Nanotechology explored in Irish medical school
Nanotechnology is being harnessed to engineer advanced clinical treatments at a college in Ireland.
Advances in biomedical research mean we understand human disease better than ever before and innovative ways to treat disease are emerging from this research, in academia and industry. The nature of these treatments includes the classic small organic drug molecule and the newer biotech molecules, including proteins, peptides and gene-based medicines. Getting therapeutics to their site of action in the body is a key step in successful treatment, and multidisciplinary research taking place at the Royal College of Surgeons in Ireland (RCSI) is overcoming the barriers to the development of next-generation treatments.
Small molecule therapeutics such as those developed for cancer treatment can be difficult to target to specific sites within the body, leading to unwanted and sometimes severe side-effects. The majority of protein-based therapeutics currently on the market are available only as injections, as other routes of administration would not enable adequate absorption of the active drug to be efficacious.
Gene-based medicines are also presented with a number of biological barriers when administered. These target disease at a genetic level that requires delivery of the active agent, in this case DNA or RNA, to the correct cell type and to the correct intracellular compartment. This level of control was not previously required for classical drug molecules in standard products. There is also a greater understanding of the body’s own healing and regenerative capacities that are being harnessed to enable tissue replacement or repair. This can require growth factors and/or cells to be delivered to the body in a spatiotemporally controlled way to support regeneration. In fact, effective delivery is proving one of the most critical aspects for the clinical translation of many of these advanced therapies.
Location, location, location
This challenge has forced pharmaceutical scientists and biomedical engineers to develop more advanced materials, formulations and devices for delivery of therapeutics, including nanomedicines. The number of nanomedicine approvals has been rising and there are ever increasing numbers of nanomedicine products currently in clinical trials with applications in a wide range of clinical fields, including cancer, inflammatory disease, infections and anaemia. For nanomedicines to properly support and enable the development of next-generation medical treatments, multidisciplinary research teams are critical.
RCSI Research Institute’s mission is to integrate basic and clinical research so that advances in medical science are translated as quickly and safely as possible into patient treatments – drug delivery is a key part of this process.
Nanomedicines and advanced therapies
Nanomedicines are now seen as playing a key role in the development of a range of medical technologies. The global nanomedicine market alone is expected to grow to over US$350bln by 2025.
The Drug Delivery and Advanced Materials team at the School of Pharmacy in RCSI, led by myself, focuses on translational and molecular pharmaceutics, including the development of advanced delivery platforms for ‘difficult-to-deliver’ therapeutic cargoes for a range of clinical diseases. Each delivery platform is developed in collaboration with relevant clinical and biomedical research groups based in Dublin hospitals which contribute innovative medicines and expertise in the relevant patient population, including collaborations with Beaumont Hospital, St James’ Hospital and Crumlin Children’s Hospital. Currently, RCSI is developing nanomedicines targeting cancer, ocular disease, neurological disease, orthopaedic disorders and respiratory inflammation and infection, as well as those for applications in regenerative medicine.
The design of nanomedicines is based largely on i) the nature of the therapeutic cargo ii) the route/method of administration and iii) the chemical composition of the platform - the materials chosen as excipients. Therefore, careful selection of nanomaterials and the process for manufacture is critical not just to ensure success in the laboratory but also to ensure the product developed is scalable and cost-effective.
Formulation scientists and the pharmaceutical industry use well-established excipients with classical drug actives in standard drug product formats – tablets, injections and creams. The field of nanomedicine is increasingly focused on developing more sophisticated materials for use as excipients. The Drug Delivery team uses established nanotechnologies, including liposomes and commercial polymers, but also works extensively with pharmaceutical and polymer chemists to develop new smart nanomaterials, which combine multiple functions such as drug release, recognition, responsiveness, tuned biodegradability and support multiple drug payloads.
There is also growing interest in harnessing medical devices as a means of effectively delivering nanomedicines to the patient. The RCSI Translational Research in (Nano)medical Devices programme (TREND Materials) is developing advanced polypeptide nanotechnologies that enable effective drug loading and can be integrated into medical devices for targeted delivery to the patient. Two examples being developed in RCSI at present are in the areas of respiratory and regenerative medicine.
There is a significant unmet clinical need for new treatments for a range of respiratory pathologies and the inhaled route of administration offers many advantages for treatment of respiratory patients, in particular targeting the disease site. The majority of the inhaled medicines currently on the market are delivering small molecule drugs, which are extremely potent and stable.
Delivery technologies are now required to facilitate the integration of advanced therapeutics into inhalers to enable efficient delivery and control their fate once delivered to the lungs. Lung-based delivery platforms to tackle infection such as tuberculosis and inflammation in chronic conditions including cystic fibrosis and chronic obstructive pulmonary disease have been developed in Ireland. These include particulate formats that can target specific cell types in the lungs once delivered using an appropriate inhaler device.
