The influence of linker length on the properties of cathepsin S cleavable 177Lu-labeled HPMA copolymers for pancreatic cancer imaging

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymers have shown promise for application in the detection and staging of cancer. However, non-target accumulation, particularly in the liver and spleen, hinders the detection of resident or nearby metastatic lesions thereby decreasing diagnostic effectiveness. Our laboratory has pursued the development of cathepsin S susceptible linkers (CSLs) to reduce the non-target accumulation of diagnostic/radiotherapeutic HPMA copolymers. In this study, we ascertain if the length of the linking group impacts the cleavage and clearance kinetics, relative to each other and a non-cleavable control, due to a reduction in steric inhibition. Three different CSLs with linking groups of various lengths (0, 6 and 13 atoms) were conjugated to HPMA copolymers. Invitro cleavage studies revealed that the longest linking group (13 atoms) led to more rapid cleavage when challenged with cathepsin S. The CSL incorporated HPMA copolymers demonstrated significantly higher levels of excretion and a significant decrease in long-term hepatic and splenic retention relative to the non-cleavable control. Contrary to invitro observations, the length of the linking group did not substantially impact the non-target invivo clearance. In the case of HPAC tumor retention, the CSL with the null (0 atom) linker demonstrated significantly higher levels of retention relative to the other CSLs. Given these results, we find that the length of the linking group of the CSLs did not substantially impact non-target clearance, but did influence tumor retention. Overall, these results demonstrate that the CSLs can substantially improve the non-target clearance of HPMA copolymers thereby enhancing clinical potential.

Original languageEnglish (US)
Pages (from-to)5760-5770
Number of pages11
JournalBiomaterials
Volume35
Issue number22
DOIs
StatePublished - Jul 2014

Fingerprint

cathepsin S
Pancreatic Neoplasms
Copolymers
Imaging techniques
Atoms
Tumors
N-(2-hydroxypropyl)methacrylamide
Cathepsins
Neoplasm Staging
Liver

Keywords

  • Cathepsin S
  • Cleavable linker
  • HPMA
  • Mononuclear phagocyte system
  • Pancreatic cancer
  • SPECT/CT imaging

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

The influence of linker length on the properties of cathepsin S cleavable 177Lu-labeled HPMA copolymers for pancreatic cancer imaging. / Shi, Wen; Ogbomo, Sunny M.; Wagh, Nilesh K.; Zhou, Zhengyuan; Jia, Yinnong; Brusnahan, Susan K.; Garrison, Jered C.

In: Biomaterials, Vol. 35, No. 22, 07.2014, p. 5760-5770.

Research output: Contribution to journalArticle

Shi, Wen ; Ogbomo, Sunny M. ; Wagh, Nilesh K. ; Zhou, Zhengyuan ; Jia, Yinnong ; Brusnahan, Susan K. ; Garrison, Jered C. / The influence of linker length on the properties of cathepsin S cleavable 177Lu-labeled HPMA copolymers for pancreatic cancer imaging. In: Biomaterials. 2014 ; Vol. 35, No. 22. pp. 5760-5770.
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AU - Zhou, Zhengyuan

AU - Jia, Yinnong

AU - Brusnahan, Susan K.

AU - Garrison, Jered C

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AB - N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymers have shown promise for application in the detection and staging of cancer. However, non-target accumulation, particularly in the liver and spleen, hinders the detection of resident or nearby metastatic lesions thereby decreasing diagnostic effectiveness. Our laboratory has pursued the development of cathepsin S susceptible linkers (CSLs) to reduce the non-target accumulation of diagnostic/radiotherapeutic HPMA copolymers. In this study, we ascertain if the length of the linking group impacts the cleavage and clearance kinetics, relative to each other and a non-cleavable control, due to a reduction in steric inhibition. Three different CSLs with linking groups of various lengths (0, 6 and 13 atoms) were conjugated to HPMA copolymers. Invitro cleavage studies revealed that the longest linking group (13 atoms) led to more rapid cleavage when challenged with cathepsin S. The CSL incorporated HPMA copolymers demonstrated significantly higher levels of excretion and a significant decrease in long-term hepatic and splenic retention relative to the non-cleavable control. Contrary to invitro observations, the length of the linking group did not substantially impact the non-target invivo clearance. In the case of HPAC tumor retention, the CSL with the null (0 atom) linker demonstrated significantly higher levels of retention relative to the other CSLs. Given these results, we find that the length of the linking group of the CSLs did not substantially impact non-target clearance, but did influence tumor retention. Overall, these results demonstrate that the CSLs can substantially improve the non-target clearance of HPMA copolymers thereby enhancing clinical potential.

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