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：
7982953
负责人：
Leaf Huang
金额：
$ 16.04万
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：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7982953
关键词：
Biodistribution Cancer Etiology Cancer cell line Cessation of life Collaborations 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 Printing 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 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