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Dextrin-rhEGF conjugates as bioresponsive nanomedicines for wound repair

Hardwicke, Joseph, Ferguson, Elaine Lesley, Moseley, Ryan, Stephens, Philip, Thomas, David William and Duncan, Ruth 2008. Dextrin-rhEGF conjugates as bioresponsive nanomedicines for wound repair. Journal of Controlled Release 130 (3) , pp. 275-283. 10.1016/j.jconrel.2008.07.023

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Abstract

Growth factors are known to act in concert to promote wound repair, but their topical application rarely leads to a significant clinical improvement of chronic wounds due to premature inactivation in wound environment. The aim of this study was to synthesise a polymer-growth factor conjugate and investigate whether the novel concept called Polymer-masking-UnMasking-Protein Therapy (PUMPT) might be used to generate bioresponsive polymer therapeutics as nanomedicines able to promote tissue repair. Succinoylated dextrin (similar to 85,000 g/mol; similar to 19 mol% succinoylation), and rhEGF were chosen as a first model combination. The conjugate synthesised contained similar to 16%wt rhEGF and <1% free protein. It exhibited increased stability towards proteolytic degradation by trypsin and the clinically relevant enzyme neutrophil elastase. The dextrin component was degraded on addition of alpha-amylase leading to sustained release of free rhEGF over time (52.7% release after 168 h). When biological activity was assessed ( +/-alpha-amylase) in proliferation assays using epidermoid carcinoma (HEp2) cells and HaCaT keratinocytes, as anticipated, polymer conjugation reduced rhEGF bioactivity (p=0.0035). However, exposure to physiological concentrations of alpha-amylase triggered dextrin degradation and this led to protein unmasking with restoration of bioactivity to the level seen for unmodified rhEGE Indeed, prolongation of HEp2 proliferation was observed over 8 days. The inability of dextrin, succinoylated dextrin or alpha-amylase alone to induce proliferative effects, and the ability of alpha-amylase-exposed dextrin-rhEGF to induce phosphorylation of the epidermal growth factor receptor (EGFR) in HEp2 cells confirmed a mechanism of action by stimulation of classical signal transduction pathways. These observations suggest that this dextrin-rhEGF, and other dextrin-growth factor conjugates have potential for further development as bioresponsive nanomedicines for tissue repair.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Dentistry
Chemistry
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QD Chemistry
R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Dextrin–rhEGF conjugate; Wound repair; PUMPT; Polymer therapeutics; Nanomedicine
Publisher: Elsevier
ISSN: 0168-3659
Last Modified: 04 Apr 2019 23:24
URI: http://orca.cf.ac.uk/id/eprint/15877

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