Development of Improved Tumor-Residualizing, GRPR-Targeted Agents: Preclinical Comparison of an Endolysosomal Trapping Approach in Agonistic and Antagonistic Constructs

Wenting Zhang, Wei Fan, Brendan M. Ottemann, Sameer Alshehri, Jered C. Garrison

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Receptor-targeted radiopharmaceuticals based on low-molecular-weight carriers offer many clinically advantageous attributes relative to macromolecules but have generally been hampered by their rapid clearance from tumors, thus diminishing tumor-to-nontarget tissue ratios. Herein, we present a strategy using irreversible inhibitors (E-64 derivative) of cysteine cathepsins (CCs) as trapping agents to increase the tumor retention of receptor-targeted agents. Methods: We incorporated these CC-trapping agents into agonistic and antagonistic pharmacophores targeting the gastrin-releasing peptide receptor (GRPR). The synthesized radioconjugates with either an incorporated CC inhibitor or a matching control were examined using in vitro and in vivo models of the GRPR-positive, PC-3 human prostate cancer cell line. Results: From the in vitro studies, multiple techniques confirmed that the CC-trapping, GRPR-targeted constructs were able to increase cellular retention by forming intracellular macromolecule adducts. In PC-3 tumor-bearing xenograft mice, the CC-trapping, GRPR-targeted agonistic and antagonistic constructs led to an approximately 2-fold increase in tumor retention with a corresponding improvement in most tumor-to-nontarget tissue ratios over 72 h. Conclusion: CC endolysosomal trapping provides a pathway to increase the efficacy and clinical potential of low-molecular-weight, receptor-targeted agents.

Original languageEnglish (US)
Pages (from-to)443-450
Number of pages8
JournalJournal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume61
Issue number3
DOIs
StatePublished - Mar 1 2020

Keywords

  • GRPR-targeted peptides
  • SPECT/CT
  • agonists and antagonists
  • cysteine cathepsin inhibitor

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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