High Density Lipoprotein Nanoparticles for siRNA Delivery

描述（由申请人提供）：我们的目标是开发一种基于靶向纳米颗粒的癌症疗法。我们选择晚期前列腺癌（PCa）是因为雄激素剥夺治疗（ADT）是唯一有效的治疗选择，在相对短暂的初始反应后失败。 由于其高死亡率和对患者生活质量的显著影响，晚期PCa的新型治疗方式非常重要且非常需要。 抗雄激素的失败至少部分是由于PCa肿瘤细胞自主的局部睾酮产生。因此，晚期前列腺癌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。 不溶于水溶液的胆固醇通过脂蛋白，特别是PCa中的高密度脂蛋白（HDL）内化。HDL和胆固醇摄取通过HDL摄取受体、清道夫受体B-1（SR-B1）发生，其在晚期PCa中上调。我们将使用增加的SR-B1表达用于用纳米缀合物靶向PCa以递送基因靶向siRNA。我们假设，使用我们小组开创的一种新方法，通过仿生球形HDL纳米颗粒的稳健和定向制造，可以促进核酸货物的有效全身递送。最近，我们的研究小组利用金纳米颗粒支架（AuNP）来产生仿生HDL，其概括了成熟球形HDL的大小，形状，表面化学和胆固醇结合特性。所得纳米颗粒（HDL AuNP）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是无毒的，在正常结合HDL的组织中积累，并起到调节靶基因表达的作用。 我们建议表征和优化负载siRNA的HDL AuNP缀合物，并在体外和前列腺癌的临床前模型中测试其性质。我们预期携带siRNA的HDL AuNP将在SR-B1表达的位点中积累，包括在SR-B1过表达的实验PCa中，并有效地将siRNA递送至PCa细胞。 如此递送的siRNA将阻断靶基因的表达。 作为模型靶点，我们选择了雄激素受体，一种晚期前列腺癌的关键介质。该项目的成功将为晚期前列腺癌提供有效的靶向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.