Cathepsin S-cleavable, multi-block HPMA copolymers for improved SPECT/CT imaging of pancreatic cancer.

Abstract

This work continues our efforts to improve the diagnostic and radiotherapeutic effectiveness of nanomedicine platforms by developing approaches to reduce the non-target accumulation of these agents. Herein, we developed multi-block HPMA copolymers with backbones that are susceptible to cleavage by cathepsin S, a protease that is abundantly expressed in tissues of the mononuclear phagocyte system (MPS). Specifically, a bis-thiol terminated HPMA telechelic copolymer containing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Three maleimide modified linkers with different sequences, including cathepsin S degradable oligopeptide, scramble oligopeptide and oligo ethylene glycol, were subsequently synthesized and used for the extension of the HPMA copolymers by thiol-maleimide click chemistry. All multi-block HPMA copolymers could be labeled by (177)Lu with high labeling efficiency and exhibited high serum stability. In vitro cleavage studies demonstrated highly selective and efficient cathepsin S mediated cleavage of the cathepsin S-susceptible multi-block HPMA copolymer. A modified multi-block HPMA copolymer series capable of Förster Resonance Energy Transfer (FRET) was utilized to investigate the rate of cleavage of the multi-block HPMA copolymers in monocyte-derived macrophages. Confocal imaging and flow cytometry studies revealed substantially higher rates of cleavage for the multi-block HPMA copolymers containing the cathepsin S-susceptible linker. The efficacy of the cathepsin S-cleavable multi-block HPMA copolymer was further examined using an in vivo model of pancreatic ductal adenocarcinoma. Based on the biodistribution and SPECT/CT studies, the copolymer extended with the cathepsin S susceptible linker exhibited significantly faster clearance and lower non-target retention without compromising tumor targeting. Overall, these results indicate that exploitation of the cathepsin S activity in MPS tissues can be utilized to substantially lower non-target accumulation, suggesting this is a promising approach for the development of diagnostic and radiotherapeutic nanomedicine platforms.

• Authors: Wei Fan, Wen Shi, Wenting Zhang, Yinnong Jia, Zhengyuan Zhou, Susan K Brusnahan, Jered C Garrison
• Journal: Biomaterials (Biomaterials) Vol. 103 Pg. 101-115 (10 2016) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 27372424 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Methacrylates
• Cathepsins
• cathepsin S
• hydroxypropyl methacrylate

Topics

• Animals
• Biomarkers, Tumor (chemistry)
• Cathepsins (chemistry)
• Cell Line, Tumor
• Female
• Humans
• Image Enhancement (methods)
• Methacrylates (chemistry)
• Mice
• Mice, SCID
• Pancreatic Neoplasms (chemistry, diagnostic imaging)
• Protein Binding
• Reproducibility of Results
• Sensitivity and Specificity
• Single Photon Emission Computed Tomography Computed Tomography (methods)
• Tissue Distribution