Nanoparticle delivery of antiangiogenic genes

描述：(申请人摘要)血管生成是一种致盲的并发症 许多眼科疾病，包括糖尿病和镰状细胞视网膜病变，视网膜病变 早产儿(ROP)和渗出性年龄相关性黄斑变性(ARMID)。 尽管目前有50多种抗血管生成因子正在进行评估 EIR对肿瘤的临床试验，只有两个正在进行临床试验 眼睛里的血管生成。抗血管生成需要垫脚石 眼睛的治疗一直是将毒剂输送到 选择性新生血管成形术。该提案将评估 编码抗血管生成剂的基因对眼内血管生成部位的作用 非病毒手段。这些基因将被包裹在壳聚糖纳米颗粒中，并 注入玻璃体内的颗粒，或注入到凸起的间隙中。这个基因 给药系统有几个吸引人的特点：1)配体可以共轭 至纳米粒以刺激受体介导的内吞作用(例如：乙酰化 低密度脂蛋白)；2)可以加入溶酶体降解剂，以减少 内体和溶酶体室中的DNA(例如：氯喹)；3)其他 生物活性物质(含蛋白质或不含蛋白质)或多重质粒可 4)DNA的生物利用度可以提高，因为 防止基质对核酸酶的降解；5)纳米颗粒可以 冷冻干燥保存，不会失去生物活性。色素上皮源性 因子(PEDF)将作为初步评估的原型基因 这种新的抗血管生成治疗方法。综上所述，壳聚糖 纳米颗粒是无毒的、可生物降解的颗粒，具有 将大基因输送到眼睛的靶细胞。这项提议的目标是 将内源性抗血管生成药物的基因输送到眼部部位 新生血管。

DESCRIPTION: (Applicant's Abstract) Angiogenesis is a blinding complication of many eye diseases including diabetic and sickle cell retinopathy, retinopathy of prematurity (ROP) and exudative age-related macular degeneration (ARMID). Although over 50 antiangiogenic factors are currently being evaluated in clinical trials for eir effect on tumors, only two are in clinical trial for angiogenesis in the eye. One needed stepping stone towards antiangiogenic therapy in the eye has been the delivery of the agents to the nieovascularization selectively. This proposal will evaluate the delivery of genes encoding for antiangiogenic agents to sites of angiogenesis in the eye by non-viral means. The genes will be encapsulated in chitosan nanoparticles and the particles injected into vitreous or the subtenon's space. This gene delivery system has several attractive features: 1) ligands can be conjugated to the nanoparticles to stimulate receptor-mediated endocytosis (ex: acetylated LDL); 2) lysosomolytic agents can be incorporated to reduce degradation of the DNA in the endosomal and lysosomal compartments (ex: chloroquine); 3) other bioactive agents (proteinacious or non-proteinacious) or multiple plasmids can be co-encapsulated; 4) bioavailability of the DNA can be improved because of protection from nuclease degradation by the matrix; 5) the nanoparticles can be lyophilized for storage without loss of bioactivity. Pigment epithelial-derived factor (PEDF) will serve as the prototypic gene to be evaluated initially by this novel antiangiogenic therapeutic approach. In summary, chitosan nanoparticles are nontoxic, biodegradable particles that have the potential of delivering large genes to target cells of the eye. The goal of this proposal is to deliver genes for endogenous antiangiogenic agents to sites of ocular neovascularization.