Advances in emergency burn care have led to increasing numbers of patients surviving burn injuries that were previously considered to be fatal. As a result, there is a growing need to address the long-term challenges of burn injuries. Scar contracture is a major complication of extensive burns that leads to prolonged pain, loss of joint mobility and severe disfigurement. Contractures develop up to 2 years after the initial injury due to cross-linking of collagen fibres, catalysed by the enzyme lysyl oxidase (LOX). Previous efforts to inhibit the action of LOX have relied on systemic delivery of the known LOX inhibitor beta-aminopropionitrile (b-APN), however this non-targeted approach has resulted in body-wide consequences which have halted its clinical use. Here we introduce a method for the topical delivery of b-APN, directly targeting the site of injury, overcoming the need for excessive doses and potentially reducing toxic side-effects. We achieve this by attaching b-APN to a lipophilic moiety via a reversible linker, forming a prodrug that enables the inhibitor to pass through the skin whilst maintaining biological activity. In this presentation we outline the synthesis and characterisation of a series of prodrugs and demonstrate their ability to dissociate in response to an environmental cue. We highlight how this dissociation is sufficient to inhibit the target enzyme at concentrations that are non-toxic to primary human cells. Furthermore, we apply the prodrugs to an in vitro model of contraction using the collagen gel contraction assay. By using this targeted approach, we aim to shorten patient rehabilitation times and reduce the need for invasive reconstructive surgery.

Development of a topical prodrug to treat burn scar contracture

2019 Spring National Meeting

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