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

Fan, Wei; Shi, Wen; Zhang, Wenting; Jia, Yinnong; Zhou, Zhengyuan; Brusnahan, Susan K.; Garrison, Jered C.

doi:10.1016/j.biomaterials.2016.05.036

Cited by 23 publications

(33 citation statements)

References 54 publications

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“…16, 17 However, to date, the impact of the copolymer block size on the cleavage and biodistribution profile of Cat-S-cleavable, mutli-block HPMA copolymers has not been studied. The molecular weight of copolymers and the degraded fragments is expected to play a key factor affecting the biological performance of the diagnostic agent.…”

Section: Discussionmentioning

confidence: 99%

“…17 It was anticipated that the peptide fragment, labeled with 177 Lu, would clear more quickly than the fragmented polymeric blocks, labeled with 125 I, due to substantially lower molecular weight. However, to our surprise, 125 I was cleared from the mice more quickly than 177 Lu at early time points (4 and 24 h).…”

Section: Discussionmentioning

confidence: 99%

“…Based on the in vitro studies to date, the in vivo mechanism of the increased non-target clearance of these Cat S-degradable HPMA copolymers is likely due to fragmentation and enhanced clearance of the smaller polymeric blocks. 17 …”

Section: Introductionmentioning

confidence: 99%

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Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers

et al. 2017

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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 non-target accumulation. Specifically, we have been investigating the use of a cathepsin S (Cat S)-cleavable peptidic linkers to degrade multi-block 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 multi-block copolymers with a smaller block size exhibited faster clearance and lower non-target retention while still achieving good tumor targeting and retention. Based on the radioisotopic ratios, fragmentation and clearance of the copolymer constructs was 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers

et al. 2017

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“…In another study, the Garrison's group developed the synthesis of cathepsin S-susceptible 177 Lu-labeled or FRET-capable multiblock PHPMA copolymers, which resulted into fast in vitro cleavage of both copolymers. Quicker clearance and lower non-target retention without reducing tumor targeting was also shown on pancreatic ductal adenocarcinoma mouse model [174]. This study therefore took benefit of the presence of Cathepsin S in MPS tissues to lower non-target accumulation.…”

Section: Cathepsins As Probes For Imaging and Theranostic 26mentioning

confidence: 76%

Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

Dheer

Nicolas

Shankar

2019

Advanced Drug Delivery Reviews

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Cathepsins are an important category of enzymes that have attracted great attention for the delivery of drugs to improve the therapeutic outcome of a broad range of nanoscale drug delivery systems. These proteases can be utilized for instance through actuation of polymer-drug conjugates (e.g., triggering the drug release) to bypass limitations of many drug candidates. A substantial amount of work has been witnessed in the design and the evaluation of Cathepsinsensitive drug delivery systems, especially based on the tetra-peptide sequence (Gly-Phe-Leu-Gly, GFLG) which has been extensively used as a spacer that can be cleaved in the presence of Cathepsin B. This Review Article will give an in-depth overview of the design and the biological evaluation of Cathepsin-sensitive drug delivery systems and their application in different pathologies including cancer before discussing Cathepsin B-cleavable prodrugs under clinical trials.

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“…In order to make the initiator capable of adhering to surfaces, 3,4‐dihydroxyphenylacetic acid (DOPAC), a metabolite of dopamine, was used to conjugate with V‐50 through amide condensation between DOPAC and V‐50 (Scheme A) . The synthesized molecule, named as DOPV, combined the characteristics of the mussel‐inspired attachment ability of DOPAC and the thermal initiation of V‐50, and could be used as a surface‐attachable initiator . The successful synthesis of DOPV was proved by 1 H‐NMR and FTIR (Figure S1, Supporting Information).…”

Section: Methodsmentioning

confidence: 99%

Mussel‐Inspired, Surface‐Attachable Initiator for Grafting of Antimicrobial and Antifouling Hydrogels

Feng

et al. 2019

Macromol. Rapid Commun.

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In this work, a novel biomimetic surface‐attachable initiator is successfully synthesized by the conjugation of 3,4‐dihydroxyphenylacetic acid and thermal 2,2′‐azobis(2‐methylpropionamide) dihydrochloride (V‐50). The synthesized initiator (DOPV) can adhere to various material surfaces in a mussel‐inspired way and initiate the surface grafting polymerization. Hydrogel coatings are facilely prepared by the thermal‐initiated radical copolymerization of antimicrobial polyhexamethylene guanidine and antifouling polyethylene glycol oligomers. The developed hydrogel coatings not only show antimicrobial activity toward gram‐negative and gram‐positive bacteria but also demonstrate protein resistance, antibiofilm efficacy, hemocompatibility, and low cytotoxicity in vitro. Most importantly, the hydrogel coatings reveal excellent antimicrobial efficacy with a log reduction above 5 in a rodent subcutaneous infection model. These results demonstrate the potential fabrication of bio‐functional coatings for biomedical devices or implants through an inexpensive, facile, and environmentally friendly mussel‐inspired technique.

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

Cited by 23 publications

References 54 publications

Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers

Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers

Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

Mussel‐Inspired, Surface‐Attachable Initiator for Grafting of Antimicrobial and Antifouling Hydrogels

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