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator were designed, synthesized, characterized in vitro, and labeled with177Lu. In vitro pretargeting was studied in HER2-expressing SKOV3 and BT474 cell lines. The biodistribution of these novel probes was evaluated in immunodeficient mice bearing SKOV3 xenografts and compared to the previously studied [177Lu]Lu-HP2. Characterization confirmed the formation of high-affinity duplexes between HP15 and the secondary probes, with the affinity correlating with the length of the complementary PNA sequences. All the PNA-based probes were bound specifically to HER2-expressing cells in vitro. In vivo studies demonstrated HER2-specific uptake of all177Lu-labeled probes in xenografts in a pretargeting setting. The ratio of cumulated radioactivity in the tumor to the radioactivity in kidneys was dependent on the secondary probe’s size and decreased with an increased number of nucleobases. The shortest PNA probe, [177Lu]Lu-HP16, showed the highest tumor-to-kidney ratio. [177Lu]Lu-HP16 is the most promising secondary probe for affibody-mediated tumor pretargeting.

Original languageEnglish
Article number500
Pages (from-to)1-20
Number of pages20
JournalCancers
Volume13
Issue number3
DOIs
Publication statusPublished - 1 Feb 2021

Keywords

  • Affibody molecules
  • HER2-expressing xenografts
  • PNA
  • Pretargeting
  • Radionuclide therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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