title: The influence of linker length on the properties of cathepsin S cleavable (177)Lu-labeled HPMA copolymers for pancreatic cancer imaging.
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. In vitro 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 in vitro observations, the length of the linking group did not substantially impact the non-target in vivo 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Wen
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Sunny M
authors.initials: SM
authors.lastname: Ogbomo
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Nilesh K
authors.initials: NK
authors.lastname: Wagh
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Yinnong
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Brusnahan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States; Eppley Cancer Center, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: jcgarrison@unmc.edu.
authors.forename: Jered C
authors.initials: JC
authors.lastname: Garrison
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008187:Lutetium / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D008689:Methacrylates / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D016513:Mice, SCID; D010179:Pancreas / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000175:diagnosis*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D008689:Methacrylates; D008187:Lutetium; D002403:Cathepsins; C028217:cathepsin S; C032802:hydroxypropyl methacrylate
keywords: Cathepsin S; Cleavable linker; HPMA; Mononuclear phagocyte system; Pancreatic cancer; SPECT/CT imaging
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