Long-acting formulations of griseofulvin for ocular neovascularization therapy

用于眼部新生血管治疗的灰黄霉素长效制剂

• 批准号: 10682059
• 负责人: Timothy W Corson
• 金额: $ 52.33万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682059
• 关键词: Acids; Angiogenesis Inhibitors; Animal Model; Antifungal Agents; Apoptosis; Biological Factors; Biological Products; Blindness; Cannulas; Cell Proliferation; Cell model; Choroid; Choroidal Neovascularization; Clinical; Complement; Custom; Data; Development; Devices; Disease; Disease Progression; Drug Delivery Systems; Drug Kinetics; Drug Stability; Encapsulated; Endothelial Cells; Ensure; Enzymes; Exudative age-related macular degeneration; Eye; Eye diseases; Formulation; Frequencies; Glycolates; Goals; Griseofulvin; Healthcare Systems; Heme; Human; Implant; In Vitro; Injections; Iron; Kinetics; Lasers; Lead; Local Therapy; Longevity; Methods; Mission; Modality; Modeling; Mus; Mutation; Oryctolagus cuniculus; Oxygen; Patients; Pharmaceutical Preparations; Polymers; Public Health; Research; Research Support; Resources; Retina; Retinal Diseases; Retinal Neovascularization; Signal Transduction; Specificity; System; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Toxic effect; Toxicity Tests; Tube; United States National Institutes of Health; Vascular Endothelial Growth Factors; Visual impairment; angiogenesis; biomaterial compatibility; biophysical properties; cell growth; clinically relevant; cost; effective therapy; experimental study; ferrochelatase; human disease; in vivo; inhibitor; innovation; intravitreal injection; knock-down; melting; migration; mouse model; neovascular; neovascularization; novel; novel therapeutics; ocular neovascularization; particle; polycaprolactone; prevent; proliferative diabetic retinopathy; protoporphyrin IX; side effect; small molecule; stem; targeted treatment; therapeutic evaluation; therapy resistant

Neovascularization in the retina or choroid of the eye is a key feature of major causes of blindness such as neovascular age-related macular degeneration and proliferative diabetic retinopathy. Anti-vascular endothelial growth factor biologics have greatly aided treatment, but resistance to therapy, side effects, frequent intravitreal injections, and high cost remain significant limitations, creating a critical need for new therapy. Previous research revealed an appealing new target for the development of such therapies: the heme synthesis enzyme ferrochelatase (FECH), which, when inhibited or genetically modified, blocks neovascularization. The approved anti-fungal drug griseofulvin is naturally metabolized in vivo to form a FECH inhibitor. Griseofulvin thus blocks angiogenesis in vitro and in retinal and choroidal neovascularization animal models, offering promise for “repurposing” this old drug for ocular neovascularization treatment. However, griseofulvin has not been optimized for ocular use. For griseofulvin to be competitive with existing therapeutic modalities, it must be made available in a long-acting formulation for intravitreal use. Preliminary data reveal that griseofulvin can be formulated into polymeric implants and polymeric microparticles, which are amenable to sustained release over at least two months and effective against laser-induced choroidal neovascularization (L-CNV) weeks after application. Given this feasibility, the long-term goal is to provide a safe and affordable alternative to existing biologic agents by developing long-acting griseofulvin systems. The hypothesis is that long-term griseofulvin delivery can prevent ocular neovascularization. The hypothesis is based on prior research supporting FECH as an effective antiangiogenic target and griseofulvin as an indirect inhibitor of FECH. Polymeric implants and particles are well- received, long-term ocular drug delivery systems. With combined expertise in formulation, drug delivery, and neovascular eye disease, and preliminary results supporting controlled griseofulvin release, the team is poised to develop long-acting griseofulvin systems as new local therapies via three specific aims: 1. To optimize release kinetics of griseofulvin-encapsulated polymeric microparticles and implants. Poly(lactic-co-glycolic acid) microparticles and hot melt extruded polymeric implants will be developed to achieve 2-12 month delivery and characterized biophysically and in vitro. 2. To evaluate griseofulvin microparticles for antiangiogenic effects. Optimized microparticle formulations will be tested for long-term drug release in vivo, toxicity, efficacy, and target engagement in the L-CNV and Vldlr-/- subretinal neovascularization mouse models. 3. To evaluate griseofulvin- releasing polymeric implants for antiangiogenic effects. The optimized implant formulation will be tested for long- term drug release in vivo, toxicity, and efficacy in the DL-aminoadipic acid rabbit retinal neovascularization model. The core innovation of this strategy is the repurposing of griseofulvin for ocular neovascularization therapy by creation of sustained release formulations. If successful, these formulations would inhibit the progression of neovascularization with minimum inconvenience to the patients and cost to the healthcare system.

眼视网膜或脉络膜中的新生血管形成是主要致盲原因的关键特征， 新生血管性年龄相关性黄斑变性和增殖性糖尿病视网膜病变。抗血管内皮 生长因子生物制剂对治疗有很大的帮助，但对治疗有抗性，副作用，频繁的玻璃体内注射， 注射和高成本仍然是显著的限制，产生了对新疗法的迫切需求。以前的研究 揭示了一个有吸引力的新目标，为发展这种疗法：血红素合成酶 铁螯合酶（FECH），当被抑制或基因修饰时，阻断新血管形成。核定 抗真菌药物灰黄霉素在体内自然代谢形成FECH抑制剂。灰黄霉素因此阻断 在体外以及视网膜和脉络膜新生血管动物模型中的血管生成， “再利用”这种旧药物用于眼部新生血管治疗。然而，灰黄霉素尚未优化 供眼部使用。灰黄霉素要想与现有的治疗方法竞争， 用于玻璃体内使用长效制剂。初步数据显示，灰黄霉素可以配制成 聚合物植入物和聚合物微粒，其适于在至少两个月内持续释放， 月，并在应用后数周有效对抗激光诱导的脉络膜新生血管形成（L-CNV）。给定 这种可行性，长期目标是提供一种安全和负担得起的替代现有的生物制剂， 研发长效灰黄霉素系统假设长期灰黄霉素给药可以预防 眼部新生血管该假设是基于先前的研究支持FECH作为一种有效的 抗血管生成靶点和灰黄霉素作为FECH的间接抑制剂。聚合物植入物和微粒- 接受的长期眼部给药系统。凭借在配方、药物输送和 新生血管性眼病，初步结果支持控制灰黄霉素释放，该小组准备 开发长效灰黄霉素系统作为新的局部疗法，通过三个具体目标：1.优化释放 灰黄霉素包封的聚合物微粒和植入物的动力学。聚乳酸-羟基乙酸共聚物 将开发微粒和热熔挤出聚合物植入物以实现2-12个月的递送， 在生物药理学和体外进行了表征。2.评价灰黄霉素微粒的抗血管生成作用。 将测试优化的微粒制剂的体内长期药物释放、毒性、功效和靶点。 在L-CNV和Vldlr-/-视网膜下新生血管形成小鼠模型中的参与。3.为了评估灰黄霉素- 释放用于抗血管生成作用的聚合物植入物。将对优化的植入物配方进行长期测试- DL-氨基己二酸兔视网膜新生血管中的体内药物释放、毒性和疗效 模型该策略的核心创新是将灰黄霉素重新用于眼部新生血管 通过创建持续释放制剂进行治疗。如果成功，这些制剂将抑制 新血管形成的进展，对患者的不便和医疗保健系统的成本最小。