Glycomacromolecules: Addressing challenges in drug delivery and therapeutic development

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Abstract

Carbohydrate-based materials offer exciting opportunities for drug delivery. They present readily available, biocompatible components for the construction of macromolecular systems which can be loaded with cargo, and can enable targeting of a payload to particular cell types through carbohydrate recognition events established in biological systems. These systems can additionally be engineered to respond to environmental stimuli, enabling triggered release of payload, to encompass multiple modes of therapeutic action, or to simultaneously fulfil a secondary function such as enabling imaging of target tissue. Here, we will explore the use of glycomacromolecules to deliver therapeutic benefits to address key health challenges, and suggest future directions for development of next-generation systems.

Introduction

Drug delivery systems have much to offer in improving the treatment of disease. Effective drug delivery systems can selectively target therapeutics to an intended site of action, improving efficacy while minimising harmful side effects. Concurrently, they can protect drugs from environmental conditions and improve the bioavailability of poorly soluble drugs. Delivery systems can additionally provide control over the release profile of a drug, enabling sustained release which can simplify dosing regimes [1,2]. Drug delivery systems often incorporate macromolecular components such as polymers, liposomes and nanoparticles. These macromolecular architectures possess many useful attributes. In addition to modifying the biodistribution profiles of drugs, their modular nature can enable the construction of systems which simultaneously deliver more than one drug, or combine therapeutic action with a secondary function such as enabling imaging. Through sustained research efforts, it is possible to design highly-targeted delivery systems which respond to external stimuli to enable triggered release of payload [[3], [4], [5]].

Meanwhile, our understanding of the diverse roles of carbohydrates in biology has advanced significantly. In addition to fulfilling important functions in metabolism, and as structural materials, carbohydrates play crucial roles in enabling cellular recognition. Mammalian cells are decorated with a carbohydrate-rich layer known as the glycocalyx - a complex and diverse mixture of glycoproteins, proteoglycans and glycosaminoglycans - which acts as a cellular ‘barcode’ for identification [6]. This recognition is key to crucial biological processes which maintain health, yet also underpins many diverse processes of disease. Many pathogens produce carbohydrate-binding proteins (lectins) which can interact with these complex sugar motifs to facilitate recognition [7,8], interactions which often constitute a key step in the processes of infection or disease progression [9,10]. Characteristic changes in cellular glycosylation patterns, and altered display of cell surface lectins, associated with cancer can provide evidence of disease, and provide a targeting mechanism to direct drugs to these tissues. Consequently, the use of carbohydrates as components within macromolecular drug delivery systems is attractive (Fig. 1). Glycomolecular architectures can be accessed via naturally-occurring polysaccharides, or through the attachment of carbohydrates to nanoparticles, or polymeric scaffolds. Alternatively, carbohydrates can be incorporated into lipid bilayers, forming glycovesicles. Polysaccharides can be used to great effect as structural components, offering readily available, biocompatible building blocks for the construction of functional systems. Beyond their use as building blocks, the ubiquity of carbohydrate recognition can be exploited to target drugs to tissues or cell types. Many of these glycomacromolecules display therapeutic properties in their own right, as we will highlight. This factor presents opportunities for the design of multi-functional delivery systems which extend the therapeutic potential of the drug.

This review will explore the use of glycomacromolecules to deliver therapeutic benefits to address selected key challenges to human health. We will explore developments in drug delivery to cancer cells, where carbohydrates can act as effective targeting ligands to selectively deliver therapeutics to cancer tissue, presenting a route to the minimisation of side effects. We will next explore the use of glycomacromolecules in tackling bacterial biofilms which contribute to chronic infections and the growing problem of antibiotic resistance, which presents a huge challenge to human health. Finally, we will explore the use of glycomacromolecules in addressing illnesses caused by viruses which account for a major global burden of disease, mindful that the effective treatment of viral pathogens remains a major challenge in contemporary medicinal chemistry.

Section snippets

Glycomacromolecular drug delivery systems to treat cancer

Cancer is the second most common cause of death globally, estimated to account for 9.6 million deaths in 2018 [12]. Many cancer therapies cause debilitating side-effects which could be partially avoided through the selective targeting of therapeutics to cancer cells – via a ‘magic bullet.’ [13] This challenge is significant, since cancer cells bear many similarities to their healthy counterparts, enabling them to evade the immune system. Excellent advances in immunotherapy and antibody-based

Glycomacromolecular drug delivery systems for bacterial infections

Bacterial infections present a major burden of mortality and morbidity, with the growing problem of antimicrobial resistance predicted to cause major challenges for healthcare systems and economies on a global scale [108]. The development of effective drug delivery systems to combat bacterial infections is complicated by the diverse range of phenotypes presented by pathogenic bacteria. Infections may be intracellular, or extracellular, either in a planktonic (‘free-floating’) state or an

Glycomacromolecular drug delivery systems for antiviral drugs

Viral pathogens, by their nature, present far fewer targets for the development of drugs. Many diseases caused by viruses have been eradicated or can be effectively supressed through vaccination strategies, such as smallpox, polio and measles, but the development of effective vaccines for other viruses, notably HIV, has thus far proven elusive. Combined with the threat of the emergence of novel viral pathogens, as exemplified by the global impact of the SARS-CoV-2 pandemic (2019-) [165], there

Outlook

The benefits of using carbohydrates in macromolecular drug delivery systems are clear. They can be used with great effect as structural components to construct stable, biocompatible macromolecular architectures which present pathways for metabolism or biodegradation. Additionally, the carbohydrate recognition processes which impact the onset or progression of disease can be harnessed to facilitate specific targeting of drugs to particular cell types, or pathogens. Many of the

Acknowledgement

The authors would like to thank the Durham University Biophysical Sciences Institute for the award of a Summer Research Bursary to W·S-W.

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