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）：我们的目标是开发一种基于纳米颗粒的靶向癌症疗法。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，但在相对短暂的初始反应后就会失败。 由于其高死亡率以及对患者生活质量的显着影响，晚期 PCa 的新治疗方式非常重要且迫切需要。 抗雄激素的失败至少部分归因于 PCa 肿瘤细胞自主局部产生睾酮。因此，晚期 PCa 对胆固醇产生了独特的需求，而胆固醇是雄激素生物合成的底物。 胆固醇不溶于水溶液，通过脂蛋白，特别是 PCa 中的高密度脂蛋白 (HDL) 内化。 HDL 和胆固醇的摄取通过 HDL 摄取受体、清道夫受体 B-1 (SR-B1) 进行，该受体在晚期 PCa 中表达上调。我们将利用增加的 SR-B1 表达用于 PCa 靶向纳米缀合物，以提供基因靶向 siRNA。我们假设，使用我们小组首创的新方法，通过稳健和定向制造仿生球形 HDL 纳米粒子，可以促进核酸货物的有效系统递送。最近，我们的小组利用金纳米颗粒支架（AuNP）来生成仿生 HDL，它概括了成熟球形 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，在通常结合 HDL 的组织中积累，并具有调节靶基因表达的功能。 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临床前模型中测试其特性。我们预计携带 siRNA 的 HDL AuNP 将在 SR-B1 表达位点积累，包括在 SR-B1 过表达的实验性 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。 我们选择雄激素受体作为模型靶点，它是晚期前列腺癌的关键介质。项目的成功将为晚期前列腺癌带来有效的靶向 siRNA 疗法。