ArticlePharmaceutical research2015
Improved pharmacokinetic and biodistribution properties of the selective urokinase inhibitor PAI-2 (SerpinB2) by site-specific PEGylation: implications for drug delivery.
Article in Pharmaceutical research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 6 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
6 citing papers in PubMed, 12 citations in OpenAlex.
- Bioproduced Nanoparticles Deliver Multiple Cargoes via Targeted Tumor Therapy In Vivo.ACS omega · 2024Article
- Review
- Site-specific PEGylation of an anti-CEA/CD3 bispecific antibody improves its antitumor efficacy.International journal of nanomedicine · 2018Article
- The Continuous Concentration of Particles and Cancer Cell Line Using Cell Margination in a Groove-Based Channel.Micromachines · 2017Article
- Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications.Oncotarget · 2017Review
- Evaluation of Tc-99 m Labeled Dimeric GX1 Peptides for Imaging of Colorectal Cancer Vasculature.Molecular imaging and biology · 2015Article
Corrections and comments
- Erratum issued
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeOverexpression of the serine protease urokinase (uPA) is recognised as an important biomarker of metastatic disease and a druggable anticancer target. Plasminogen activator inhibitor type-2 (PAI-2/SerpinB2) is a specific uPA inhibitor with proven potential for use in targeted therapy. However, PAI-2 is rapidly cleared via the renal system which impairs tumor uptake and efficacy. Here we aimed to improve the pharmacological properties of PAI-2 by site-specific PEGylation.
methodsSeveral cysteine to serine substitution mutants were generated for PEGylation with PEG-maleimide (size range 12-30 kDa) and the physico-chemical and biochemical properties of the PEG-PAI-2 conjugates characterised. Radiolabeled proteins were used for evaluation of blood clearance and tissue uptake profiles in an orthotopic breast tumor xenograft mouse model.
resultsPEGylation of the PAI-2(C161S) mutant gave a predominant mono-PEGylated-PAI-2 product (~90%) with full uPA inhibitory activity, despite a significant increase in hydrodynamic radius. Compared to un-PEGylated protein the plasma half-life and AUC for PEG20-PAI-2(C161S) were significantly increased. This translated to a 10-fold increase in tumor retention after 24 h compared to PAI-2(C161S), an effect not seen in non-target organs.
conclusionsOur data underscores the potential for PEG20-PAI-2(C161S) drug conjugates to be further developed as anti-uPA targeted therapeutics with enhanced tumor retention.
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