Crystalline Antiproliferative Drugs for Intraocular Diseases

治疗眼内疾病的结晶抗增殖药物

• 批准号: 8132308
• 负责人: William R. Freeman
• 金额: $ 50.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8132308
• 关键词: Age related macular degeneration; Animal Model; Animals; Antiviral Agents; Biological; Blindness; Cell Count; Cell Line; Cell Proliferation; Cell Survival; Cells; Chemicals; Chemistry; Choroid; Choroidal Neovascularization; Cicatrix; Collaborations; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug toxicity; Endothelial Cells; Evaluation; Exudative age-related macular degeneration; Eye; Eye diseases; Fibroblasts; Foscarnet; Future; Goals; Grant; Growth; Half-Life; Human; In Vitro; Injection of therapeutic agent; Interphase Cell; Laboratory Research; Lasers; Lead; Lipids; Liposomes; Local Therapy; Maximum Tolerated Dose; Measures; Medicine; Methods; Modeling; Modification; Neuroglia; Neurons; New Agents; Nucleosides; Oryctolagus cuniculus; Particle Size; Peptides; Performance; Pharmaceutical Preparations; Prodrugs; Proliferative Vitreoretinopathy; Prophylactic treatment; Rattus; Recurrence; Relative (related person); Research; Research Project Grants; Retina; Retinal Detachment; Retinal Diseases; Retinal Ganglion Cells; Retinitis; Safety; Solubility; Stress; Structure; Structure of retinal pigment epithelium; System; Testing; Therapeutic Index; Toxic effect; Toxicity Tests; Toxicology; Trauma; Vascular Endothelial Growth Factor Receptor; Water; Work; analog; antiproliferative drugs; design; drug distribution; improved; in vivo; inhibitor/antagonist; novel; nucleoside analog; nucleotide analog; pharmacokinetic model; phosphonate; prevent; prototype; public health relevance; retinal damage; small molecule; success; tissue culture; water solubility; wound

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.

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过多的增殖引起的；我们计划采用一种新型的药物方法来靶向的主要主要是由于创伤和增生性玻璃体肾上腺病以及与年龄相关的黄斑变性而导致的视网膜脱离。使用局部治疗进行视网膜疾病的主要问题之一是大多数必须经常服用的眼内药物的半衰期。有一个重要的未满足需要开发一种方法来延长玻璃体内或类似施用的抗增殖药物的眼内持续时间。我们开发了一种新的化学方法来修饰核苷，从而提供低溶解度和长效抗抗逆变活性或抗病毒活性。单次注射后，我们已经证明了原型化合物的持续生物学活性长达20周或更长时间。我们的总体目标是开发长作用的结晶药物，这些药物可以在小体积中注入眼睛的玻璃体腔。由于这些结晶化合物的化学设计为低水溶性，因此它们将作为极长的作用抗增殖化合物，这将有助于减少上述疾病和其他视网膜疾病的视网膜损伤和视力丧失。这项赠款的重点是增殖疾病，但我们强调的是，如果这种结晶药物递送系统在动物中以及将来，在人类研究中取得成功，它将能够扩展以治疗许多其他眼内疾病。这笔赠款是两个研究小组的合作，分别是雅各布斯视网膜中心（Jacobs Retina Center）（Freeman和Cheng博士）的Retina研究实验室，以及在UCSD的医学部的Karl Hostetler博士。 Hostetler博士的小组以合成和评估脂质核苷类似物而闻名，而Freeman博士的小组在眼内药物的发育和表征和视网膜疾病的动物模型方面非常熟练。总之，我们将合成和评估晶体可溶性抗增殖化合物的关键脂质类似物。各种体外和体内评估将确定最佳的结构和配方变量，以提供高治疗指数和长期的眼内半寿命。最好的化合物和配方将在上述重要视网膜疾病的公认动物模型中进行测试。该项目可能会为药物提供长时间的作用持续时间，这将是安全的，并且具有较高的治疗指数，并可能导致重要视网膜疾病的新药物和治疗方法。 公共卫生相关性：这项研究补助金将允许开发长效的人工注射，以防止视网膜脱离并减少因年龄相关的黄斑变性而导致的损害。我们的研究小组发现了修改小抗增生分子的方法，使它们可以持续5个月以上，因此最佳可帮助防止这些严重的失明原因。