Enhanced tumor retention of NTSR1-targeted agents by employing a hydrophilic cysteine cathepsin inhibitor

Wei Fan, Wenting Zhang, Sameer Alshehri, Trey R. Neeley, Jered C. Garrison

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


We explored the approach of using an analog of E−64, a well-known and hydrophilic cysteine cathepsin (CC)inhibitor, as a potent cysteine cathepsin-trapping agent (CCTA)to improve the tumor retention of low-molecular-weight, receptor-targeted radiopharmaceuticals. The synthesized hydrophilic CCTA-incorporated, NTSR1-targeted agents demonstrated a substantial increase in cellular retention upon uptake into the NTRS1-positive HT-29 human colon cancer cell line. Similarly, biodistribution studies using HT-29 xenograft mice revealed a significant and substantial increase in tumor retention for the CCTA-incorporated, NTSR1-targeted agent. The intracellular trapping mechanism of the CCTA-incorporated agents by macromolecular adduct formation was confirmed using multiple in vitro and in vivo techniques. Furthermore, utilization of the more hydrophilic CCTA greatly increased the hydrophilicity of the resulting NTSR1-targeted constructs leading to substantial decreases in most non-target tissues in contrast to our previously reported dipeptidyl acyloxymethyl ketone (AOMK)constructs. This work further confirms that the CCTA trapping approach can make significant improvements in the clinical potential of NTSR1-and other receptor-targeted radiopharmaceuticals.

Original languageEnglish (US)
Pages (from-to)386-400
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
StatePublished - Sep 1 2019


  • Cysteine cathepsin inhibitor
  • E−64 analogue
  • NTSR1
  • Radiopharmaceutical
  • Trapping agent
  • Tumor retention

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


Dive into the research topics of 'Enhanced tumor retention of NTSR1-targeted agents by employing a hydrophilic cysteine cathepsin inhibitor'. Together they form a unique fingerprint.

Cite this