Prof Sally-Ann Cryan explains how getting therapeutics to their site of action in the body is key to successful treatment and how RCSI's multidisciplinary research is overcoming barriers to the development of next-generation treatments
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Author: Prof Sally-Ann Cryan, associate professor of pharmaceutics and research convenor, School of Pharmacy, Royal College of Surgeons in Ireland

Advances in biomedical research mean we understand human disease and the sites of disease better than ever before. New and exciting ways to treat disease are emerging from this research internationally, both in academia and in industry.

The nature of these treatments is changing from the classic small, organic drug molecule of old to the newer biotech molecules including proteins, peptides and gene-based medicines. There is also a greater understanding of the body’s own healing and regenerative capacities that is being harnessed to enable tissue replacement or repair and this may require cell-based treatments to be delivered to the body.

These advances in biomedical research have come alongside a greater understanding of the anatomical and physiological barriers presented by the human body to drug targeting. The body is designed to protect us from the introduction of foreign toxins and pathogens and as such can present considerable barriers to the delivery of large biotherapeutics.

For this reason, the majority of protein-based therapeutics currently on the market are available only as injections as other routes, such as the oral route, would not enable adequate absorption of the drug active to be efficacious.

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Equally, gene-based medicines are being developed to target disease at a genetic level and this involves delivering the active, in this case DNA or RNA, not only to the correct cell type, but to the correct intracellular compartment. This level of control was not previously required for classical drug molecules in standard drug products. Cell-based therapies will require protection of the cells during targeted delivery and retention and support of the cells once in situ.

This has forced pharmaceutical scientists and biomedical engineers to develop more advanced formulations and devices for delivery of these so-called ‘difficult-to-deliver cargoes’. The last two decades has seen a logarithmic increase in both publications and patents in the fields of advanced drug delivery and medical devices but, for these areas to be truly disruptive, multidisciplinary research teams, such as those in the RCSI (Royal College of Surgeons in Ireland) Research Institute, are critical.

RCSI is internationally renowned for excellence in basic pre-clinical and clinical research and the RCSI Research Institute’s mission is to integrate basic and clinical research, so that advances in medical science are translated as quickly as possible into patient treatments.

Ireland has a lot of expertise in these areas, both industrially and in academia, strongly supported by IDA Ireland, Enterprise Ireland, the Health Research Board and Science Foundation Ireland, so this is something we already do well and for which we can be internationally recognised.

DELIVERY PLATFORMS FROM NANO- TO MICROSCALE

Figure 1: Delivery vectors from the nano- to the macroscale (Reproduced with permission from Putnam D., Polymers for gene delivery across length scales, Nature Materials 5, 439 – 451 (2006)) (click to enlarge)

The Cryan group in the School of Pharmacy, RCSI focuses on translational and molecular pharmaceutics including development of advanced delivery platforms from the nano- to the macroscale (Figure 1) for ‘difficult-to-deliver’ therapeutic cargoes for a range of clinical diseases.

Spatiotemporal control of drug delivery in the body to provide targeted delivery of a therapeutic or ‘the magic bullet’ depends on i) the route of administration, ii) the chemical composition of the platform i.e. the materials chosen as excipients and iii) the format in which it is presented to the body e.g. nanoparticle, tablet, implant.

Therefore, careful selection of excipient materials and process is critical not just to ensure success in the laboratory, but also to ensure the product developed is scalable and cost effective. Each delivery platform is developed in RCSI in collaboration with relevant clinical and biomedical research groups, who contribute innovative medicines and a relevant patient samples and populations on which to trial them including collaborations with Beaumont Hospital, St James’ Hospital and Crumlin Children’s Hospital.

Nanomedicines

Figure 2: Uptake of drug-loaded nanomedicines (red) into human cells (green)

The pharmaceutical industry and formulation scientists use well-established excipients with classical drug actives in standard drug product formats e.g. tablets, injections and creams. The biotech revolution has generated interest in developing more sophisticated materials for use as excipients. In many cases, these materials sneak the therapy into the body by encapsulating the drug in lipids bilayers e.g. liposomes or in polymeric particles, often in the nano-size range (Figure 2).

In fact, the global nanomedicine market alone is expected to grow to over $130 billion by 2016. The Cryan group works extensively with pharmaceutical chemists, including the Polymer Research Group in DCU, to develop completely new materials, with bioresponsive properties that enable targeting to specific cell types in the body e.g. immune cells or to specific disease sites e.g. sites of inflammation (Figure 3).

Figure 3: Bioresponsive delivery platforms for application and integration with a range of biomedical devices (click to enlarge)

These advanced materials are then processed to create nanomedicines, which can if required be integrated with an appropriate medical device. Currently, nanomedicines targeting cancer, inflammation and infection are all being developed within the group using these materials. Two areas where these nanomedicines and advanced materials are converging with biomedical engineering are in the areas of respiratory drug delivery and tissue engineering (discussed below).

Therapeutic aerosol bioengineering

There is a significant clinical and commercial need for new treatments for a range of respiratory pathologies and the worldwide market for prescription respiratory medicines is now more than $64 billion. The majority of the inhaler devices currently on the market are delivering small molecule drugs, which are extremely potent and do not need a very efficient delivery system to have a clinical effect.

Technologies are now required to facilitate biotech drug delivery via inhalation to enable i) efficient delivery ii) control their fate once delivered to the lungs. Recent market reports predict a global pulmonary drug delivery technologies market of up to $44 billion by 2016, with a significant portion of this growth supported by technological advances in formulation including biomaterials-based delivery systems which has lagged behind device development to-date.

