Nanoparticle delivery of antiangiogenic genes

描述：（申请人的摘要）血管生成是一种致盲性并发症， 许多眼部疾病，包括糖尿病和镰状细胞性视网膜病变，视网膜病变 早产儿（ROP）和渗出性年龄相关性黄斑变性（ARMID）。 尽管目前正在评估超过50种抗血管生成因子， 临床试验的eir对肿瘤的影响，只有两个是在临床试验， 眼睛里的血管生成。一个需要垫脚石走向抗血管生成 眼睛中的治疗一直是将药剂递送到 选择性新生血管本提案将评估以下方面的交付情况： 编码抗血管生成剂的基因，通过以下途径将其转移至眼睛中的血管生成位点： 非病毒手段。这些基因将被封装在壳聚糖纳米颗粒中， 颗粒注入玻璃体或眼球筋膜下间隙。该基因 递送系统具有几个吸引人的特征：1）配体可以缀合 以刺激受体介导的内吞作用（例如：乙酰化的 LDL）; 2）可以掺入溶酶体溶解剂以减少脂质体的降解; 内体和溶酶体隔室中的DNA（例如：氯喹）; 3）其他 生物活性剂（蛋白质的或非蛋白质的）或多个质粒可 4）DNA的生物利用度可以提高，因为 保护免受基质的核酸酶降解; 5）纳米颗粒可以 冻干保存而不损失生物活性。色素上皮源性 因子（PEDF）将作为原型基因进行初步评估， 这种新的抗血管生成治疗方法。总之，壳聚糖 纳米颗粒是无毒的、可生物降解的颗粒， 将大基因传递到眼睛的靶细胞。这项提案的目的是 将内源性抗血管生成剂的基因递送至眼部的 新生血管形成

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.