title: Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers.
abstract: N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers have been studied as an efficient carrier for drug delivery and tumor imaging. However, as with many macromolecular platforms, the substantial accumulation of HPMA copolymer by the mononuclear phagocyte system (MPS)-associated tissues, such as the blood, liver, and spleen, has inhibited its clinical translation. Our laboratory is pursuing approaches to improve the diagnostic and radiotherapeutic effectiveness of HPMA copolymers by reducing the nontarget accumulation. Specifically, we have been investigating the use of a cathepsin S (Cat S)-cleavable peptidic linkers to degrade multiblock HPMA copolymers to increase MPS-associated tissue clearance. In this study, we further our investigation into this area by exploring the impact of copolymer block size on the biological performance of Cat S-degradable HPMA copolymers. Using a variety of in vitro and in vivo techniques, including dual labeling of the copolymer and peptide components, we investigated the constructs using HPAC pancreatic ductal adenocarcinoma models. The smaller copolymer block size (S-CMP) demonstrated significantly faster Cat S cleavage kinetics relative to the larger system (L-CMP). Confocal microscopy demonstrated that both constructs could be much more efficiently internalized by human monocyte-differentiated macrophage (hMDM) compared to HPAC cells. In the biodistribution studies, the multiblock copolymers with a smaller block size exhibited faster clearance and lower nontarget retention while still achieving good tumor targeting and retention. Based on the radioisotopic ratios, fragmentation and clearance of the copolymer constructs were higher in the liver compared to the spleen and tumor. Overall, these results indicate that block size plays an important role in the biological performance of Cat S-degradable polymeric constructs.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Center for Drug Delivery and Nanomedicine, ∥Department of Biochemistry and Molecular Biology, College of Medicine, and ⊥Eppley Cancer Center, University of Nebraska Medical Center , Omaha, Nebraska 985830, United States.
authors.forename: Wei
authors.identifier: 0000-0001-5893-6045
authors.initials: W
authors.lastname: Fan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Center for Drug Delivery and Nanomedicine, ∥Department of Biochemistry and Molecular Biology, College of Medicine, and ⊥Eppley Cancer Center, University of Nebraska Medical Center , Omaha, Nebraska 985830, United States.
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Center for Drug Delivery and Nanomedicine, ∥Department of Biochemistry and Molecular Biology, College of Medicine, and ⊥Eppley Cancer Center, University of Nebraska Medical Center , Omaha, Nebraska 985830, United States.
authors.forename: Yinnong
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Center for Drug Delivery and Nanomedicine, ∥Department of Biochemistry and Molecular Biology, College of Medicine, and ⊥Eppley Cancer Center, University of Nebraska Medical Center , Omaha, Nebraska 985830, United States.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Brusnahan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, ‡Center for Drug Delivery and Nanomedicine, ∥Department of Biochemistry and Molecular Biology, College of Medicine, and ⊥Eppley Cancer Center, University of Nebraska Medical Center , Omaha, Nebraska 985830, United States.
authors.forename: Jered C
authors.identifier: 0000-0002-8376-9821
authors.initials: JC
authors.lastname: Garrison
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D008689:Methacrylates / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D010190:Pancreatic Neoplasms / Q000378:metabolism; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008689:Methacrylates; D011108:Polymers; D002403:Cathepsins; C028217:cathepsin S; C032802:hydroxypropyl methacrylate
keywords: Cathepsin S; HPMA; dual-isotope labeling; mononuclear phagocyte system; pancreatic cancer