Biodegradable serpin-peptide-carrying nano- and microparticles for wet AMD

用于湿性 AMD 的可生物降解的丝氨酸蛋白酶抑制剂肽携带纳米颗粒和微米颗粒

• 批准号: 8425250
• 负责人: Jordan Green
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425250
• 关键词: Affect; Age; Age related macular degeneration; Angiogenesis Inhibitors; Biocompatible Materials; Biological; Biomimetics; Blindness; Characteristics; Choroidal Neovascularization; Development; Disadvantaged; Drug Formulations; Encapsulated; Endothelial Cells; Ensure; Evaluation; Eye; Frequencies; Genetic Models; Half-Life; Human; In Vitro; Injection of therapeutic agent; Mediating; Modality; Modeling; Pathway interactions; Patients; Peptide Receptor; Peptides; Property; Proteolysis; Research Proposals; Resistance; Retinal; Serpins; Solutions; Specificity; System; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Vascular Endothelial Growth Factors; Work; angiogenesis; aqueous; base; controlled release; design; improved; in vitro Assay; in vitro activity; in vivo; intravitreal injection; mouse model; nano; nanoparticle; neovascularization; novel; particle; pigment epithelium-derived factor; pre-clinical; public health relevance; receptor; research study; rho

DESCRIPTION (provided by applicant): Wet age-related macular degeneration (AMD) is the most prevalent cause of severe vision loss and blindness in patients over the age of 60 in the US. Subretinal neovascularization is responsible for most severe loss of vision. A newly discovered peptide, SP6001, is promising for treating wet AMD as it works through multiple antiangiogenic mechanisms. Small peptides possess many advantageous characteristics as therapeutic agents, such as high specificity and low toxicity, but their main disadvantage is their short half-life. To counter this possible limitation, a novel retroinverted version of the peptide ill be constructed and it will be protected from degradation by being encapsulated within a polymeric particle system. The particle delivery systems will ensure safe and effective delivery of the novel antiangiogenic peptide along with its controlled release within the eye. New biomaterials and particle formulations will be synthesized and then particle properties, peptide release, and biological activity in vitro evaluated. Following experiments on human retinal endothelial cells, the particle/peptide systems will be tested in vivo in mouse models for wet AMD. Retroinverted peptide will be compared to standard and scrambled peptide and efficacy of particle formulations will be evaluated for 4 months. In vitro assays will also be performed to identify the receptors that the peptide acts on and the distribution of these receptors in the eye under normal conditions and under AMD conditions. A new validated treatment modality that can inhibit both VEGF-mediated and non-VEGF- mediated angiogenic pathways and that can reduce the frequency of necessary intravitreal injections would significantly improve the currently used treatments for AMD.

描述（由申请人提供）：湿性年龄相关性黄斑变性 (AMD) 是美国 60 岁以上患者严重视力丧失和失明的最常见原因。视网膜下新生血管形成是导致最严重视力丧失的原因。新发现的肽 SP6001 通过多种抗血管生成机制发挥作用，有望用于治疗湿性 AMD。小肽作为治疗剂具有许多有利的特性，例如高特异性和低毒性，但其主要缺点是 半衰期短。为了克服这种可能的限制，我们将构建一种新的反向反转形式的肽，并将其封装在聚合物颗粒系统中以防止降解。颗粒递送系统将确保新型抗血管生成肽的安全有效递送及其在眼内的受控释放。将合成新的生物材料和颗粒制剂，然后评估颗粒特性、肽释放和体外生物活性。在人视网膜内皮细胞上进行实验后，颗粒/肽系统将在湿性 AMD 小鼠模型中进行体内测试。逆向肽将与标准肽和乱序肽进行比较，并在 4 个月内评估颗粒制剂的功效。还将进行体外测定，以确定该肽作用的受体以及这些受体在正常条件和 AMD 条件下在眼睛中的分布。一种新的经过验证的治疗方式可以抑制 VEGF 介导和非 VEGF 介导的血管生成途径，并且可以减少必要的玻璃体内注射的频率，这将显着改善目前使用的 AMD 治疗方法。