Extending the range of tamponades for the delivery of therapeutic agents to treat proliferative vitreoretinopathy

This proposal will develop novel silicone oil tamponades providing controlled drug delivery to the back of the eye to prevent proliferative vitreoretinopathy, a blinding condition with no gold standard for treatment. Proliferative vitreoretinopathy (PVR) is a disease that can develop following retinal detachment. It is the primary cause of failure following surgery to re-attach the retina and often results in poor visual outcome. Despite many strategies, there has been no improvement in outcome over the last 20 years and these patients can lose their sight. Complicated retinal detachments require silicone oil to re-attach the retina. Effective pharmacological treatment of PVR requires controlled, sustained release of a drug. A key challenge is that certain drugs that could be used to control PVR cannot dissolve in the oil. If injected into the eye they accumulate around the oil and cause toxicity to the retina. Furthermore, repeat injections increase the risk of complications. Thus, an entirely new approach is required.
This proposal uniquely aims to develop a silicone oil tamponade with a dual role, firstly to act as a tamponade agent and secondly to be a novel drug-delivery system. It will use non-steroidal anti-inflammatory drugs (NSAIDS), which have the potential to address the inflammatory as well as the proliferative stages of PVR. The project will use novel chemical techniques to bind drugs to the silicone oil so that they will be released in a sustained, controlled manner. Preliminary data has demonstrated that drugs can be bound to silicone oil, and that the release profile of the drug can be changed by varying the blend of the oil. An in vitro model of the oil-filled eye, incorporating the flow of aqueous out of the eye, has also been developed. This will allow studies of drug clearance from the eye.
This programme proposes the combined development and in vitro biological evaluation of a new drug delivery system, focussed on NSAIDS, with additional drug candidates for risk mitigation. Furthermore, it will develop a new approach to biological evaluation that will make future animal trials more efficient. Drugs will be bound to silicone oil using several strategies and release studies undertaken. The conditions required to release the drug under clinically relevant conditions, at a concentration identified as being non-toxic but effective at controlling cell behaviour, will be identified. Drug-oil products will also be assessed in a variety of laboratory models to assess how effective they are at controlling PVR-like behaviour, using techniques that are well-established in the host laboratories. The testing will be iterative, with results being fed back to inform the development of the prototype oils. The physical and optical properties of the drug-oil products, as well as suitable methods for sterilisation, will also be assessed.
Development of new methods for drug delivery could have significant benefits for industry and the healthcare system. Furthermore, the repurposing of existing drugs for treatment of PVR would speed the translation of treatments to the clinic and represent a new stream of revenue for these drugs. The potential to protect any intellectual property from this project will be kept under review, with a view to future commercial exploitation. Results will also be shared with patient groups in St Paul's Eye Hospital, ensuring end-user engagement. Output from this project will stimulate research into novel routes of ocular drug delivery and further development of in vitro modelling of the eye. Both aspects of the research will be of great interest to academic and industrial researchers.
This project will deliver a novel, drug-containing oil that can release drugs at therapeutic levels over several weeks and that will be ready to be tested in animals prior to human trials. This is designed to be an effective therapy for a sight-threatening condition that at the moment has no reliable treatment.

Economy
Successful drug treatment for proliferative vitreoretinopathy (PVR), scar tissue formed following repair of a detached retina, would be a major step forward in the treatment of vision loss. Relevant exploitation of research on this subject will provide significant benefits for the pharmaceutical industry and the healthcare sector. It is anticipated that the re-purposing of non-steroidal anti-inflammatory drugs will be of great interest to pharmaceutical companies because of the wide range of conditions this type of drug delivery could be applied to. Further, re-purposing would save companies huge resources normally required to bring a new drug to market. The proposed research could lead to improved application of silicones throughout the biomedical sector. In addition, silicone is an industrial lubricant and the controlled binding and release of additives may improve performance in some applications (e.g. manufacturing processes). The University will seek to protect and exploit any new intellectual property and, building on a strong track record of previous successful industry collaborations, would expect to attract significant investment in new start-up companies to commercialise this technology, creating new jobs and contributing to local wealth creation. For the NHS and other healthcare providers, drug delivery via novel silicone oils could lead to significant time and cost savings through the reduction in the number of invasive treatments and associated hospital visits.

Society
Silicone oil able to act as a drug delivery device would change clinical practice: this would reduce the burden (time and cost) to the NHS, dramatically improve quality of life for patients and finally offer an effective treatment for a blinding condition. The incidences of PVR and the high number of surgical re-interventions required following retinal detachment surgery could be reduced significantly, thus avoiding the need for patients to undergo further invasive treatments and regular hospital visits. A reduction in PVR would leave patients with improved sight in the long term.
The proposed project is also an important step towards developing an in vitro model of drug delivery to the eye, which would reduce the number of animal studies required to take a product through to development. Such a model would be invaluable for companies as it offers a much cheaper and ethically beneficial alternative to expensive animal studies.

Knowledge
The proposed work will provide more knowledge on the synthesis of silicone oil-drug conjugates, providing data for future grant applications, publications and product development. The PI will be a direct beneficiary of this project, gaining experience in a discipline outside, but related to, her current training which is vital for progression in the field of biomaterials.
The academic community will benefit directly from the new knowledge generated by this project. It will be of specific interest to groups in the universities of Sheffield, Ulster, and UCL, where there is already research into the development of biomaterials for ophthalmic applications. The knowledge generated will have applications outside of ocular drug delivery, including biomedical research and wider industrial applications of silicones.

People
The PI will continue to gain valuable experience in the protection and exploitation of intellectual property, direct experience of working with industry and valuable new skills in inter-related disciplines such as drug delivery and nanoparticle chemistry. The PDRA will gain experience in the field of silicone chemistry and drug delivery, and of working in the biomaterials arena, in particular working with clinicians. Prof Rannard will gain a better understanding of ophthalmic bioengineering and in particular has an interest in exploring further applications of the drug delivery techniques he is developing for treatment of HIV/AIDS.