Investigation of the potential of polymer therapeutics in corneal re-epithelialisation

Abstract

In this study, the first use of a bioresponsive polymer therapeutic agent in the promotion of corneal reepithelialisation after injury in an ex vivo whole-eye organ culture model was described. A polymereprotein conjugate consisting of dextrin and recombinant human epidermal growth factor was synthesised and applied as a single dose to a 2 mm ex vivo corneal ulcer, in culture. Enhanced wound healing was observed in response to dextrinerecombinant human epidermal growth factor, when exposed to a-amylase, compared with controls.This highlights the potential for polymer therapeutics to provide a platform for bioresponsive drug/protein delivery in the field of ophthalmology. INNOVATIONThe descriptor 'polymer therapeutic' is an umbrella term used to describe polymeric drugs, polymeredrug conjugates, polyplexes, polymereprotein conjugates, and polymeric micelles, to which a drug can be bound.

Controlled release of dextrin-conjugated growth factors to support growth and differentiation of neural stem cells

“…Modification of dextrin's molecular weight and degree of succinoylation have been demonstrated to control the polymer's degradation rate (Duncan et al, 2008), thereby altering the release rate of growth factors. Conjugation of colistin to 1 mol% succinoylated 7500 g/mol dextrin led to ∼80% drug release by amylase degradation within 48 h (Ferguson et al, 2014), compared to 52.7% after 168 h for EGF conjugated to 19 mol% succinoylated 42,000 g/mol dextrin (Hardwicke et al, 2010b). Since the desired exposure to bFGF is days ( vs. weeks for EGF), this could readily be achieved by its conjugation to a lower molecular weight dextrin with less modification.…”

“…Succinoylated dextrin (27.8 mol% succinoylation, 74,000 g/mol) was synthesized according to the method of Hreczuk-Hirst et al (Hreczuk-Hirst et al, 2001) and characterized as described by Ferguson and Duncan (2009). The succinoylated dextrin intermediate was conjugated to EGF using EDC and sulfo-NHS as coupling agents, as described by Hardwicke et al (Hardwicke et al, 2010b). For dextrin-bFGF conjugation, a modified version of the same method was employed, however, since bFGF's molecular weight is 2.8 times greater than EGF, a molar ratio of 1 bFGF to 1 dextrin was used.…”

“…Polymer therapeutics are increasingly being developed as innovative therapies for tissue repair and regeneration (Duncan and Vicent, 2013). We have previously developed and characterized dextrin-growth factor conjugates using EGF as a model growth factor to promote tissue repair (Hardwicke et al, 2008; Hardwicke et al, 2010a; Hardwicke et al, 2010b; Hardwicke et al, 2011). Such conjugates exhibit sustained and controlled degradation of the dextrin component in the presence of physiological concentrations of α-amylase, an enzyme that is widely distributed in extracellular fluids and serum (30–110 IU/L), leading to sustained release of free EGF, protein unmasking and restoration of bioactivity to the level seen for unmodified EGF (Hardwicke et al, 2008).…”

“…In this wound healing model, we demonstrated not only increased dermal cell proliferation and migration with the dextrin-EGF, but also that the duration of effect was longer than that observed with free EGF (Hardwicke et al, 2008; Hardwicke et al, 2010a). In an ex vivo organotypic model of re-epithelialisation, dextrin-conjugated EGF was as effective as free EGF at 10× lower doses (Hardwicke et al, 2010b), and in an in vivo model of impaired wound healing in diabetic (db/db) mice, topical application of dextrin-EGF significantly enhanced dermal wound healing (Hardwicke et al, 2011). The potential for using such polymer therapeutics to support stem cell therapy is clear, to both improve the efficiency and cost-effectiveness of in vitro stem cell expansion, and increase the survival, integration and differentiation of transplanted stem cells in vivo .…”

Dextrin

“…[119] An ex vivo whole-eye organ model was also to demonstrate that dextrin-rhEGF conjugate stimulates corneal reepithelialization, post-wounding. [120] These studies on dextrin conjugation with growth factor underline the general potential of dextrin as bioresponsive polymer integrating a novel nanomedicine for tissue regeneration and repair. Actually, Regranex ® (Becaplermin), a carboxymethylcellulose gel containing recombinant human platelet-derived growth factor, is the only FDAapproved growth factor therapy for chronic wounds, [121] with its use limited to the treatment of deep, neuropathic diabetic foot ulcers.…”