Therapeutic Targeting of the Ras Pathway By Nanoparticle Delivery of siRNA

通过 siRNA 纳米颗粒递送来治疗 Ras 通路

基本信息

批准号：
8540374
负责人：
Leaf Huang
金额：
$ 14.43万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8540374
关键词：
Biodistribution Cancer Center Cancer Etiology Cancer cell line Cessation of life Collaborations DNA Development Dose Drug Formulations Drug Kinetics EGFR inhibition Encapsulated Endosomes Epidermal Growth Factor Receptor Gene Expression Gene Silencing Genetic Genetically Engineered Mouse Human Image In Vitro Injection of therapeutic agent Lesion Lipids Liposomes Liver Luciferases Lung Adenocarcinoma Lung Neoplasms MEKs Maintenance Malignant Neoplasms Malignant neoplasm of lung Mediating Membrane Metabolism Molecular Analysis Molecular Weight Mono-S Mus Mutation Nanotechnology Non-Small-Cell Lung Carcinoma Oncogene Activation Oncogenes Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Signal Transduction Small Interfering RNA Spleen Structure Surface Swelling Testing Therapeutic Tissues Toxic effect Treatment Efficacy Tumor Suppressor Genes Tyrosine Kinase Inhibitor United States Woman Work Xenograft procedure c-Myc Staining Method calcium phosphate cancer cell chemotherapy density design efficacy testing gemcitabine improved inorganic phosphate knock-down men mortality mouse model mutant nanoencapsulated nanoparticle neoplastic cell novel novel strategies polycation response small molecule standard care therapeutic target tumor tumor growth tumor xenograft uptake

项目摘要

Project 2: Therapeutic Targeting of the Ras Pathway by Nanoparticle Delivery of siRNA Three types of nanoparticles, i.e. LPD, LCP and PRINT, will be used to deliver siRNA to lung cancer cells in a genetically engineered mouse (GEM) model (Kim, co-PI). LPD is a self-assembled, core/membrane nanoparticle, the unique feature of which is the high density ofthe surface grafted PEG chains. Previous work by Huang (co-PI) has shown that LPD accumulates in xenografted human lung tumors at the level of 60-80 % injected dose per g of tissue with minimal uptake by liver and spleen. Three daily i.v. injections of LPD containing siRNA effectively silenced the tumor target gene expression. LCP is similar in structure to LPD, but the core is replaced with calcium phosphate amorphous nanoprecipltate that dissolves in the endosomal acidic pH to release its cargo and swells and bursts the endosomes. The PRINT (DeSimone, co-1) are topdown manufactured nanoparticles In which any carrier and cargo materials can be readily loaded. Dr. DeSimone has shown that siRNA can be successfully loaded in PRINT and delivered to tumor cells for gene silencing. A salient feature of the project is the KRas driven lung cancer GEM. sIRNAs designed against Ras and Ras effector pathways will be tested and delivered as therapeutics. This is particularly significant, because Ras is considered an undruggable target by conventional medicinal chemistry approaches. Furthermore, gemcitabine mono (or di-) phosphate (GMP or GDP), metabolites of gemcitabine will be formulated in LCP nanoparticles and delivered to the tumor cells by itself or together with siRNA. This is a novel approach that takes advantage of the large cargo capacity of these nanoparticles. The project is milestone driven in that by the end of the year 3, at least one nanoparticle formulation will be identified for therapy, pharmacokinetics and toxicity studies In GEM. The formulation should be ready for detailed characterization and toxicity studies in collaboration with Nanotechnology Characterization Lab at NCI for further translational development

项目2：通过纳米颗粒的递送对RAS途径的治疗靶向三种类型的纳米颗粒，即LPD，LCP和印刷，将用于在基因工程小鼠（GEM）模型（KIM，CO-PI）中向肺癌细胞传递siRNA。 LPD是一种自组装的核/膜纳米颗粒，其独特特征是表面移植的钉链的高密度。黄（Co-Pi）先前的工作表明，LPD在异种移植的人肺肿瘤中积聚，在每克组织的60-80％注射剂量的水平下，肝脏和脾脏摄入最少。每天三个i.v.注射含有siRNA的LPD有效地沉默了肿瘤靶基因表达。 LCP的结构与LPD相似，但是核心被磷酸钙的无定形纳米固定材料代替，溶解在内体酸性pH中以释放其货物并膨胀并破裂内体。印刷品（Desimone，CO-1）是对制造的纳米颗粒，其中任何载体和货物材料都可以轻松加载。 Desimone博士表明，siRNA可以成功加载到印刷中，并将其输送到肿瘤细胞中进行基因沉默。该项目的一个显着特征是KRAS驱动的肺癌宝石。针对RAS和RAS效应途径设计的siRNA将被测试并作为治疗剂进行测试。这尤其重要，因为通过常规药物化学方法，RAS被认为是不良目标。此外，吉西他滨单（或Di-）磷酸盐（GMP或GDP），吉西他滨的代谢产物将在LCP纳米颗粒中配制，并与siRNA本身或与siRNA一起递送至肿瘤细胞。这是一种新颖的方法，它利用了这些纳米颗粒的大型货物容量。该项目的里程碑是在第3年底驱动的，至少将确定一种纳米颗粒制剂用于GEM的治疗，药代动力学和毒性研究。该配方应准备好与NCI的纳米技术表征实验室合作进行详细的表征和毒性研究进一步的翻译发展