High Density Lipoprotein Nanoparticles for siRNA Delivery

描述(申请人提供)：我们的目标是开发一种基于纳米颗粒的靶向癌症治疗方法。我们选择晚期前列腺癌(PCA)是因为雄激素剥夺疗法(ADT)是唯一有效的治疗选择，在相对较短的初始反应后失败。由于其高死亡率和对患者生活质量的显著影响，晚期PCa的新的治疗方式是非常重要和迫切需要的。抗雄激素的失败至少在一定程度上是由于前列腺癌肿瘤细胞自主产生局部睾酮。因此，高级PCA对胆固醇产生了独特的需求，胆固醇是雄激素生物合成的底物。胆固醇不溶于水，通过脂蛋白，特别是前列腺癌中的高密度脂蛋白(HDL)内化。高密度脂蛋白和胆固醇的摄取通过高密度脂蛋白摄取受体清道夫受体B-1(SR-B1)发生，后者在晚期前列腺癌中上调。我们将利用增加的SR-B1表达用于以纳米偶联物为靶向的PCA来传递基因靶向的siRNA。我们假设，利用我们团队首创的一种新方法，通过稳健和定向的仿生球形高密度脂蛋白纳米颗粒的制造，可以促进高效的系统地运送核酸货物。最近，我们团队利用金纳米颗粒支架(AuNP)来生成仿生高密度脂蛋白，它概括了成熟球形高密度脂蛋白的大小、形状、表面化学和胆固醇结合特性。由此产生的纳米颗粒(高密度脂蛋白、金纳米颗粒)以高亲和力吸附核酸。初步的体外和体内实验表明，这些独特的生物材料无毒，在正常结合高密度脂蛋白的组织中蓄积，并具有调节靶基因表达的功能。我们建议对负载siRNA的高密度脂蛋白AuNP结合物进行表征和优化，并在体外和前列腺癌临床前模型中测试它们的性质。我们预计携带siRNA的HDLAuNPs将积聚在SR-B1表达的部位，包括SR-B1过度表达的实验性PCa，并有效地将siRNA运送到PCa细胞。如此一来，小干扰RNA将阻断靶基因的表达(S)。作为一个模型靶点，我们选择了雄激素受体，这是晚期前列腺癌的关键媒介。该项目的成功将导致对晚期前列腺癌进行有效和有针对性的siRNA治疗。

DESCRIPTION (provided by applicant): We aim to develop a targeted nanoparticle-based cancer therapy. We chose advanced prostate cancer (PCa) because androgen deprivation therapy (ADT), the only effective therapeutic option, fails after a relatively brief initial respone. Because of its high mortality rate, and significant impact on patient quality of life, novel treatment modalities for advanced PCa are highly important and much needed. The failure of anti-androgens is due, at least in part, to autonomous local testosterone production by PCa tumor cells. As a result, advanced PCa develops a unique requirement for cholesterol, which is a substrate for androgen biosynthesis. Cholesterol, insoluble in aqueous solution, is internalized via lipoproteins, specifically high density lipoproteins (HDL) in PCa. HDL and cholesterol uptake occur through the HDL uptake receptor, scavenger receptor B-1 (SR-B1), which is up-regulated in advanced PCa. We will employ the increased SR-B1 expression for PCa targeting with nanoconjugates to deliver gene targeted siRNA. We hypothesize that efficient systemic delivery of nucleic acid cargo can be facilitated by the robust and directed fabrication of biomimetic spherical HDL nanoparticles using a novel approach pioneered by our group. Recently, our group utilized a gold nanoparticle scaffold (AuNP) to generate biomimetic HDLs that recapitulate the size, shape, surface chemistry, and cholesterol binding properties of mature spherical HDLs. The resulting nanoparticles (HDL AuNPs) adsorb nucleic acids with high affinity. Initial in vitro and in vivo experiments show that these unique biomaterials are non-toxic, accumulate in the tissues that normally bind HDL, and function to regulate target gene expression. We propose to characterize and optimize the HDL AuNP conjugates loaded with siRNA and to test their properties in vitro and in preclinical model of prostate cancer. We expect that HDL AuNPs carrying siRNA will accumulate in the sites of SR-B1 expression, including in experimental PCa where SR-B1 is over-expressed, and efficiently deliver siRNA to PCa cells. Thus delivered, siRNA will block the expression of target gene(s). As a model target we chose the androgen receptor, a critical mediator of advanced prostate cancer. Project success will result in an effective and targeted siRNA therapy for advanced prostate cancer.