The RCSI Tissue Engineering Research Group (TERG), led by Professor Fergal O’Brien, is a multi-PI research cluster that uses biomaterials, bioengineering and stem cell expertise to develop tissue engineering scaffolds that can recapitulate the natural extracellular matrix (ECM) of the body, thereby restoring the structural and functional properties of damaged or degenerated tissue types.
Ongoing research includes projects focusing on bone, cartilage, cardiovascular, corneal, nerve and respiratory tissue repair. The group has always maintained a strong translational focus. A number of technologies from TERG labs have been patented resulting in the spin out from O’Brien’s lab in 2011 of a high-potential startup called SurgaColl Technologies. The first product from the group commercialised by the startup was HydroxyColl, a collagen-hydroxyapatite bone graft substitute which received regulatory approval in November 2015, and which is currently in clinical use. A second product, ChondroColl, a multi-layered scaffold for cartilage repair, entered clinical trials in 2018.
A major focus has been the integration of nanomedicines within these tissue engineering scaffolds to facilitate the localised and controlled delivery of relevant growth factors. The nature of the growth factors is dependent on the tissue type being regenerated, and TERG is working on delivering these growth factors as either proteins or genes that target host cells and to engineer functional proteins. The cluster has successfully integrated growth-factor loaded nanomedicines into scaffolds for bone, cartilage alone/osteochondral repair, skin/diabetic wounds and peripheral nerves. Advanced processing methods, including electrospinning and 3D printing, are now being harnessed to enable effective and controlled integration of nanomedicines within tissue-engineered scaffolds.
The RCSI Drug Delivery and TERG clusters work closely with the Trinity Centre for Bioengineering and form part of the Advanced Materials and BioEngineering Research Centre (AMBER), the Science Foundation Ireland centre for materials science. AMBER facilitates partnerships between leading researchers in materials science and industry working across the disciplines of physics, chemistry, bioengineering and medicine. The centre’s success in facilitating research excellence is evidenced by Ireland’s international ranking in the areas of nanoscience and materials science, which has increased from sixth and eighth respectively in 2013, when the centre was established, to first and third in 2017.
Together with an international network of collaborators and companies, AMBER has supported new innovations in materials for health, a core research theme for the centre. Facilitating collaboration across disciplines is enabling truly disruptive materials research. For example in 2018, AMBER lead researcher in the School of Physics Professor Johnathan Coleman, and RCSI and Deputy Director of AMBER Professor Fergal O’Brien, published the results of their research collaboration on the development of a new biohybrid material. This biohybrid incorporates collagen with graphene to create a new biomaterial with the potential to regenerate tissues that respond to electrical stimuli, such as the nerves, spinal cord, heart, brain and muscles.
Innovative research of this kind is attracting leading industry engagement in materials for health. In 2018, DePuy Ireland Unlimited Company and Johnson & Johnson Services, Inc. announced a new collaboration, TRANSITION, with AMBER researchers from across Trinity College Dublin, RCSI, University College Dublin and Dublin City University. This five-year project funded under Science Foundation Ireland’s Spokes programme will develop a new class of 3D-printed biological implants that will regenerate, rather than replace, diseased joints. Supporting new research networks and engaging industry is the cornerstone of the centre’s mandate, and will facilitate translation of next-generation nano and materials science innovation from laboratory to therapeutic settings.
A bridge for translation
Along with nanomedicines, researchers are developing new tools for their clinical and commercial translation, including harnessing high content analysis (HCA) to calculate therapeutic dosing at a cellular and potentially even a sub-cellular level, and developing three-dimensional models of disease. There is growing interest from the pharma and biopharma industries and regulators, including the Food and Drug Administration (FDA) and EMA, in developing more appropriate models to develop drugs for human use. A huge percentage of therapeutics effectively get lost in translation. Three-dimensional human tissue models are also being investigated in RCSI for use in drug development, including the assessment of nanomedicines, and for studying cellular crosstalk to understand disease states in cancer, angiogenesis, immunology and infection.
In addition to patenting and commercialising its own biomedical discoveries and delivery platforms, RCSI works closely with a range of industries to fully realise the clinical and commercial potential of its molecules, biomaterials and/or devices. Work with pharma and biopharma companies can often involve overcoming formulation and drug targeting issues for specific therapeutic molecules and, in some cases, match-making these with appropriate materials and biomedical devices for delivery – enabling the convergent technologies on which the next generation of human medicines will be based. RCSI acts as a bridge for translation of cutting-edge biomedical research as it encompasses pharmaceutical, medical, surgical and regulatory know-how and facilities.
The science of formulation has come a long way from the pestle and mortar of old, but by developing nanomedicines in a truly multidisciplinary and cutting-edge research environment, RCSI seeks to contribute to more effective clinical translation of nanomedicines to enhance human health.