Abstract
Controlled, localized drug delivery is a long-standing goal of medical research, realization of which could reduce the harmful side-effects of drugs and allow more effective treatment of wounds, cancers, organ damage and other diseases. This is particularly the case for protein “drugs” and other therapeutic biological cargoes, which can be challenging to deliver effectively by conventional systemic administration. However, developing biocompatible materials that can sequester large quantities of protein and release them in a sustained and controlled manner has proven challenging. Glycosaminoglycans (GAGs) represent a promising class of bio-derived materials that possess these key properties and can additionally potentially enhance the biological effects of the delivered protein. They are a diverse group of linear polysaccharides with varied functionalities and suitabilities for different cargoes. However, most investigations so far have focused on a relatively small subset of GAGs – particularly heparin, a readily available, promiscuously-binding GAG. There is emerging evidence that for many applications other GAGs are in fact more suitable for regulated and sustained delivery. In this review, we aim to illuminate the beneficial properties of various GAGs with reference to specific protein cargoes, and to provide guidelines for informed choice of GAGs for therapeutic applications.
Highlights
Glycosaminoglycan-based biomaterials have emerged as attractive candidates for drug delivery and tissue engineering applications
As angiogenesis in vivo is stimulated by the orchestrated action of fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) amongst other factors, some recent biomaterial design has focused on sequential delivery of multiple factors rather than single-factor regimens [41,122,147,148,149]
Heparin-based biomaterials have been shown to be generally effective for a variety of applications, and for certain proteins and biological contexts are the most appropriate choice
Summary
Glycosaminoglycan-based biomaterials have emerged as attractive candidates for drug delivery and tissue engineering applications. Used in the clinic as an anticoagulant, heparin is readily available in bulk and has a comparatively high degree of sulfation As a result, it is a strongly negative polyelectrolyte and is able to effectively bind multiple growth factors and cytokines [30]. One can consider the potential chemical modifications that can be achieved with a given GAG – these may be required to add additional functionality, or to allow conjugation to a bulk material These modifications can lead to changes in binding affinity for proteins depending on the functional group selected. The remaining unspecific affinity of GAGs for proteins after modification with these strategies is still sufficient for them to be useful as biomaterials for controlled delivery, as the percentage of modified disaccharide units does not typically exceed 40–50%. We will identify areas where informed choice based on our suggested considerations is challenging due to a lack of available data and suggest how these areas might be clarified
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