177Lu-labeled HPMA copolymers utilizing cathepsin B and S cleavable linkers: Synthesis, characterization and preliminary in vivo investigation in a pancreatic cancer model

Sunny M. Ogbomo, Wen Shi, Nilesh K. Wagh, Zhengyuan Zhou, Susan K. Brusnahan, Jered C. Garrison

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Introduction: A major barrier to the advancement of therapeutic nanomedicines has been the non-target toxicity caused by the accumulation of the drug delivery systems in organs associated with the reticuloendothelial system, particularly the liver and spleen. Herein, we report the development of peptide based metabolically active linkers (MALs) that are enzymatically cleaved by cysteine cathepsin B and S, two proteases highly expressed in the liver and spleen. The overall goal of this approach is to utilize the MALs to lower the non-target retention and toxicity of radiolabeled drug delivery systems, thus resulting in higher diagnostic and radiotherapeutic efficacy. Methods: In this study three MALs (MAL0, MAL1 and MAL2) were investigated. MAL1 and MAL2 are composed of known substrates of cathepsin B and S, respectively, while MAL0 is a non-cleavable control. Both MAL1 and MAL2 were shown to undergo enzymatic cleavage with the appropriate cathepsin protease. Subsequent to conjugation to the HPMA copolymer and radiolabeling with 177Lu, the peptide-polymer conjugates were renamed 177Lu-metabolically active copolymers (177Lu-MACs) with the corresponding designations: 177Lu-MAC0, 177Lu-MAC1 and 177Lu-MAC2. Results: In vivo evaluation of the 177Lu-MACs was performed in an HPAC human pancreatic cancer xenograft mouse model. 177Lu-MAC1 and 177Lu-MAC2 demonstrated 3.1 and 2.1 fold lower liver retention, respectively, compared to control (177Lu-MAC0) at 72h post-injection. With regard to spleen retention, 177Lu-MAC1 and 177Lu-MAC2 each exhibited a nearly fourfold lower retention, relative to control, at the 72h time point. However, the tumor accumulation of the 177Lu-MAC0 was two to three times greater than 177Lu-MAC1 and 177Lu-MAC2 at the same time point. The MAL approach demonstrated the capability of substantially reducing the non-target retention of the 177Lu-labeled HPMA copolymers. Conclusions: While further studies are needed to optimize the pharmacokinetics of the 177Lu-MACs design, the ability of the MAL to significantly decrease non-target retention establishes the potential this avenue of research may have for the improvement of diagnostic and radiotherapeutic drug delivery systems.

Original languageEnglish (US)
Pages (from-to)606-617
Number of pages12
JournalNuclear Medicine and Biology
Issue number5
StatePublished - Jul 2013


  • Cathepsins
  • Cleavable linkers and pancreatic cancer
  • HPMA copolymers
  • Lutetium-177

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research


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