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.

眼睛视网膜或脉络膜中的新生血管形成是导致失明的主要原因的一个关键特征，例如 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。抗血管内皮细胞 生长因子生物制剂对治疗有很大帮助，但治疗抵抗、副作用、频繁玻璃体内注射 注射和高成本仍然是重大限制，因此迫切需要新的治疗方法。先前的研究 揭示了开发此类疗法的一个有吸引力的新目标：血红素合成酶 铁螯合酶（FECH），当被抑制或基因修饰时，会阻止新血管形成。经批准的 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 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，为 “重新利用”这种老药来治疗眼部新生血管。然而，灰黄霉素尚未得到优化 供眼用。为了使灰黄霉素与现有的治疗方式竞争，必须提供它 用于玻璃体内使用的长效制剂。初步数据显示灰黄霉素可配制成 聚合物植入物和聚合物微粒，其能够在至少两个时间内持续释放 应用后数月，可有效对抗激光诱导的脉络膜新生血管（L-CNV）。给定 鉴于这种可行性，长期目标是通过以下方式为现有生物制剂提供安全且负担得起的替代品： 开发长效灰黄霉素系统。假设长期施用灰黄霉素可以预防 眼部新生血管形成。该假设基于先前的研究，支持 FECH 是一种有效的方法 抗血管生成靶点和灰黄霉素作为 FECH 的间接抑制剂。聚合物植入物和颗粒非常适合 已接受的长期眼部药物输送系统。凭借在制剂、药物输送和 新生血管性眼病，以及支持控制灰黄霉素释放的初步结果，该团队已做好准备 通过三个具体目标开发长效灰黄霉素系统作为新的局部疗法： 1. 优化释放 灰黄霉素封装的聚合物微粒和植入物的动力学。聚(乳酸-乙醇酸) 将开发微粒和热熔挤出聚合物植入物，以实现 2-12 个月的交付和 具有生物物理和体外特征。 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、功效和靶标 参与 L-CNV 和 Vldlr-/- 视网膜下新生血管形成小鼠模型。 3. 评价灰黄霉素- 释放聚合物植入物以发挥抗血管生成作用。优化的种植体配方将进行长期测试 DL-氨基己二酸兔视网膜新生血管的体内长期药物释放、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形成 通过创建缓释制剂进行治疗。如果成功的话，这些配方将抑制 新生血管形成的进展，对患者造成的不便和医疗保健系统的成本最小化。