Figure 4: Therapeutic aerosol bioengineering of RNAi medicines (Reproduced with permission from RNAi in Respiratory Diseases by Sally-Ann Cryan, Ciara Kelly, Awadh B. Yadav et al., Advanced Delivery and Therapeutic Applications of RNAi, Kun Cheng and Ram I. Mahato (Eds), John Wiley & Sons Ltd, Chichester. Copyright (2013) John Wiley & Sons Ltd) (click to enlarge)

In work supported by the Fulbright Commission of Ireland, the Irish Research Council and the Health Research Board, the Cryan group has now harnessed therapeutic aerosol bioengineering to develop lung-targeted delivery platforms to tackle infection such as tuberculosis and inflammation in chronic conditions including cystic fibrosis and chronic obstructive pulmonary disease (or COPD).

These include nano- and microparticle formats that can target biotherapeutics, including RNAi-based medicines, to specific cell types in the lungs, using appropriate inhaler devices (Figure 4).

Tissue engineering scaffolds

The Tissue Engineering Research Group (TERG), one of the largest research groups in RCSI, utilises biomaterials and stem cells expertise to develop construct and living system technologies that can recapitulate the natural extracellular matrix (ECM) of the body and thereby restore the structural and functional properties of damaged or degenerated tissue types.

Ongoing research includes projects focussing on bone, cartilage, cardiovascular, corneal, nerve and respiratory tissue repair amongst others. The group collaborates closely with the Trinity Centre for Bioengineering and is part of the recently announced €50 million SFI-funded Advanced Materials and BioEngineering Research Centre.

Figure 5: Gene-loaded scaffolds for tissue engineering (Reproduced with permission from Tierney et al. The development of non-viral gene-activated matrices for bone regeneration using polyethyleneimine (PEI) and collagen-based scaffolds, Journal of Controlled Release, 158, (2) 304–311.)

The global market for transplantation products, devices and pharmaceuticals is projected to grow to over $80 billion by 2015. As a PI in this multidisciplinary research team, I focus on how agents such as growth factors can be released from macro-scale scaffolds implanted into the body to help tissue to regenerate.

The nature of the growth factors is dependent on the tissue type being regenerated and work ongoing is looking at delivering these growth factors as either proteins or genes (Figure 5). This work includes two academic-industrial EU FP7-funded projects developing advanced materials and devices for cell and drug delivery.

ENGINEERING TOOLS FOR TRANSLATION

Along with developing new materials and formats for delivery, the group is developing new tools for their development including harnessing high content analysis (HCA) in nanotoxicology. The Cryan group is one of the first groups internationally to apply HCA to the study of the cellular uptake of nanomedicines, allowing researchers to calculate therapeutic dosing at a cellular and potentially even a sub-cellular level.

There is a growing interest from pharma and biopharma industry and the regulators, including the Food and Drug Administration and European Medicines Evaluation Agency, in developing more appropriate models to develop drugs for human use.

A huge percentage of therapeutics get ‘lost in translation’. In the TERG in RCSI, we are developing three-dimensional models of parts of the lung so that the toxicity and efficacy of new drugs can be tested using human cells that can cross-talk to each other as they might in the body.

Combining these 3D cell models with high throughput screening technologies through the use of robotics would enable more rapid screening of both drugs and biomaterials in the future and this is an area the group is now working on with collaborators in the U.S.

RCSI: A BRIDGE FOR TRANSLATION

The School of Pharmacy in RCSI is part of the Science Foundation Ireland-funded Irish Drug Delivery Network, bringing academia and industry together to meet unmet delivery and drug development needs.

Along with patenting and commercialising its own biomedical discoveries and delivery platforms (some 16 patents have been filed to-date), the School works closely with clinicians/biomedical researchers and industry to fully realise the clinical and commercial potential of their molecules, biomaterials and/or devices.

Figure 6: School of Pharmacy, Royal College of Surgeons in Ireland

RCSI is ideally placed to act as a bridge for translation of cutting edge biomedical research encompassing as it does pharmaceutical, engineering, medical, surgical and regulatory know-how and facilities (Figure 6).

The School has secured research funding of over €12 million since it opened in 2002 and has worked extensively with a range of pharmaceutical and medical device companies including MNCs and SMEs both on individual projects and through large SFI and EU-funded academic-industry research consortia. The nature of the projects depends on company needs.

For example, work with Aerogen’s vibrating mesh nebuliser device has focused on optimising device performance through control of fluid physicochemical properties, expanding clinical applications through work on a range of drug actives and development of a convergent nanoparticle-device platform to bring really added-value to their device.

Work with pharma and biopharma companies can often involve overcoming formulation and drug targeting issues for specific biomolecules and in some cases match-making these with appropriate materials and biomedical devices for delivery i.e. enabling the convergence of technologies on which the next generation of human medicines will be based.

The science of formulation has come a long way from the old mortar and pestle of old but the fundamental focus of making good medicines remains and technology is enabling us to get ever closer to the “magic bullet”.

Prof Sally-Ann Cryan is associate professor of pharmaceutics and research convenor for the School of Pharmacy in the Royal College of Surgeons in Ireland. For more information on the technologies and opportunities outlined, telephone: (01) 4022741, email scryan@rcsi.ie or visit http://www.rcsi.ie/research

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  Author: Prof Sally-Ann Cryan, associate professor of pharmaceutics and research convenor, School of Pharmacy, Royal College of Surgeons in Ireland Advances in biomedical research mean we understand human disease and the sites of disease better than ever before. New and exciting ways to treat disease are emerging from this research...