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

这项提案将开发新型硅油填充物，提供受控的眼后药物输送，以防止增殖性玻璃体视网膜病变，这是一种没有黄金治疗标准的失明疾病。增殖性玻璃体视网膜病变(PVR)是视网膜脱离后的一种疾病。这是手术后视网膜重新附着失败的主要原因，通常会导致较差的视觉结果。尽管采取了许多策略，但在过去的20年里，结果并没有改善，这些患者可能会失去视力。复杂的视网膜脱离需要硅油来重新连接视网膜。PVR的有效药物治疗需要控制、持续的药物释放。一个关键的挑战是，某些可以用来控制PVR的药物无法在石油中溶解。如果注射到眼睛里，它们会聚集在油脂周围，对视网膜造成毒性。此外，重复注射会增加并发症的风险。因此，需要一种全新的方法。该方案的独特目的是开发一种具有双重作用的硅油填充物，首先作为填充剂，其次作为一种新型的药物输送系统。它将使用非类固醇抗炎药(NSAID)，这些药物有可能解决PVR的炎症和增殖期。该项目将使用新的化学技术将药物绑定到硅油上，以便它们将以持续、受控的方式释放。初步数据表明，药物可以结合到硅油上，并且药物的释放情况可以通过改变油的混合物来改变。一个充满油的眼睛的体外模型，结合了眼内水的流动，也已经被开发出来。这将使药物从眼睛中清除的研究成为可能。该方案建议结合开发和体外生物评价一种新的药物输送系统，重点放在非类固醇抗炎药上，并增加用于降低风险的候选药物。此外，它还将开发一种新的生物评估方法，使未来的动物试验更加有效。药物将使用几种策略结合到硅油上，并进行释放研究。将确定在临床相关条件下释放药物所需的条件，该浓度被确定为无毒但有效地控制细胞行为。药油产品还将在各种实验室模型中进行评估，以评估它们在控制PVR样行为方面的有效性，使用东道国实验室成熟的技术。测试将是迭代的，结果将被反馈，以告知原型油的开发。还将评估药物-油产品的物理和光学性质，以及合适的灭菌方法。开发新的药物输送方法可能会对工业和医疗体系产生重大好处。此外，改变现有治疗PVR的药物的用途将加快将治疗转化为临床的速度，并为这些药物提供新的收入来源。保护该项目知识产权的可能性将不断得到审查，以期在未来进行商业开发。结果还将与圣保罗眼科医院的患者小组分享，以确保最终用户的参与。该项目的成果将促进对眼部药物输送新途径的研究，并进一步发展眼睛的体外模型。这两个方面的研究都将引起学术和工业研究人员的极大兴趣。该项目将提供一种新型的含药油，可以在几周内释放出治疗水平的药物，并准备在人体试验之前在动物身上进行测试。这被设计成一种有效的治疗方法，用于治疗目前还没有可靠治疗方法的视力威胁疾病。

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.