Abstract：
PURPOSE:Overexpression 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. METHODS:Several 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. RESULTS:PEGylation 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. CONCLUSIONS:Our data underscores the potential for PEG20-PAI-2(C161S) drug conjugates to be further developed as anti-uPA targeted therapeutics with enhanced tumor retention.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Vine KL,Lobov S,Indira Chandran V,Harris NL,Ranson Mdoi
10.1007/s11095-014-1517-xsubject
Has Abstractpub_date
2015-03-01 00:00:00pages
1045-54issue
3eissn
0724-8741issn
1573-904Xjournal_volume
32pub_type
杂志文章abstract：PURPOSE:Simvastatin (SIM), a HMG-CoA reductase inhibitor widely prescribed for hypercholesterolemia, has been reported to ameliorate inflammation and promote osteogenesis. Its clinical applications on these potential secondary indications, however, have been hampered by its lack of osteotropicity and poor water solubil...
journal_title：Pharmaceutical research
pub_type： 杂志文章
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016405126656
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abstract：PURPOSE:The objective of this study was to elucidate the different mechanisms of action of different excipients on the oxidation of Met1, Met122, Met127, and Met138 in granulocyte colony-stimulating factor (G-CSF) by using hydrogen peroxide as the oxidant. METHODS:The oxidation of Met1, Met127, and Met138 was quantifi...
journal_title：Pharmaceutical research
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doi：10.1007/s11095-004-9019-x
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abstract：:Transport studies using intestinal brush-border membrane vesicles isolated from rats and rabbits have failed to demonstrate proton- or Na(+)-dependent carrier-mediated transport of thyrotropin-releasing hormone (TRH), despite a pharmacologically relevant oral bioavailability. To examine the hypothesis that reported le...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1018947430018
更新日期：1993-05-01 00:00:00
abstract：PURPOSE:We have evaluated a new process, involving solution-enhanced dispersion by supercritical fluids (SEDS), for the production of polymeric microparticles. METHODS:The biodegradable polymers, Poly (DL-lactide-co-glycolide): copolymer composition 50:50 (DL-PLG), Poly (L-lactide) (L-PLA), Poly (DL-lactide) (DL-PLA) ...
journal_title：Pharmaceutical research
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更新日期：1999-05-01 00:00:00
abstract：PURPOSE:In this study, we aimed to illustrate the utility of fractional radiofrequency (RF) that generated microchannels in the skin, allowing delivery of peptide and siRNA via the skin. The mechanisms involved in the correlation between macromolecule permeation and skin structure were also elucidated. METHODS:The mor...
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doi：10.1007/s11095-014-1568-z
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abstract：PURPOSE:Some therapeutic peptides exhibit amyloidogenic properties that cause insolubility and cytotoxicity against neuronal cells in vitro. Here, we characterize the conformational change in monomeric therapeutic peptide to its fibrillar aggregate in order to prevent amyloidogenic formation during clinical application...
journal_title：Pharmaceutical research
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doi：10.1023/b:pham.0000033016.36825.2c
更新日期：2004-07-01 00:00:00
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journal_title：Pharmaceutical research
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journal_title：Pharmaceutical research
pub_type： 杂志文章,已发布勘误
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更新日期：2013-03-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/A:1016382426347
更新日期：1985-03-01 00:00:00
abstract：:Molecular dynamics simulations and the generation of ad hoc chemical libraries are playing an increasingly important and recognized role in structure-based virtual screening. These approaches are important for treating target flexibility and improving the drug discovery pipeline. In this article I will comment on thes...
journal_title：Pharmaceutical research
pub_type： 杂志文章
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更新日期：2013-05-01 00:00:00
abstract：PURPOSE:The objective of this work is to understand the sequence specificity of HAV peptides and to improve their selectivity in regulating E-cadherin-E-cadherin interactions in the intercellular junctions. METHODS:Peptide 1 was modified using an alanine scanning method to give peptides 2-6. The ability of these pepti...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1011094025008
更新日期：2001-04-01 00:00:00
abstract：PURPOSE:To employ in vitro experiments combined with computational fluid dynamics (CFD) analysis to determine which aerodynamic factors were most responsible for deaggregating carrier-free powders to form micrometer and submicrometer aerosols from a capsule-based platform. METHODS:Eight airflow passages were evaluated...
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更新日期：2013-06-01 00:00:00
abstract：PURPOSE:This work investigated the effect of relative humidity (RH) on bipolar electrostatic charge profiles of dry powder inhaler aerosols using the Bipolar Charge Analyzer (BOLAR). METHODS:Two commercial products, Pulmicort® (400 μg, budesonide) and Bricanyl® (500 μg, terbutaline sulfate) Turbuhaler®, were used as m...
journal_title：Pharmaceutical research
pub_type： 杂志文章
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更新日期：2017-08-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016008102587
更新日期：1996-08-01 00:00:00
abstract：:Four lipophilic, low molecular weight drugs solubilized in phosphatidylcholine-bile salt mixed micelles were injected s.c. into the hind legs of sheep and their cumulative recoveries in lymph draining from the site of application were determined. Surprisingly, the cumulative recoveries (percentage of dose) varied betw...
journal_title：Pharmaceutical research
pub_type： 杂志文章
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abstract：:To evaluate the effects of a neutron activation radiolabeling technique on an enteric-coated multiparticulate formulation of erythromycin, test quantities were produced under industrial pilot scale conditions. The pellets contained the stable isotope erbium oxide (Er-170), which was later converted by neutron activati...
journal_title：Pharmaceutical research
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abstract：PURPOSE:Nanocrystalline drug-polymer dispersions are of significant interest in pharmaceutical delivery. The purpose of this work is to demonstrate the applicability of methods based on two-dimensional (2D) and multinuclear solid-state NMR (SSNMR) to a novel nanocrystalline pharmaceutical dispersion of ebselen with pol...
journal_title：Pharmaceutical research
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更新日期：2012-07-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：2021-01-26 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
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更新日期：2013-06-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：1999-03-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：2003-04-01 00:00:00
abstract：PURPOSE:To group microcrystalline celluloses (MCCs) using a combination of artificial neural network (ANN) and data clustering. METHODS:Radial basis function (RBF) network was used to model the torque measurements of the various MCCs. Output from the RBF network was used to group the MCCs using a data clustering techn...
journal_title：Pharmaceutical research
pub_type： 杂志文章
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更新日期：2004-12-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：2004-03-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：2008-05-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
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更新日期：2008-11-01 00:00:00
abstract：PURPOSE:Pulmonary antibiotic delivery is recommended as maintenance therapy for cystic fibrosis (CF) patients who experience chronic infections. However, abnormally thick and sticky mucus present in the respiratory tract of CF patients impairs mucus penetration and limits the efficacy of inhaled antibiotics. To overcom...
journal_title：Pharmaceutical research
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doi：10.1007/s11095-016-1921-5
更新日期：2016-08-01 00:00:00
