Crystalline Antiproliferative Drugs for Intraocular Diseases

描述（由申请人提供）：几种重要的视网膜疾病是由眼睛中细胞的过度增殖引起的;我们计划用新的药理学方法靶向的主要疾病包括由于创伤和增殖性玻璃体视网膜病变以及年龄相关性黄斑变性中的脉络膜新血管形成引起的视网膜脱离。使用局部疗法治疗视网膜疾病的主要问题之一是必须频繁施用的大多数眼内药物的半衰期短。存在一个重要的未满足的需求，即开发一种延长玻璃体内或类似地施用的抗增殖药物的眼内持续时间的方法。我们已经开发了一种新的化学修饰核苷的方法，该方法提供了低溶解度和长效抗增殖或抗病毒活性。在单次玻璃体内注射后，我们已经证明原型化合物的持续生物活性长达20周或更长时间。我们的首要目标是开发长效晶体药物，可以小体积注射到眼睛的玻璃体腔中。由于这些结晶化合物在化学上被设计为具有低水溶性，因此它们将充当极长效的抗增殖化合物，这将有助于减少上述疾病和其他视网膜疾病引起的视网膜损伤和视力丧失。这项资助主要针对增殖性疾病，但我们强调，如果这种晶体药物输送系统在动物和未来的人类研究中取得成功，它将能够扩展到许多其他眼内疾病的治疗。这项资助是两个研究小组的合作，雅各布斯视网膜中心的视网膜研究实验室（弗里曼博士和郑博士）和部门的卡尔霍斯特勒博士。两人都在UCSD Hostetler博士的团队以脂质核苷类似物的合成和评价而闻名，而Freeman博士的团队在眼内药物和视网膜疾病动物模型的开发和表征方面具有高度的技能。我们将一起合成和评估晶体微溶抗增殖化合物的关键脂质类似物。各种体外和体内评价将确定最佳结构和制剂变量，以提供高治疗指数和长眼内半衰期。将在上述重要视网膜疾病的公认动物模型中测试最佳化合物和制剂。该项目可能提供具有延长作用时间的药物，这些药物将是安全的并且具有高治疗指数，并且可能导致用于重要视网膜疾病的新药剂和治疗方法。 公共卫生相关性：这项研究资助将允许开发一种长效眼内注射剂，以防止视网膜脱落，并减少因年龄相关性黄斑变性疤痕造成的损害。我们的研究小组已经发现了修改小抗增殖分子的方法，使它们在眼睛中持续超过5个月，从而最佳地帮助预防这些严重的失明原因。

DESCRIPTION (provided by applicant): Several important retinal disease are caused by excess proliferation of cells in the eye; major ones which we plan to target with a novel pharmacologic approach include retinal detachment due to trauma and proliferative vitreoretinopathy as well as choroidal neovascularization in age related macular degeneration. One of the major problems in using local therapy for retinal diseases is the short half-life of most intraocular drugs that must be administered frequently. There is an important unmet need to develop a way to prolong the intraocular duration of intravitreally or similarly administered antiproliferative drugs. We have developed a novel chemical method of modifying nucleosides which provides for low solubility and long-acting antiproliferative or antiviral activity. Following a single intravitreal injection, we have already demonstrated persistent biological activity of prototype compounds for up to 20 weeks or longer. Our overarching goal is to develop long acting crystalline drugs that can be injected into the vitreous cavity in the eye in small volumes. Because these crystalline compounds are chemically designed to have low water solubility, they will act as extremely long acting anti-proliferative compounds which will help reduce retinal damage and vision loss from the above diseases and other retinal diseases. This grant focuses on diseases of proliferation but we stress that should this crystalline drug delivery system be successful in animal and in the future, in human studies, it will be able to be extended for treatment of many other intraocular diseases. This grant is a collaboration of two research groups, the Retina Research Laboratory at the Jacobs Retina Center (Drs. Freeman and Cheng) and Dr. Karl Hostetler in the Dept. of Medicine, both at UCSD. Dr. Hostetler's group is well known for synthesis and evaluation of lipid nucleoside analogs while Dr. Freeman's group is highly skilled in development and characterization of intraocular drugs and animal models of retinal disease. Together, we will synthesize and evaluate key lipid analogs of crystalline minimally soluble anti-proliferative compounds. Various in vitro and in vivo evaluations will determine the optimal structural and formulation variables to provide for a high therapeutic index and long intraocular half life. The best compounds and formulations will be tested in accepted animal models of the important retinal diseases mentioned above. This project may provide drugs with a prolonged duration of action which will be safe and have a high therapeutic index and may lead to new agents and treatment methods for important retinal diseases. Public Health Relevance: This research grant will allow the development of a long-acting intraocular injection that will prevent retina detachment and reduce the damage due to scarring from age-related macular degeneration. Our research group has discovered ways to modify small antiproliferative molecules so that they last for over 5 months in the eye and are thus optimal to help prevent these severe causes of blindness.