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

• 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
• 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

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 siRNA 纳米颗粒递送对 Ras 通路进行治疗性靶向 三种类型的纳米颗粒，即 LPD、LCP 和 PRINT，将用于将 siRNA 递送至基因工程小鼠 (GEM) 模型中的肺癌细胞 (Kim, co-PI)。 LPD是一种自组装的核/膜纳米粒子，其独特之处在于表面接枝的PEG链密度高。 Huang (co-PI) 之前的研究表明，LPD 在异种移植的人肺肿瘤中以每克组织 60-80% 注射剂量的水平积累，而肝脏和脾脏的吸收量最少。每日 3 次静脉注射注射含有siRNA的LPD可有效沉默肿瘤靶基因的表达。 LCP 的结构与 LPD 相似，但其核心被磷酸钙无定形纳米沉淀物取代，该沉淀物溶解在内体酸性 pH 中，释放其货物，并膨胀并破裂内体。 PRINT（DeSimone，co-1）是自上而下制造的纳米颗粒，可以轻松装载任何载体和货物材料。 DeSimone 博士表明，siRNA 可以成功加载到 PRINT 中并递送至肿瘤细胞以实现基因沉默。该项目的一个显着特点是 KRas 驱动的肺癌 GEM。针对 Ras 和 Ras 效应通路设计的 sIRNA 将作为治疗药物进行测试和交付。这一点尤其重要，因为 Ras 被传统药物化学方法认为是不可成药的靶点。 此外，吉西他滨单（或二）磷酸盐（GMP或GDP），吉西他滨的代谢物将被配制在LCP纳米粒子中，并单独或与siRNA一起递送至肿瘤细胞。这是一种利用这些纳米粒子的大载货能力的新颖方法。该项目具有里程碑意义，因为到第三年年底，将确定至少一种纳米颗粒制剂用于 GEM 中的治疗、药代动力学和毒性研究。该配方应准备好与 NCI 纳米技术表征实验室合作进行详细表征和毒性研究 进一步转化发展