Bioresponsive dextrin-rhEGF conjugates: in vitro evaluation in models relevant to its proposed use as a treatment for chronic wounds

Hardwicke, Joseph, Moseley, Ryan ORCID: https://orcid.org/0000-0002-2812-6735, Stephens, Philip ORCID: https://orcid.org/0000-0002-0840-4996, Harding, Keith Gordon, Duncan, Ruth and Thomas, David William ORCID: https://orcid.org/0000-0001-7319-5820 2010. Bioresponsive dextrin-rhEGF conjugates: in vitro evaluation in models relevant to its proposed use as a treatment for chronic wounds. Molecular Pharmaceutics 7 (3) , pp. 699-707. 10.1021/mp9002656

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Abstract

We recently developed a bioresponsive dextrin-recombinant human epidermal growth factor (rhEGF) conjugate as a polymer therapeutic with potential for use in the promotion of tissue repair. The aim of these studies was to use patient-derived wound fluid and fibroblasts to evaluate its potential for further development as a treatment for chronic wounds, such as venous leg ulceration, a growing clinical challenge in the aging population. First, the levels of EGF (ELISA assay), alpha-amylase and elastase (enzyme assays) were measured in patient-derived acute and chronic wound fluid. EGF was detected in acute, but not in chronic wound fluid. alpha-Amylase concentrations were higher in acute (188 IU/L), compared to chronic wound fluid (52 IU/L), but both were in the range of human serum levels. Although elastase was present in chronic wound fluid (2.1 +/- 1.2 RFU/min), none was detected in acute wound fluid. Dextrin-rhEGF incubation in chronic wound fluid led to endogenous a-amylase-mediated release of rhEGF (ELISA) that was maximal at 48 h. When the migration of HaCaT keratinocytes and of human fibroblasts (isolated from patient-matched, normal skin and chronic dermal wounds) was studied in vitro using the scratch wound assay, enhanced cell migration was observed in response to both free rhEGF and a-amylase-activated dextrin-rhEGF conjugate compared to controls. In addition, fibroblasts displayed increased proliferation (normal dermal fibroblasts similar to 160%; chronic wound fibroblasts similar to 140%) following incubation (72 h) with dextrin-rhEGF that had been exposed to physiological levels of alpha-amylase (93 IU/L). These results suggest further preclinical in vivo evaluation of dextrin-rhEGF is warranted to determine whether conjugate pharmacokinetics and rhEGF liberation into such a complex and aggressive environment can still lead to bioactivity.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Pharmacy Schools > Dentistry Schools > Chemistry Schools > Medicine Research Institutes & Centres > Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	Polymer therapeutics; chronic wounds; dextrin−epidermal growth factor conjugate; fibroblasts; keratinocytes
Publisher:	American Chemical Society
ISSN:	1543-8384
Last Modified:	06 Nov 2024 22:23
URI:	https://orca.cardiff.ac.uk/id/eprint/15878

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