High Density Lipoprotein Nanoparticles for siRNA Delivery

用于 siRNA 递送的高密度脂蛋白纳米颗粒

• 批准号: 9088367
• 负责人: Colby Shad Thaxton
• 金额: $ 32.06万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9088367
• 关键词: Address; Affinity; Anabolism; Androgen Antagonists; Androgen Receptor; Androgens; Antisense Oligonucleotides; Binding; Biocompatible; Biocompatible Materials; Biological; Biomimetics; Bypass; Caliber; Cell Culture Techniques; Cells; Chemical Engineering; Chemistry; Cholesterol; Clinical; Cytoplasm; Early Endosome; Epithelial Cells; Exocytosis; Failure; Gene Expression; Gene Expression Regulation; Gene Targeting; Gold; Growth; Health; Hepatocyte; High Density Lipoprotein Cholesterol; High Density Lipoproteins; In Situ; In Vitro; KDR gene; Kinetics; Lipoprotein Receptor; Lipoproteins; Low-Density Lipoproteins; Lysosomes; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediator of activation protein; Methods; MicroRNAs; Modality; Modeling; Mus; Nanoconjugate; Nanostructures; Nuclear; Nucleic Acids; Pathway interactions; Patients; Pharmacology; Pre-Clinical Model; Production; Property; Prostate; Quality of life; Recombinants; Resistance; Serum; Shapes; Site; Small Interfering RNA; Specificity; Surface; Technology; Testing; Testosterone; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; aqueous; base; cancer cell; cancer therapy; combat; deprivation; effective therapy; flexibility; gene therapy; high density lipoprotein receptor; in vivo; innovation; knock-down; macrophage; migration; mortality; multidisciplinary; nanoparticle; neoplastic cell; novel; novel strategies; prostate cancer cell; prototype; receptor; receptor expression; research study; response; scaffold; scavenger receptor; self assembly; small molecule therapeutics; success; targeted delivery; therapeutic siRNA; tumor; tumor progression; uptake

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.

描述（由申请人提供）：我们旨在开发靶向纳米颗粒的癌症治疗。我们之所以选择晚期前列腺癌（PCA），因为雄激素剥夺治疗（ADT）是唯一有效的治疗选择，在相对短暂的初始疗法后失败。 由于其高死亡率高以及对患者生活质量的重大影响，因此高级PCA的新型治疗方式非常重要，而且非常需要。 抗雄激素的失败至少部分归因于PCA肿瘤细胞产生的局部睾丸激素。结果，晚期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（不溶于水溶液）是通过脂蛋白内化的，特别是PCA中的高密度脂蛋白（HDL）。 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，该受体在晚期PCA中被上调。我们将使用纳米偶联物靶向PCA靶向的SR-B1表达增加，以传递靶向siRNA的基因。我们假设使用我们组启用的新方法，可以通过强大而定向的仿生球形HDL纳米颗粒来促进核酸货物的有效全身性递送。最近，我们的小组利用金纳米颗粒支架（AUNP）生成仿生HDL，以概括成熟球形HDL的大小，形状，表面化学和胆固醇结合特性。所得的纳米颗粒（HDL AUNPS）具有高亲和力的吸附核酸。初始体外和体内实验表明，这些独特的生物材料是无毒的，积累在通常结合HDL的组织中，并功能以调节靶基因表达。 我们建议表征和优化带有siRNA的HDL AUNP结合物，并在前列腺癌的临床前模型中测试其特性。我们预计，携带siRNA的HDL AUNP会在SR-B1表达的位点积聚，包括在SR-B1过度表达的实验PCA中，并有效地将siRNA传递到PCA细胞中。 因此，传递的siRNA将阻止靶基因的表达。 作为模型目标，我们选择了雄激素受体，这是晚期前列腺癌的关键介体。项目成功将导致晚期前列腺癌的有效且有针对性的siRNA治疗。